Cancer Chemother Pharmacol (2014) 74:1105–1111 DOI 10.1007/s00280-014-2559-9
REVIEW ARTICLE
MicroRNAs: a new key in lung cancer Yunlong Zhang · Qian Yang · Siwang Wang
Received: 9 June 2014 / Accepted: 26 July 2014 / Published online: 19 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Lung cancer as a malignance has been killing numerous patients around the world annually, and small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are the two major types, the later accounting for nearly 80 % of lung cancer. There are multiple causes for lung cancer, and more researches have been carried out to prevent, anticipate, and diagnose the cancer. MicroRNAs (miRNAs) are small non-coding RNA molecules capable of regulating expression of over 50 % of protein-coding genes. The RNA molecules are stable in tissues and blood, so it can tend to be a biomarker in anti-lung cancer. Here, this is a review on the roles of miRNAs for possible ways to prevent lung cancer in clinical trials. Keywords MicroRNA · Cancer · Lung · Biomarker
Introduction Recent studies show that lung cancer as one of the most dangerous malignancies is the leading cause of cancerrelated mortality in the world. And it can be divided into two different groups: non-small cell lung cancers (NSCLC),
Y. Zhang · Q. Yang · S. Wang (*) Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, 169 West Changle Road, Xi’an 710032, People’s Republic of China e-mail: [email protected]
which approximately account for 80 % of lung cancer cases [1–3], and small cell lung cancers (SCLC), which account for the remaining 20 % [4]. Nowadays, patients who suffered from lung cancer are mainly applying chemotherapy to cure or control lung cancer. We are particularly interested in NSCLC, since it is relatively insensitive to chemotherapy [5]. Thus, to find out effective methods to diagnose, anticipate, and even prevent, this malignance is of importance. miRNAs are a highly conserved family of small and non-coding RNAs and gradually emerged as a novel class of gene expression modulators at post-transcriptional level [7–9]. This occurs through perfect or imperfect base pairing at the miRNA recognition elements (MREs) within the 39 un-translated region (UTR) of target mRNAs, resulting in miRNA destabilization and translational repression [7, 10, 11]. The aberrant expression of miRNAs has been texted in various human cancers including lung cancer [12, 13] and so on. Recently, clinical studies have been carried out to correlate dysregulation of particular miRNA expression with tumor responsiveness to chemotherapies [6, 14– 16], which have obtained some achievements. So to explore the roles of miRNAs in lung cancer is what really counts to the clinical trials, such as whether it can be treated as a biomarker to anticipate, diagnose, and against this malignance and/or whether the mechanism underling it correlated with some special signaling pathways. Together, we simply reviewed recent study of this fields to pave a solid way for further researches on the application of miRNAs in lung cancer clinically.
Y. Zhang e-mail: [email protected] Y. Zhang · Q. Yang · S. Wang Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, 169 West Changle Road, Xi’an 710032, People’s Republic of China
miRNAs in cancer miRNAs are short, single-stranded, endogenous, non-coding RNA molecules. A small switch of miRNAs could lead
13
1106
Cancer Chemother Pharmacol (2014) 74:1105–1111
Fig. 1 miRNAs in lung cancer. Different types of miRNAs play a different role in the progress of lung cancer which can be divided into two groups: tumor suppressive miRNAs by targeting oncogenes, and oncogenic miRNAs by targeting tumor suppressors
to an important relative biological effectiveness such as growth, proliferation, and apoptosis. Stfan Volinia [17] and other researchers worked together applied gene microarray to demonstrate that compared with the normal tissues, miRNAs in tumors have a significant different expression, which testified the roles miRNAs played in tumors. Now, we have a relative accurate global gene expression profile which, according to Lu’s report, has been demonstrated the numerous miRNAs deregulated in tumor compared with normal tissues [18]. miRNAs can trigger many signaling pathways to cause different effects. Based on the signaling pathways, they can be classified with two main types: the tumor suppressive miRNAs and oncogenic miRNAs (oncomirs). For example, miRNA-15a and miRNA-16-1, which belong to the tumor suppressive miRNAs, were revealed downregulated in the majority of patients with chronic lymphocytic leukemia (CLL) and enhanced apoptosis by regulated B cell lymphoma 2 (Bcl-2) which can be against apoptosis [19]. Other examples are miRNA-21 and miRNA-9. For miRNA21 which is usually highly expressed in solid and hematologic tumors including liver, lung, colon, and other tumors, to lower its expression might suppress cell growth and even induce apoptosis by targeting tumors genes such as PTEN [20]. miRNA-9, which maintain high level in many cancers, has been reported that through inhibiting its expression, it could markedly decrease lymphoma outgrowth in liver [21]. Using the specificity and sensitivity as index to evaluate whether miRNAs can be served as biomarkers for the diagnostic and prognostic of cancers. And miRNAs-based therapeutic approaches have been paid more attentions by clinical trials. miRNA-34 which was the first miRNAs-based drug against tumors has been applied [22].
miRNAs in lung cancer There are significant differential expressions of miRNAs between the lung cancer cell lines and non-tumor cell
13
lines and normal lung tissues, and some kinds of miRNAs among them possess the specificity and sensitivity to lung cancer as well. miRNAs status in lung cancer, as in other forms of cancer, can be divided into two categories: down-regulation of tumor suppressive miRNAs that target oncogenes, and up-regulation of oncogenic miRNAs that target tumor suppressors (Fig. 1). miRNAs involved in lung cancer have the ability to regulate the tumorigenesis, survival, angiogenesis and migration and invasion of tumor (Fig. 2). For example, decreased level of expression of the let-7 miRNA family is the majority of patients in lung cancer and with a relative poor prognosis in that by targeting KRAS, NRAS, HMGA2, and Cdc25 and some other oncogenes which are associated with tumor development [23]. Similarly, decreased level of tumor suppressive miRNA-16 in NSCLC patients samples leading to inhibiting the tumor cell lines growth and motility by targeting hepatoma-derived growth factor (HDGF) [24]. The increased expression of oncogenic miRNA-221/miRNA-222 was demonstrated aggressive in NSCLC compared with less invasive or normal tissues by targeting PTEN and metalloproteinase inhibitors 3 (TIMP3) to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance and lead to cell migration by activating AKT signaling pathway [25]. And for many types of cancers, miRNA-146a through targeting the EGFR to show differential expression and which owning the specificity to lung cancer. And research has been made to reveal that it might suppress cell growth, induce apoptosis, inhibit tumor cells migration and suppress the downstream of EGFR signaling [26]. To sum it up, there are a lot of miRNAs that contributing to the tumorigenesis, survival, angiogenesis and migration and invasion of SCLC and NSCLC cell lines as given in Fig. 2, and multiple data have been demonstrated that, via targeting various targets, miRNAs can function as either tumor activators or suppressors, and above all to consist of the different roles of miRNAs in lung cancer.
Cancer Chemother Pharmacol (2014) 74:1105–1111
1107
Fig. 2 miRNAs and targets in lung cancer. miRNAs through targeting numerous protein targets to regulate the tumorigenesis, survival, angiogenesis, migration and invasion of lung cancer
miRNAs in the diagnosis of lung cancer miRNAs on the pathological classification Currently, the pathological classification of NSCLC focuses on lung adenocarcinoma (AD) and squamous cell lung carcinoma (SCC), which are also the most important histological types of lung cancer and exhibiting unique pathological features and different response to therapy. Study has been made to demonstrate that of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for NSCLC patients who cannot administrate operation, the advanced tumor patients or non-SCC patients [27]. And treatment with bevacizumab alone to SCC patients might cause serious side effects in advanced SCC patients [28]. Therefore, to make an accurate pathological classification of NSCLC contributes to individual-based treatment of this cancer. However, there are no efficient methods to clarify the pathological classification of NSCLC about the low differentiated tumor tissues. And the expression profiles of miRNAs can make up this blank for they are able to predictive the origin of the tumor accurately. Lots of studies have been made to reveal that miRNAs including miRNA-205, miRNA-99b, miRNA-203, miRNA-202 and miRNA-102, pre-miRNA-204 exhibiting different expression between AD and SCC [18, 29–31], especially for the miRNA-205 that can be acted as a tool to distinguish AD and SCC, when the quantitative analysis has been applied. miRNA-205 has a higher sensitivity (96 %) and specificity
(90 %) in low differentiated tumor tissues, which make a better foundation for the relationship between miRNAs and the pathological classification of lung cancer [32]. miRNAs in tissues There is a significant difference between the tumors and the normal lung tissues on the expression levels and patterns of miRNAs, and based on that, miRNAs can be applied in the early diagnosis of lung cancer in clinics. It has been demonstrated that, after using meta-analysis, compared with the normal lung tissues, miRNA-210, miRNA-21, miRNA-31 and miRNA-182 stay apparently up-regulated in lung cancer tissues, while, on the contrary, miRNA126 and miRNA-145 down-regulated [33]. Sun and other recearchers have applied the technology of gene microarray to detect the expression difference about between the normal lung tissues, metastatic lung carcinoma tissues and primary lung carcinoma tissues. And they found that there are four kinds of miRNAs (miRNA-150, miRNA-18b-5p, miR-643 and miR-3940-5p) exist expression difference between metastatic lung carcinoma tissues and primary lung carcinoma tissues, and compared with the normal lung tissues, miRNA-150 and miRNA-3940-5p keeps down-regulation in lung carcinoma tissues [34]. And what’s more, lots of researches show that miRNA-182, miRNA-183 and miRNA-96 exhibit up-regulated in lung carcinoma tissues [35]. Thus, miRNAs in tissues play an important role in the diagnosis of lung cancer.
13
1108
miRNAs in serum and plasma The majority of patients who suffering from lung cancer, especially non-small cell lung cancer, are belonging to terminal cancer. Comparing to the early-stage cancer patients, who 5-year survival rates are over 80 %, their survival estimates in terminal cancer are only under 20 %. So the diagnosis in the early stage of lung cancer is what really counts to improve the 5-year survival rates of patients. The expression patterns of miRNAs in serum and plasma exhibit significant difference between lung cancer patients and healthy persons. miRNAs in serum and plasma are in a very stable form which can resist high temperatures, strong acid and alkali, quench condensation and the degradation of enzyme, and RT-PCR can be used to detect miRNAs accurately [36]. It has been demonstrated that the majority of miRNAs (91/101) in healthy persons have co-expression in serum and plasma, while in NSCLC patients, there are also 76 kinds of miRNAs that express in serum only, which prompting speculation that the majority of miRNAs in serum belong to tumor tissues [36]. In NSCLC patients, the abnormal expression of miRNAs in serum and in tumor tissues aligned fairly well [37–39], which lay the foundations on using miRNAs in serum as a method to diagnose the early stage of lung cancer clinically. Foss et al. [37] found that miRNA-1254 and miRNA-574-5p in patients in early stage of NSCLC maintain up-regulation, which can make a conclusion that they are sensitive (sensitivity is 82 %) in early diagnosis of NSCLC. And for the miRNAs in plasma, miRNA-21, miRNA-126, miRNA210 and miRNA-486-5p stay at high sensitivity (86.22 %) in the diagnosis of NSCLC, especially in the diagnosis of early stage of NSCLC (73.33 %) [38]. Compared with the miRNAs in plasma in NSCLC patients and healthy persons, they found that there are 27 miRNAs which show statistical differences in expression, and among them, 24 miRNAs including miRNA126 and let-7 and so on have a significant advantage in sensitivity (92.5 %), veracity (95.4 %) and specificity (98.1 %) in the diagnosis of lung cancer [39]. miRNAs as biomarkers Numerous miRNAs contributing to the malignant phenotype maintain differential expression in tumors compared with the normal lung tissues and normal adjacent tissues. And these miRNAs also have a close relationship with sorts of cancer-associated proteins, which can show a unique function in the development of lung cancer. For example, researchers have tested that p53 by mutanting p53R175H to induce expression as if oncogenic miRNA-128-2, which can decrease the apoptosis and increase resistance to drugs such as cisplatin by targeting E2F5 [40]. miRNA-494 also has relationship with ERK1/2 signaling, which activated ERK1/2 to promote miRNA-494 to increase resistance of
13
Cancer Chemother Pharmacol (2014) 74:1105–1111
NSCLC cells to TRAIL-induced apoptosis [41]. miRNAs are highly stable in tissues and blood, and tumor origin, histotype and their stage of illness can form their expression patterns [42]. Thus, they have great values in diagnosis and prognosis, which makes them promising candidates for biomarker for lung cancer detection [43]. For instance, some kinds of miRNAs confer high specificity as miRNA182, which was overexpressed neither in primary lung cancer nor in other types of epithelial and non-epithelial malignances [44]. The sensitivity and expression specificity of miRNAs make them like a biomarker to diagnose and anticipate lung cancer. On the one hand, as a prognostic biomarker, it has been reported that there are numerous miRNAs that can be applied in early-stage operable NSCLC patients such as improving the levels of circulating miRNA-142-3p [45] and increasing levels of miRNA-328 in peripheral blood can also contribute to early detection of NCSLC [46]. Some researchers have demonstrated that the low expression of miRNAs-146a in lung cancer often relates to the advanced stage of tumor. So miRNAs-146a may serve as a prognostic biomarker and hold the therapeutic potential since elevated levels of it could longer progression-free survival [26]. On the other hand, miRNAs can also act as predictive biomarkers for treatment response in SCLC and NSCLC patients. First, for SCLC patients who have a good response to chemotherapy and radiotherapy, usually leading to tumor relapse and its development spread just because the evolution of the resistant cells began. At this transformation, miRNA-92a-2 plays an important role, since higher level of miRNA-92a-2 were related to chemoresistance and could lower the survival rate of patients. So miRNA-92a-2 could act as a predictive biomarker for de novo chemoresistance in SCLC patients [47]. Second, for NSCLC patients, there are also some kinds of miRNAs in plasma and serum that contributing to serve as predictive biomarkers. Examples as miRNA-210 in NSCLC patients’ serum, who’s high level of it associated with clinical stage as well as poor response to cisplatin-based chemotherapy [48]. And the level of oncogenic miRNA-21 in the plasma of NSCLC patients was correlated with NSCLC stage and platinum-based chemotherapy [49], while in the whole blood, the high level of miRNA-22 has a relationship with the lack of response to pemetrexed chemotherapy. That is to say, miRNA-22 may also be a biomarker for pemetrexed chemotherapy in NSCLC patients [50].
miRNAs in the treatment of lung cancer Therapeutic approaches to cure lung cancer Based on the classification of lung cancer, the therapeutic approaches should also own specificity, because of the
Cancer Chemother Pharmacol (2014) 74:1105–1111
treatment response of chemotherapy and radiotherapy between SCLC and NSCLC. Some SCLC patients are not suit for surgical excision. Because SCLC as the most aggressive type of lung cancer, owning the capacity of high metastatic spread to other region of the body, for example, it can spread to the brain at the early stage of tumor formation. So this type of lung cancer is usually treated by cisplatin and etoposide (combination chemotherapy), and the survival rate is still only 1 year at early stage and no more than 3 years at advanced stage [51]. However, for NSCLC patients who insensitive to chemotherapy and radiotherapy, surgical excision comes to be their best option. And if patients cannot administrate an operation, chemotherapy and radiotherapy come to be their last choice, such as platinum-based chemotherapy and targets therapy [43]. Targets therapy such as monoclonal antibody-based and small tyrosine kinase inhibitor-based drugs [52] turns to be a novel therapeutic approach to cure lung cancer as well as early detection and prognostic markers. miRNAs in regulation of resistance/sensitivity of lung cancer to treatment Different pathological classifications of lung cancer have different resistance/sensitivity to treatment. So miRNAs may play a dominate role in regulation of the resistance and sensitivity. On the one hand, numerous miRNAs have been figured out that show differentially expression in radiotherapy compared with radiotherapy-resistant NSCLC patients and NSCLCs. The overexpression of the miRNA-126 could inhibit cell growth and induce apoptosis of radiotherapyresistant NSCLC cells by PI3K–AKT signaling pathway [53]. By targeting K-Ras, let-7g, which is upregulated in radiosensitive H460 cell line compared with radioresistant H1299 cell line, could increase cells sensitivity to IR [54]. In 549 cell line, overexpression of miRNA-7 was able to lead cell radiosensitization, prolong radiation-induced formation of DNA DSBs by activated EGFR–PI3K–AKT signaling pathway, and decreased levels of EGFR and AKT [55]. Overexpression of miRNA-101, which is a tumor suppressive miRNA, could also promote radiosensitization by decreased expression of ATM- and DNA-dependent kinases [56]. And the tumor suppressor miRNA family such as miRNA-34 which by targeting p53 to promote radiosensitization, as well [57]. In addition, downregulation of oncogenic miRNA-21 could not only inhibit cell growth but also cause enhancement of radiosensitivity of NSCLCs [58]. miRNA-214 has two functions: overexpression might protect radiosensitivity by regulating P38 MAPK signaling pathways, and downexpression by RNAi sensitized radioresistant cells to IR [59]. miRNA-210 can regulate radioresistance of hypoxic lung cancer cells [60]. Above them all, these are miRNAs in radioresistance of lung cancer. On
1109
the other hand, through inducing apoptosis of cancer cells, chemotherapeutic agents can display their anticancer effects. Lots of researches have been made to reveal that miRNAs are associated with modulation of drug resistance pathways. Initially, researchers have made efforts to addressing the role of miRNA-1 as a mediator in lung cancer A549’s chemoresistance to doxorubicin [61], which make a foundation for further study of this field. And after that report, multiple miRNAs, such as overexpression of miRNA-138, were shown differentially expressed in AD with increased resistance to cisplatin [62]. Increasingly, numerous reports revealed that multiple tumor suppressive miRNAs mediated the tumor cells sensitivity to cytotoxic treatment. For example, the tumor suppressor miRNA-100 which exerts its function of suppression of cell proliferation and inducement of apoptosis by downregulated in docetaxel-resistant AD [63]. While miRNA-34c-5p would protect cells from paclitaxelinduced apoptosis by targeting Bcl-2-modifying factor [64, 65]. There are not only the tumor suppressive miRNAs, but also some oncogenic miRNAs that can serve as markers to chemosensitivity. For example, pre-miRNA-630 conferred resistance of A549 cells to cisplatin and carboplatin, and could lead to decreasing proliferation and suppressing DNA damage signaling and activating p53 [65, 66]. Another example is the oncogenic miRNA-205, which was overexpressing in NSCLC cell lines and could promote cell growth metastasis and chemoresistance to cisplatin by targeting PTEN [67]. There are also multiple oncogenic miRNAs that can contribute in chemoresistance such as miRNA-31 [68] and so on. Thus, it is of importance to figure out the roles of miRNAs in lung cancer treatment.
Conclusions Lung cancer, the leading cause of cancer deaths worldwide, can be divided into two major types, which has drawn enough attention: SCLC and NSCLC. But we have not found an efficient system to prevent, diagnose, prognose, and even treat lung cancer. As discussed above, numerous miRNAs contributing to the malignant phenotype maintain differential expression in tumors compared with the normal lung tissues and normal adjacent tissues. And these types of miRNAs are stable in tissue sections and blood and reflect tumororigin, histotype, and stage. They also have a close relationship with sorts of cancer-associated proteins, which can be served as a uniquely biomarker in lung cancer such as apoptosis, migration, invasion, and proliferation in that some of them owned the specificity and sensitivity to lung cancer. However, in spite of the marketable role of miRNAs in the prevention, diagnosis, and treatment on lung cancer, there are also some questions that we can miss. For example, multiple targets can contribute to one miRNA
13
1110
and vice versa. In addition, many factors can effect on the function of miRNAs in lung cancer, and the mechanism underlying this is still a myth, which give us the opportunities to explore this field. Recently, increasingly numerous miRNAs have been found which are associated with lung cancer based on the methods as miRNAs profiles enhanced. For instance, let-7 mimetic is going to be the first miRNA therapeutic to enter clinical trials, which make a huge progress in treatment of lung cancer clinically [69]. To make a conclusion based on the researches of miRNAs may pave a novel way to treat anti-lung cancer.
References 1. Pan X, Zhang X, Sun H, Zhang J, Yan M, Zhang H (2013) Autophagy inhibition promotes 5-fluorouraci-induced apoptosis by stimulating ROS formation in human non-small cell lung cancer A549 cells. PLoS One 8(2):e56679 2. Hsin IL, Ou CC, Wu TC, Jan MS, Wu MF, Chiu LY et al (2011) GMI, an immunomodulatory protein from Ganoderma microsporum, induces autophagy in non-small cell lung cancer cells. Autophagy 7(8):873–882 3. Liu J, Hu XJ, Jin B, Qu XJ, Hou KZ, Liu YP (2012) β-Elemene induces apoptosis as well as protective autophagy in human non-small-cell lung cancer A549 cells. J Pharm Pharmacol 64:146–153 4. Chen HS, Portier K, Ghosh K, Naishadham D, Kim HJ, Zhu L et al (2012) Predicting US and state-level cancer counts for the current calendar year: part I—evaluation of temporal projection methods for mortality. Cancer 118(4):1091–1099 5. Saintigny P, Burger JA (2012) Recent advances in non-small cell lung cancer biology and clinical management. Discov Med 13:287–297 6. Ajabnoor GM, Crook T, Coley HM (2012) Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells. Cell Death Dis 3:e260 7. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297 8. Hornstein E, Mansfield JH, Yekta S, Hu JK, Harfe BD et al (2005) The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature 438:671–674 9. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355 10. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233 11. Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655 12. Macfarlane LA, Murphy PR (2010) MicroRNA: biogenesis, function and role in cancer. Curr Genomics 11:537–561 13. Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579 14. Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269 15. Zhou M, Liu Z, Zhao Y, Ding Y, Liu H et al (2010) MicroRNA125b confers the resistance of breast cancer cells to paclitaxel through suppression of proapoptotic Bcl-2 antagonist killer 1 (Bak1) expression. J Biol Chem 285:21496–21507 16. Fujita Y, Kojima K, Ohhashi R, Hamada N, Nozawa Y et al (2010) MiR-148a attenuates paclitaxel resistance of hormonerefractory, drug-resistant prostate cancer PC3 cells by regulating MSK1 expression. J Biol Chem 285:19076–19084
13
Cancer Chemother Pharmacol (2014) 74:1105–1111 17. Aora T, Liu B, He H (2003) PIASx is a transcriptional co-repressor of signal transducer and activator of transcription. J Biol Chem 278(24):21327–21330 18. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838 19. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102:13944–13949 20. Garzon R, Calin GA, Croce CM (2009) MicroRNAs in cancer. Annu Rev Med 60:167–179 21. Leucci E, Zriwil A, Gregersen LH, Jensen KT, Obad S, Bellan C, Leoncini L, Kauppinen S, Lund AH (2012) Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo. Oncogene 31:5081–5089 22. Ling H, Fabbri M, Calin GA (2013) MicroRNAs and other noncoding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12:847–865 23. Osada H, Takahashi T (2011) let-7 and miR-17-92: small-sized major players in lung cancer development. Cancer Sci 102:9–17 24. Ke Y, Zhao W, Xiong J, Cao R (2013) Downregulation of miR-16 promotes growth and motility by targeting HDGF in non-small cell lung cancer cells. FEBS Lett 587:3153–3157 25. Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, Gasparini P, Gonelli A, Costinean S, Acunzo M, Condorelli G, Croce CM (2009) miR221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16:498–509 26. Chen G, Umelo IA, Lv S, Teugels E, Fostier K, Kronenberger P, Dewaele A, Sadones J, Geers C, De Greve J (2013) miR-146a inhibits cell growth, cell migration and induces apoptosis in nonsmall cell lung cancer cells. PLoS One 8:e60317 27. Reck M, Von Pawel J, Zatloukal P et al (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancel: AVAil. J Clin Oncol 27:1227–1234 28. Seagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage nonsmall-cell lung cancer. J Clin Oncol 26:3543–3551 29. Yanaihara N, Caplen N, Bowman E et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198 30. Lebanony D, Benjamin H, Gilad S et al (2009) Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from non-squamous non-small cell lung carcinoma. J Clin Oncol 27:2030–2037 31. Landi MT, Zhao Y, Rotunno M et al (2010) MicroRNA expression differentiates histology and predicts survival of lung cancer. Clin Cancer Res 16:430–441 32. Del Vescovo V, Cantaloni C, Cucino A et al (2011) miR-205 Expression levels in non-small cell lung cancer do not always distinguish adenocarcinomas from squamous cell carcinomas. Am J Surg Pathol 35:268–275 33. Guan P, Yin Z, Li X et al (2012) Meta-analysis of human lung cancer microRNA expression profiling studies comparing cancer tissues with normal tissues. J Exp Clin Cancer Res 31:54 34. Sun Y, Su B, Zhang P et al (2013) Expression of miR-150 and miR-3940-5p is reduced in non-small lung carcinoma and correlates with clinicopathological features. Oncol Rep 29:704–712 35. Zhu W, Liu X, He J et al (2011) Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study. BMC Cancer 11:393
Cancer Chemother Pharmacol (2014) 74:1105–1111 36. Chen X, Ba Y, Ma L et al (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006 37. Foss KM, Sima C, Ugolini D et al (2011) miR-1254 and miR574-5p: serum-based microRNA biomarkers for early stage nonsmall cell lung cancer. J Thorac Oncol 6(3):482–488 38. Shen J, Todd NW, Zhang H et al (2011) Plasma microRNAs as potential biomarkers for non-small cell lung cancer. Lab Invest 91(4):579–587 39. Keller A, Leidinger P, Borries A et al (2009) miRNAs in lung cancer studying complex fingerprints in patients blood cells by microarray experiments. BMC Cancer 9:353 40. Donzelli S, Fontemaggi G, Fazi F, Di Agostino S, Padula F, Biagioni F, Muti P, Strano S, Blandino G (2012) MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function. Cell Death Differ 19:1038–1048 41. Romano G, Acunzo M, Garofalo M, Di Leva G, Cascione L, Zanca C, Bolon B, Condorelli G, Croce CM (2012) MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non-small-cell lung cancer through BIM down-regulation. Proc Natl Acad Sci USA 109:16570–16575 42. Melo SA, Esteller M (2011) Dysregulation of microRNAs in cancer: playing with fire. FEBS Lett 585:2087–2099 43. Zandberga E, Kozirovskis V, Abols A, Andrejeva D, Purkalne G, Line A (2013) Cell-free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer. Genes Chromosomes Cancer 52:356–369 44. Barshack I, Lithwick-Yanai G, Afek A, Rosenblatt K, TabibianKeissar H, Zepe-niuk M, Cohen L, Dan H, Zion O, Strenov Y, Polak-Charcon S, Perelman M (2010) MicroRNA expression differentiates between primary lung tumors and metastases to the lung. Pathol Res Pract 206:578–584 45. Kaduthanam S, Gade S, Meister M, Brase JC, Johannes M, Dienemann H, Warth A, Schnabel PA, Herth FJ, Sultmann H, Muley T, Kuner R (2013) SerummiR-142-3p is associated with early relapse in operable lung adenocarcinoma patients. Lung Cancer 80:223–227 46. Ulivi P, Foschi G, Mengozzi M, Scarpi E, Silvestrini R, Amadori D, Zoli W (2013) Peripheral blood miR-328 expression as a potential biomarker for the early diagnosis of NSCLC. Int J Mol Sci 14:10332–10342 47. Ranade AR, Cherba D, Sridhar S, Richardson P, Webb C, Paripati A, Bowles B, Weiss GJ (2010) MicroRNA 92a-2*: a biomarker predictive for chemoresistance and prognostic for survival in patients with small cell lung cancer. J Thorac Oncol 5:1273–1278 48. Li ZH, Zhang H, Yang ZG, Wen GQ, Cui YB, Shao GG (2013) Prognostic significance of serum microRNA-210 levels in nonsmall-cell lung cancer. J Int Med Res 41:1437–1444 49. Wei J, Gao W, Zhu CJ, Liu YQ, Mei Z, Cheng T, Shu YQ (2011) Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer. Chin J Cancer 30:407–414 50. Franchina T, Amodeo V, Bronte G, Savio G, Ricciardi GR, Picciotto M, Russo A, Giordano A, Adamo V (2014) Circulating miR-22, miR-24 and miR-34a as novel predictive biomarkers to pemetrexed-based chemotherapy in advanced non-small cell lung cancer. J Cell Physiol 229:97–99 51. William WN Jr, Glisson BS (2011) Novel strategies for the treatment of small-cell lung carcinoma. Nat Rev Clin Oncol 8:611–619 52. Larsen JE, Cascone T, Gerber DE, Heymach JV, Minna JD (2011) Targeted therapies for lung cancer: clinical experience and novel agents. Cancer J 17:512–527 53. Wang XC, Du LQ, Tian LL, Wu HL, Jiang XY, Zhang H, Li DG, Wang YY, Wu HY, She Y, Liu QF, Fan FY, Meng AM (2011) Expression and function of miRNA in postoperative radiotherapy
1111 sensitive and resistant patients of non-small cell lung cancer. Lung Cancer 72:92–99 54. Jeong SH, Wu HG, Park WY (2009) LIN28B confers radio resistance through the posttranscriptional control of KRAS. Exp Mol Med 41:912–918 55. Lee KM, Choi EJ, Kim IA (2011) microRNA-7 increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Radiother Oncol 101:171–176 56. Chen S, Wang H, Ng WL, Curran WJ, Wang Y (2011) Radiosensitizing effects of ectopic miR-101 on non-small-cell lung cancer cells depend on the endogenous miR-101 level. Int J Radiat Oncol Biol Phys 81:1524–1529 57. Balca-Silva J, Sousa Neves S, Goncalves AC, Abrantes AM, Casalta-Lopes J, Botelho MF, Sarmento-Ribeiro AB, Silva HC (2012) Effect of miR-34b overexpression on the radiosensitivity of non-small cell lung cancer cell lines. Anticancer Res 32:1603–1609 58. Liu ZL, Wang H, Liu J, Wang ZX (2013) MicroRNA-21 (miR21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem 372:35–45 59. Salim H, Arvanitis A, de Petris L, Kanter L, Haag P, Zovko A, Ozata DM, Lui WO, Lundholm L, Zhivotovsky B, Lewensohn R, Viktorsson K (2013) miRNA-214 is related to invasiveness of human non-small cell lung cancer and directly regulates alpha protein kinase 2 expression. Genes Chromosomes Cancer 52:895–911 60. Grosso S, Doyen J, Parks SK, Bertero T, Paye A, Cardinaud B, Gounon P, Lacas-Gervais S, Noel A, Pouyssegur J, Barbry P, Mazure NM, Mari B (2013) MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis 4:e544 61. Nasser MW, Datta J, Nuovo G, Kutay H, Motiwala T, Majumder S, Wang B, Suster S, Jacob ST, Ghoshal K (2008) Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicininduced apoptosis by miR-1. J Biol Chem 283:33394–33405 62. Wang Q, Zhong M, Liu W, Li J, Huang J, Zheng L (2011) Alterations of microRNAs in cisplatin-resistant human non-small cell lung cancer cells (A549/DDP). Exp Lung Res 37:427–434 63. Feng B, Wang R, Chen LB (2012) MiR-100 resensitizes docetaxel-resistant human lung adenocarcinoma cells (SPC-A1) to docetaxel by targeting Plk1. Cancer Lett 317:184–191 64. Catuogno S, Cerchia L, Romano G, Pognonec P, Condorelli G, de Franciscis V (2013) miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis. Oncogene 32:341–351 65. Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L, Criollo A, Servant N, Paccard C, Hupe P, Robert T, Ripoche H, Lazar V, Harel-Bellan A, Dessen P, Barillot E, Kroemer G (2010) miR181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res 70:1793–1803 66. Lei L, Huang Y, Gong W (2013) miR-205 promotes the growth, metastasis and chemoresistance of NSCLC cells by targeting PTEN. Oncol Rep 30:2897–2902 67. Dong Z, Zhong Z, Yang L, Wang S, Gong Z (2014) MicroRNA-31 inhibits cisplatin-induced apoptosis in non-small cell lung cancer cells by regulating the drug transporter ABCB9. Cancer Lett 343:249–257 68. Huang JY, Cui SY, Chen YT, Song HZ, Huang GC, Feng B, Sun M, De W, Wang R, Chen LB (2013) MicroRNA-650 was a prognostic factor in human lung adenocarcinoma and confers the docetaxel chemoresistance of lung adenocarcinoma cells via regulating Bcl-2/Bax expression. PLoS One 8:e72615 69. Uchino K, Ochiya T, Takeshita F (2013) RNAi therapeutics and applications of microRNAs in cancer treatment. Jpn J Clin Oncol 43:596–607
13
REVIEW ARTICLE
MicroRNAs: a new key in lung cancer Yunlong Zhang · Qian Yang · Siwang Wang
Received: 9 June 2014 / Accepted: 26 July 2014 / Published online: 19 August 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Lung cancer as a malignance has been killing numerous patients around the world annually, and small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are the two major types, the later accounting for nearly 80 % of lung cancer. There are multiple causes for lung cancer, and more researches have been carried out to prevent, anticipate, and diagnose the cancer. MicroRNAs (miRNAs) are small non-coding RNA molecules capable of regulating expression of over 50 % of protein-coding genes. The RNA molecules are stable in tissues and blood, so it can tend to be a biomarker in anti-lung cancer. Here, this is a review on the roles of miRNAs for possible ways to prevent lung cancer in clinical trials. Keywords MicroRNA · Cancer · Lung · Biomarker
Introduction Recent studies show that lung cancer as one of the most dangerous malignancies is the leading cause of cancerrelated mortality in the world. And it can be divided into two different groups: non-small cell lung cancers (NSCLC),
Y. Zhang · Q. Yang · S. Wang (*) Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, 169 West Changle Road, Xi’an 710032, People’s Republic of China e-mail: [email protected]
which approximately account for 80 % of lung cancer cases [1–3], and small cell lung cancers (SCLC), which account for the remaining 20 % [4]. Nowadays, patients who suffered from lung cancer are mainly applying chemotherapy to cure or control lung cancer. We are particularly interested in NSCLC, since it is relatively insensitive to chemotherapy [5]. Thus, to find out effective methods to diagnose, anticipate, and even prevent, this malignance is of importance. miRNAs are a highly conserved family of small and non-coding RNAs and gradually emerged as a novel class of gene expression modulators at post-transcriptional level [7–9]. This occurs through perfect or imperfect base pairing at the miRNA recognition elements (MREs) within the 39 un-translated region (UTR) of target mRNAs, resulting in miRNA destabilization and translational repression [7, 10, 11]. The aberrant expression of miRNAs has been texted in various human cancers including lung cancer [12, 13] and so on. Recently, clinical studies have been carried out to correlate dysregulation of particular miRNA expression with tumor responsiveness to chemotherapies [6, 14– 16], which have obtained some achievements. So to explore the roles of miRNAs in lung cancer is what really counts to the clinical trials, such as whether it can be treated as a biomarker to anticipate, diagnose, and against this malignance and/or whether the mechanism underling it correlated with some special signaling pathways. Together, we simply reviewed recent study of this fields to pave a solid way for further researches on the application of miRNAs in lung cancer clinically.
Y. Zhang e-mail: [email protected] Y. Zhang · Q. Yang · S. Wang Collaborative Innovation Center for Chinese Medicine in Qinba Mountains, 169 West Changle Road, Xi’an 710032, People’s Republic of China
miRNAs in cancer miRNAs are short, single-stranded, endogenous, non-coding RNA molecules. A small switch of miRNAs could lead
13
1106
Cancer Chemother Pharmacol (2014) 74:1105–1111
Fig. 1 miRNAs in lung cancer. Different types of miRNAs play a different role in the progress of lung cancer which can be divided into two groups: tumor suppressive miRNAs by targeting oncogenes, and oncogenic miRNAs by targeting tumor suppressors
to an important relative biological effectiveness such as growth, proliferation, and apoptosis. Stfan Volinia [17] and other researchers worked together applied gene microarray to demonstrate that compared with the normal tissues, miRNAs in tumors have a significant different expression, which testified the roles miRNAs played in tumors. Now, we have a relative accurate global gene expression profile which, according to Lu’s report, has been demonstrated the numerous miRNAs deregulated in tumor compared with normal tissues [18]. miRNAs can trigger many signaling pathways to cause different effects. Based on the signaling pathways, they can be classified with two main types: the tumor suppressive miRNAs and oncogenic miRNAs (oncomirs). For example, miRNA-15a and miRNA-16-1, which belong to the tumor suppressive miRNAs, were revealed downregulated in the majority of patients with chronic lymphocytic leukemia (CLL) and enhanced apoptosis by regulated B cell lymphoma 2 (Bcl-2) which can be against apoptosis [19]. Other examples are miRNA-21 and miRNA-9. For miRNA21 which is usually highly expressed in solid and hematologic tumors including liver, lung, colon, and other tumors, to lower its expression might suppress cell growth and even induce apoptosis by targeting tumors genes such as PTEN [20]. miRNA-9, which maintain high level in many cancers, has been reported that through inhibiting its expression, it could markedly decrease lymphoma outgrowth in liver [21]. Using the specificity and sensitivity as index to evaluate whether miRNAs can be served as biomarkers for the diagnostic and prognostic of cancers. And miRNAs-based therapeutic approaches have been paid more attentions by clinical trials. miRNA-34 which was the first miRNAs-based drug against tumors has been applied [22].
miRNAs in lung cancer There are significant differential expressions of miRNAs between the lung cancer cell lines and non-tumor cell
13
lines and normal lung tissues, and some kinds of miRNAs among them possess the specificity and sensitivity to lung cancer as well. miRNAs status in lung cancer, as in other forms of cancer, can be divided into two categories: down-regulation of tumor suppressive miRNAs that target oncogenes, and up-regulation of oncogenic miRNAs that target tumor suppressors (Fig. 1). miRNAs involved in lung cancer have the ability to regulate the tumorigenesis, survival, angiogenesis and migration and invasion of tumor (Fig. 2). For example, decreased level of expression of the let-7 miRNA family is the majority of patients in lung cancer and with a relative poor prognosis in that by targeting KRAS, NRAS, HMGA2, and Cdc25 and some other oncogenes which are associated with tumor development [23]. Similarly, decreased level of tumor suppressive miRNA-16 in NSCLC patients samples leading to inhibiting the tumor cell lines growth and motility by targeting hepatoma-derived growth factor (HDGF) [24]. The increased expression of oncogenic miRNA-221/miRNA-222 was demonstrated aggressive in NSCLC compared with less invasive or normal tissues by targeting PTEN and metalloproteinase inhibitors 3 (TIMP3) to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance and lead to cell migration by activating AKT signaling pathway [25]. And for many types of cancers, miRNA-146a through targeting the EGFR to show differential expression and which owning the specificity to lung cancer. And research has been made to reveal that it might suppress cell growth, induce apoptosis, inhibit tumor cells migration and suppress the downstream of EGFR signaling [26]. To sum it up, there are a lot of miRNAs that contributing to the tumorigenesis, survival, angiogenesis and migration and invasion of SCLC and NSCLC cell lines as given in Fig. 2, and multiple data have been demonstrated that, via targeting various targets, miRNAs can function as either tumor activators or suppressors, and above all to consist of the different roles of miRNAs in lung cancer.
Cancer Chemother Pharmacol (2014) 74:1105–1111
1107
Fig. 2 miRNAs and targets in lung cancer. miRNAs through targeting numerous protein targets to regulate the tumorigenesis, survival, angiogenesis, migration and invasion of lung cancer
miRNAs in the diagnosis of lung cancer miRNAs on the pathological classification Currently, the pathological classification of NSCLC focuses on lung adenocarcinoma (AD) and squamous cell lung carcinoma (SCC), which are also the most important histological types of lung cancer and exhibiting unique pathological features and different response to therapy. Study has been made to demonstrate that of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for NSCLC patients who cannot administrate operation, the advanced tumor patients or non-SCC patients [27]. And treatment with bevacizumab alone to SCC patients might cause serious side effects in advanced SCC patients [28]. Therefore, to make an accurate pathological classification of NSCLC contributes to individual-based treatment of this cancer. However, there are no efficient methods to clarify the pathological classification of NSCLC about the low differentiated tumor tissues. And the expression profiles of miRNAs can make up this blank for they are able to predictive the origin of the tumor accurately. Lots of studies have been made to reveal that miRNAs including miRNA-205, miRNA-99b, miRNA-203, miRNA-202 and miRNA-102, pre-miRNA-204 exhibiting different expression between AD and SCC [18, 29–31], especially for the miRNA-205 that can be acted as a tool to distinguish AD and SCC, when the quantitative analysis has been applied. miRNA-205 has a higher sensitivity (96 %) and specificity
(90 %) in low differentiated tumor tissues, which make a better foundation for the relationship between miRNAs and the pathological classification of lung cancer [32]. miRNAs in tissues There is a significant difference between the tumors and the normal lung tissues on the expression levels and patterns of miRNAs, and based on that, miRNAs can be applied in the early diagnosis of lung cancer in clinics. It has been demonstrated that, after using meta-analysis, compared with the normal lung tissues, miRNA-210, miRNA-21, miRNA-31 and miRNA-182 stay apparently up-regulated in lung cancer tissues, while, on the contrary, miRNA126 and miRNA-145 down-regulated [33]. Sun and other recearchers have applied the technology of gene microarray to detect the expression difference about between the normal lung tissues, metastatic lung carcinoma tissues and primary lung carcinoma tissues. And they found that there are four kinds of miRNAs (miRNA-150, miRNA-18b-5p, miR-643 and miR-3940-5p) exist expression difference between metastatic lung carcinoma tissues and primary lung carcinoma tissues, and compared with the normal lung tissues, miRNA-150 and miRNA-3940-5p keeps down-regulation in lung carcinoma tissues [34]. And what’s more, lots of researches show that miRNA-182, miRNA-183 and miRNA-96 exhibit up-regulated in lung carcinoma tissues [35]. Thus, miRNAs in tissues play an important role in the diagnosis of lung cancer.
13
1108
miRNAs in serum and plasma The majority of patients who suffering from lung cancer, especially non-small cell lung cancer, are belonging to terminal cancer. Comparing to the early-stage cancer patients, who 5-year survival rates are over 80 %, their survival estimates in terminal cancer are only under 20 %. So the diagnosis in the early stage of lung cancer is what really counts to improve the 5-year survival rates of patients. The expression patterns of miRNAs in serum and plasma exhibit significant difference between lung cancer patients and healthy persons. miRNAs in serum and plasma are in a very stable form which can resist high temperatures, strong acid and alkali, quench condensation and the degradation of enzyme, and RT-PCR can be used to detect miRNAs accurately [36]. It has been demonstrated that the majority of miRNAs (91/101) in healthy persons have co-expression in serum and plasma, while in NSCLC patients, there are also 76 kinds of miRNAs that express in serum only, which prompting speculation that the majority of miRNAs in serum belong to tumor tissues [36]. In NSCLC patients, the abnormal expression of miRNAs in serum and in tumor tissues aligned fairly well [37–39], which lay the foundations on using miRNAs in serum as a method to diagnose the early stage of lung cancer clinically. Foss et al. [37] found that miRNA-1254 and miRNA-574-5p in patients in early stage of NSCLC maintain up-regulation, which can make a conclusion that they are sensitive (sensitivity is 82 %) in early diagnosis of NSCLC. And for the miRNAs in plasma, miRNA-21, miRNA-126, miRNA210 and miRNA-486-5p stay at high sensitivity (86.22 %) in the diagnosis of NSCLC, especially in the diagnosis of early stage of NSCLC (73.33 %) [38]. Compared with the miRNAs in plasma in NSCLC patients and healthy persons, they found that there are 27 miRNAs which show statistical differences in expression, and among them, 24 miRNAs including miRNA126 and let-7 and so on have a significant advantage in sensitivity (92.5 %), veracity (95.4 %) and specificity (98.1 %) in the diagnosis of lung cancer [39]. miRNAs as biomarkers Numerous miRNAs contributing to the malignant phenotype maintain differential expression in tumors compared with the normal lung tissues and normal adjacent tissues. And these miRNAs also have a close relationship with sorts of cancer-associated proteins, which can show a unique function in the development of lung cancer. For example, researchers have tested that p53 by mutanting p53R175H to induce expression as if oncogenic miRNA-128-2, which can decrease the apoptosis and increase resistance to drugs such as cisplatin by targeting E2F5 [40]. miRNA-494 also has relationship with ERK1/2 signaling, which activated ERK1/2 to promote miRNA-494 to increase resistance of
13
Cancer Chemother Pharmacol (2014) 74:1105–1111
NSCLC cells to TRAIL-induced apoptosis [41]. miRNAs are highly stable in tissues and blood, and tumor origin, histotype and their stage of illness can form their expression patterns [42]. Thus, they have great values in diagnosis and prognosis, which makes them promising candidates for biomarker for lung cancer detection [43]. For instance, some kinds of miRNAs confer high specificity as miRNA182, which was overexpressed neither in primary lung cancer nor in other types of epithelial and non-epithelial malignances [44]. The sensitivity and expression specificity of miRNAs make them like a biomarker to diagnose and anticipate lung cancer. On the one hand, as a prognostic biomarker, it has been reported that there are numerous miRNAs that can be applied in early-stage operable NSCLC patients such as improving the levels of circulating miRNA-142-3p [45] and increasing levels of miRNA-328 in peripheral blood can also contribute to early detection of NCSLC [46]. Some researchers have demonstrated that the low expression of miRNAs-146a in lung cancer often relates to the advanced stage of tumor. So miRNAs-146a may serve as a prognostic biomarker and hold the therapeutic potential since elevated levels of it could longer progression-free survival [26]. On the other hand, miRNAs can also act as predictive biomarkers for treatment response in SCLC and NSCLC patients. First, for SCLC patients who have a good response to chemotherapy and radiotherapy, usually leading to tumor relapse and its development spread just because the evolution of the resistant cells began. At this transformation, miRNA-92a-2 plays an important role, since higher level of miRNA-92a-2 were related to chemoresistance and could lower the survival rate of patients. So miRNA-92a-2 could act as a predictive biomarker for de novo chemoresistance in SCLC patients [47]. Second, for NSCLC patients, there are also some kinds of miRNAs in plasma and serum that contributing to serve as predictive biomarkers. Examples as miRNA-210 in NSCLC patients’ serum, who’s high level of it associated with clinical stage as well as poor response to cisplatin-based chemotherapy [48]. And the level of oncogenic miRNA-21 in the plasma of NSCLC patients was correlated with NSCLC stage and platinum-based chemotherapy [49], while in the whole blood, the high level of miRNA-22 has a relationship with the lack of response to pemetrexed chemotherapy. That is to say, miRNA-22 may also be a biomarker for pemetrexed chemotherapy in NSCLC patients [50].
miRNAs in the treatment of lung cancer Therapeutic approaches to cure lung cancer Based on the classification of lung cancer, the therapeutic approaches should also own specificity, because of the
Cancer Chemother Pharmacol (2014) 74:1105–1111
treatment response of chemotherapy and radiotherapy between SCLC and NSCLC. Some SCLC patients are not suit for surgical excision. Because SCLC as the most aggressive type of lung cancer, owning the capacity of high metastatic spread to other region of the body, for example, it can spread to the brain at the early stage of tumor formation. So this type of lung cancer is usually treated by cisplatin and etoposide (combination chemotherapy), and the survival rate is still only 1 year at early stage and no more than 3 years at advanced stage [51]. However, for NSCLC patients who insensitive to chemotherapy and radiotherapy, surgical excision comes to be their best option. And if patients cannot administrate an operation, chemotherapy and radiotherapy come to be their last choice, such as platinum-based chemotherapy and targets therapy [43]. Targets therapy such as monoclonal antibody-based and small tyrosine kinase inhibitor-based drugs [52] turns to be a novel therapeutic approach to cure lung cancer as well as early detection and prognostic markers. miRNAs in regulation of resistance/sensitivity of lung cancer to treatment Different pathological classifications of lung cancer have different resistance/sensitivity to treatment. So miRNAs may play a dominate role in regulation of the resistance and sensitivity. On the one hand, numerous miRNAs have been figured out that show differentially expression in radiotherapy compared with radiotherapy-resistant NSCLC patients and NSCLCs. The overexpression of the miRNA-126 could inhibit cell growth and induce apoptosis of radiotherapyresistant NSCLC cells by PI3K–AKT signaling pathway [53]. By targeting K-Ras, let-7g, which is upregulated in radiosensitive H460 cell line compared with radioresistant H1299 cell line, could increase cells sensitivity to IR [54]. In 549 cell line, overexpression of miRNA-7 was able to lead cell radiosensitization, prolong radiation-induced formation of DNA DSBs by activated EGFR–PI3K–AKT signaling pathway, and decreased levels of EGFR and AKT [55]. Overexpression of miRNA-101, which is a tumor suppressive miRNA, could also promote radiosensitization by decreased expression of ATM- and DNA-dependent kinases [56]. And the tumor suppressor miRNA family such as miRNA-34 which by targeting p53 to promote radiosensitization, as well [57]. In addition, downregulation of oncogenic miRNA-21 could not only inhibit cell growth but also cause enhancement of radiosensitivity of NSCLCs [58]. miRNA-214 has two functions: overexpression might protect radiosensitivity by regulating P38 MAPK signaling pathways, and downexpression by RNAi sensitized radioresistant cells to IR [59]. miRNA-210 can regulate radioresistance of hypoxic lung cancer cells [60]. Above them all, these are miRNAs in radioresistance of lung cancer. On
1109
the other hand, through inducing apoptosis of cancer cells, chemotherapeutic agents can display their anticancer effects. Lots of researches have been made to reveal that miRNAs are associated with modulation of drug resistance pathways. Initially, researchers have made efforts to addressing the role of miRNA-1 as a mediator in lung cancer A549’s chemoresistance to doxorubicin [61], which make a foundation for further study of this field. And after that report, multiple miRNAs, such as overexpression of miRNA-138, were shown differentially expressed in AD with increased resistance to cisplatin [62]. Increasingly, numerous reports revealed that multiple tumor suppressive miRNAs mediated the tumor cells sensitivity to cytotoxic treatment. For example, the tumor suppressor miRNA-100 which exerts its function of suppression of cell proliferation and inducement of apoptosis by downregulated in docetaxel-resistant AD [63]. While miRNA-34c-5p would protect cells from paclitaxelinduced apoptosis by targeting Bcl-2-modifying factor [64, 65]. There are not only the tumor suppressive miRNAs, but also some oncogenic miRNAs that can serve as markers to chemosensitivity. For example, pre-miRNA-630 conferred resistance of A549 cells to cisplatin and carboplatin, and could lead to decreasing proliferation and suppressing DNA damage signaling and activating p53 [65, 66]. Another example is the oncogenic miRNA-205, which was overexpressing in NSCLC cell lines and could promote cell growth metastasis and chemoresistance to cisplatin by targeting PTEN [67]. There are also multiple oncogenic miRNAs that can contribute in chemoresistance such as miRNA-31 [68] and so on. Thus, it is of importance to figure out the roles of miRNAs in lung cancer treatment.
Conclusions Lung cancer, the leading cause of cancer deaths worldwide, can be divided into two major types, which has drawn enough attention: SCLC and NSCLC. But we have not found an efficient system to prevent, diagnose, prognose, and even treat lung cancer. As discussed above, numerous miRNAs contributing to the malignant phenotype maintain differential expression in tumors compared with the normal lung tissues and normal adjacent tissues. And these types of miRNAs are stable in tissue sections and blood and reflect tumororigin, histotype, and stage. They also have a close relationship with sorts of cancer-associated proteins, which can be served as a uniquely biomarker in lung cancer such as apoptosis, migration, invasion, and proliferation in that some of them owned the specificity and sensitivity to lung cancer. However, in spite of the marketable role of miRNAs in the prevention, diagnosis, and treatment on lung cancer, there are also some questions that we can miss. For example, multiple targets can contribute to one miRNA
13
1110
and vice versa. In addition, many factors can effect on the function of miRNAs in lung cancer, and the mechanism underlying this is still a myth, which give us the opportunities to explore this field. Recently, increasingly numerous miRNAs have been found which are associated with lung cancer based on the methods as miRNAs profiles enhanced. For instance, let-7 mimetic is going to be the first miRNA therapeutic to enter clinical trials, which make a huge progress in treatment of lung cancer clinically [69]. To make a conclusion based on the researches of miRNAs may pave a novel way to treat anti-lung cancer.
References 1. Pan X, Zhang X, Sun H, Zhang J, Yan M, Zhang H (2013) Autophagy inhibition promotes 5-fluorouraci-induced apoptosis by stimulating ROS formation in human non-small cell lung cancer A549 cells. PLoS One 8(2):e56679 2. Hsin IL, Ou CC, Wu TC, Jan MS, Wu MF, Chiu LY et al (2011) GMI, an immunomodulatory protein from Ganoderma microsporum, induces autophagy in non-small cell lung cancer cells. Autophagy 7(8):873–882 3. Liu J, Hu XJ, Jin B, Qu XJ, Hou KZ, Liu YP (2012) β-Elemene induces apoptosis as well as protective autophagy in human non-small-cell lung cancer A549 cells. J Pharm Pharmacol 64:146–153 4. Chen HS, Portier K, Ghosh K, Naishadham D, Kim HJ, Zhu L et al (2012) Predicting US and state-level cancer counts for the current calendar year: part I—evaluation of temporal projection methods for mortality. Cancer 118(4):1091–1099 5. Saintigny P, Burger JA (2012) Recent advances in non-small cell lung cancer biology and clinical management. Discov Med 13:287–297 6. Ajabnoor GM, Crook T, Coley HM (2012) Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells. Cell Death Dis 3:e260 7. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297 8. Hornstein E, Mansfield JH, Yekta S, Hu JK, Harfe BD et al (2005) The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature 438:671–674 9. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355 10. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233 11. Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655 12. Macfarlane LA, Murphy PR (2010) MicroRNA: biogenesis, function and role in cancer. Curr Genomics 11:537–561 13. Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579 14. Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269 15. Zhou M, Liu Z, Zhao Y, Ding Y, Liu H et al (2010) MicroRNA125b confers the resistance of breast cancer cells to paclitaxel through suppression of proapoptotic Bcl-2 antagonist killer 1 (Bak1) expression. J Biol Chem 285:21496–21507 16. Fujita Y, Kojima K, Ohhashi R, Hamada N, Nozawa Y et al (2010) MiR-148a attenuates paclitaxel resistance of hormonerefractory, drug-resistant prostate cancer PC3 cells by regulating MSK1 expression. J Biol Chem 285:19076–19084
13
Cancer Chemother Pharmacol (2014) 74:1105–1111 17. Aora T, Liu B, He H (2003) PIASx is a transcriptional co-repressor of signal transducer and activator of transcription. J Biol Chem 278(24):21327–21330 18. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838 19. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102:13944–13949 20. Garzon R, Calin GA, Croce CM (2009) MicroRNAs in cancer. Annu Rev Med 60:167–179 21. Leucci E, Zriwil A, Gregersen LH, Jensen KT, Obad S, Bellan C, Leoncini L, Kauppinen S, Lund AH (2012) Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo. Oncogene 31:5081–5089 22. Ling H, Fabbri M, Calin GA (2013) MicroRNAs and other noncoding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12:847–865 23. Osada H, Takahashi T (2011) let-7 and miR-17-92: small-sized major players in lung cancer development. Cancer Sci 102:9–17 24. Ke Y, Zhao W, Xiong J, Cao R (2013) Downregulation of miR-16 promotes growth and motility by targeting HDGF in non-small cell lung cancer cells. FEBS Lett 587:3153–3157 25. Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, Gasparini P, Gonelli A, Costinean S, Acunzo M, Condorelli G, Croce CM (2009) miR221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16:498–509 26. Chen G, Umelo IA, Lv S, Teugels E, Fostier K, Kronenberger P, Dewaele A, Sadones J, Geers C, De Greve J (2013) miR-146a inhibits cell growth, cell migration and induces apoptosis in nonsmall cell lung cancer cells. PLoS One 8:e60317 27. Reck M, Von Pawel J, Zatloukal P et al (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancel: AVAil. J Clin Oncol 27:1227–1234 28. Seagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage nonsmall-cell lung cancer. J Clin Oncol 26:3543–3551 29. Yanaihara N, Caplen N, Bowman E et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198 30. Lebanony D, Benjamin H, Gilad S et al (2009) Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from non-squamous non-small cell lung carcinoma. J Clin Oncol 27:2030–2037 31. Landi MT, Zhao Y, Rotunno M et al (2010) MicroRNA expression differentiates histology and predicts survival of lung cancer. Clin Cancer Res 16:430–441 32. Del Vescovo V, Cantaloni C, Cucino A et al (2011) miR-205 Expression levels in non-small cell lung cancer do not always distinguish adenocarcinomas from squamous cell carcinomas. Am J Surg Pathol 35:268–275 33. Guan P, Yin Z, Li X et al (2012) Meta-analysis of human lung cancer microRNA expression profiling studies comparing cancer tissues with normal tissues. J Exp Clin Cancer Res 31:54 34. Sun Y, Su B, Zhang P et al (2013) Expression of miR-150 and miR-3940-5p is reduced in non-small lung carcinoma and correlates with clinicopathological features. Oncol Rep 29:704–712 35. Zhu W, Liu X, He J et al (2011) Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study. BMC Cancer 11:393
Cancer Chemother Pharmacol (2014) 74:1105–1111 36. Chen X, Ba Y, Ma L et al (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006 37. Foss KM, Sima C, Ugolini D et al (2011) miR-1254 and miR574-5p: serum-based microRNA biomarkers for early stage nonsmall cell lung cancer. J Thorac Oncol 6(3):482–488 38. Shen J, Todd NW, Zhang H et al (2011) Plasma microRNAs as potential biomarkers for non-small cell lung cancer. Lab Invest 91(4):579–587 39. Keller A, Leidinger P, Borries A et al (2009) miRNAs in lung cancer studying complex fingerprints in patients blood cells by microarray experiments. BMC Cancer 9:353 40. Donzelli S, Fontemaggi G, Fazi F, Di Agostino S, Padula F, Biagioni F, Muti P, Strano S, Blandino G (2012) MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function. Cell Death Differ 19:1038–1048 41. Romano G, Acunzo M, Garofalo M, Di Leva G, Cascione L, Zanca C, Bolon B, Condorelli G, Croce CM (2012) MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non-small-cell lung cancer through BIM down-regulation. Proc Natl Acad Sci USA 109:16570–16575 42. Melo SA, Esteller M (2011) Dysregulation of microRNAs in cancer: playing with fire. FEBS Lett 585:2087–2099 43. Zandberga E, Kozirovskis V, Abols A, Andrejeva D, Purkalne G, Line A (2013) Cell-free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer. Genes Chromosomes Cancer 52:356–369 44. Barshack I, Lithwick-Yanai G, Afek A, Rosenblatt K, TabibianKeissar H, Zepe-niuk M, Cohen L, Dan H, Zion O, Strenov Y, Polak-Charcon S, Perelman M (2010) MicroRNA expression differentiates between primary lung tumors and metastases to the lung. Pathol Res Pract 206:578–584 45. Kaduthanam S, Gade S, Meister M, Brase JC, Johannes M, Dienemann H, Warth A, Schnabel PA, Herth FJ, Sultmann H, Muley T, Kuner R (2013) SerummiR-142-3p is associated with early relapse in operable lung adenocarcinoma patients. Lung Cancer 80:223–227 46. Ulivi P, Foschi G, Mengozzi M, Scarpi E, Silvestrini R, Amadori D, Zoli W (2013) Peripheral blood miR-328 expression as a potential biomarker for the early diagnosis of NSCLC. Int J Mol Sci 14:10332–10342 47. Ranade AR, Cherba D, Sridhar S, Richardson P, Webb C, Paripati A, Bowles B, Weiss GJ (2010) MicroRNA 92a-2*: a biomarker predictive for chemoresistance and prognostic for survival in patients with small cell lung cancer. J Thorac Oncol 5:1273–1278 48. Li ZH, Zhang H, Yang ZG, Wen GQ, Cui YB, Shao GG (2013) Prognostic significance of serum microRNA-210 levels in nonsmall-cell lung cancer. J Int Med Res 41:1437–1444 49. Wei J, Gao W, Zhu CJ, Liu YQ, Mei Z, Cheng T, Shu YQ (2011) Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer. Chin J Cancer 30:407–414 50. Franchina T, Amodeo V, Bronte G, Savio G, Ricciardi GR, Picciotto M, Russo A, Giordano A, Adamo V (2014) Circulating miR-22, miR-24 and miR-34a as novel predictive biomarkers to pemetrexed-based chemotherapy in advanced non-small cell lung cancer. J Cell Physiol 229:97–99 51. William WN Jr, Glisson BS (2011) Novel strategies for the treatment of small-cell lung carcinoma. Nat Rev Clin Oncol 8:611–619 52. Larsen JE, Cascone T, Gerber DE, Heymach JV, Minna JD (2011) Targeted therapies for lung cancer: clinical experience and novel agents. Cancer J 17:512–527 53. Wang XC, Du LQ, Tian LL, Wu HL, Jiang XY, Zhang H, Li DG, Wang YY, Wu HY, She Y, Liu QF, Fan FY, Meng AM (2011) Expression and function of miRNA in postoperative radiotherapy
1111 sensitive and resistant patients of non-small cell lung cancer. Lung Cancer 72:92–99 54. Jeong SH, Wu HG, Park WY (2009) LIN28B confers radio resistance through the posttranscriptional control of KRAS. Exp Mol Med 41:912–918 55. Lee KM, Choi EJ, Kim IA (2011) microRNA-7 increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Radiother Oncol 101:171–176 56. Chen S, Wang H, Ng WL, Curran WJ, Wang Y (2011) Radiosensitizing effects of ectopic miR-101 on non-small-cell lung cancer cells depend on the endogenous miR-101 level. Int J Radiat Oncol Biol Phys 81:1524–1529 57. Balca-Silva J, Sousa Neves S, Goncalves AC, Abrantes AM, Casalta-Lopes J, Botelho MF, Sarmento-Ribeiro AB, Silva HC (2012) Effect of miR-34b overexpression on the radiosensitivity of non-small cell lung cancer cell lines. Anticancer Res 32:1603–1609 58. Liu ZL, Wang H, Liu J, Wang ZX (2013) MicroRNA-21 (miR21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem 372:35–45 59. Salim H, Arvanitis A, de Petris L, Kanter L, Haag P, Zovko A, Ozata DM, Lui WO, Lundholm L, Zhivotovsky B, Lewensohn R, Viktorsson K (2013) miRNA-214 is related to invasiveness of human non-small cell lung cancer and directly regulates alpha protein kinase 2 expression. Genes Chromosomes Cancer 52:895–911 60. Grosso S, Doyen J, Parks SK, Bertero T, Paye A, Cardinaud B, Gounon P, Lacas-Gervais S, Noel A, Pouyssegur J, Barbry P, Mazure NM, Mari B (2013) MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis 4:e544 61. Nasser MW, Datta J, Nuovo G, Kutay H, Motiwala T, Majumder S, Wang B, Suster S, Jacob ST, Ghoshal K (2008) Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicininduced apoptosis by miR-1. J Biol Chem 283:33394–33405 62. Wang Q, Zhong M, Liu W, Li J, Huang J, Zheng L (2011) Alterations of microRNAs in cisplatin-resistant human non-small cell lung cancer cells (A549/DDP). Exp Lung Res 37:427–434 63. Feng B, Wang R, Chen LB (2012) MiR-100 resensitizes docetaxel-resistant human lung adenocarcinoma cells (SPC-A1) to docetaxel by targeting Plk1. Cancer Lett 317:184–191 64. Catuogno S, Cerchia L, Romano G, Pognonec P, Condorelli G, de Franciscis V (2013) miR-34c may protect lung cancer cells from paclitaxel-induced apoptosis. Oncogene 32:341–351 65. Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L, Criollo A, Servant N, Paccard C, Hupe P, Robert T, Ripoche H, Lazar V, Harel-Bellan A, Dessen P, Barillot E, Kroemer G (2010) miR181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res 70:1793–1803 66. Lei L, Huang Y, Gong W (2013) miR-205 promotes the growth, metastasis and chemoresistance of NSCLC cells by targeting PTEN. Oncol Rep 30:2897–2902 67. Dong Z, Zhong Z, Yang L, Wang S, Gong Z (2014) MicroRNA-31 inhibits cisplatin-induced apoptosis in non-small cell lung cancer cells by regulating the drug transporter ABCB9. Cancer Lett 343:249–257 68. Huang JY, Cui SY, Chen YT, Song HZ, Huang GC, Feng B, Sun M, De W, Wang R, Chen LB (2013) MicroRNA-650 was a prognostic factor in human lung adenocarcinoma and confers the docetaxel chemoresistance of lung adenocarcinoma cells via regulating Bcl-2/Bax expression. PLoS One 8:e72615 69. Uchino K, Ochiya T, Takeshita F (2013) RNAi therapeutics and applications of microRNAs in cancer treatment. Jpn J Clin Oncol 43:596–607
13
