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The pathological role of microRNAs and inflammation in colon carcinogenesis Lin Zhang , Xiao-Ming Fan ∗ Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, 1508, Longhang road, 201508 Shanghai, China
Summary Evidence of an association between inflammation, microRNAs (miRNAs) and tumorigenesis has emerged in recent years. Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer (CRC) development, suggesting that inflammatory mediators play a causative role in colon carcinogenesis. MiRNAs are small (19—22 nucleotides) non-coding RNA molecules that regulate gene expression at the post-transcriptional level by base-pairing to specific messenger RNAs (mRNAs), promoting their degradation or suppressing translation. MiRNAs can act as inflammatory mediators, oncogenes or tumor suppressors in different cellular environments. MiRNAs also serve as biomarkers and therapeutic targets in CRC. The risk of CRC is also influenced by miRNA polymorphisms and binding sites. Their functions as early diagnostic biomarkers or prognostic classifiers has been demonstrated. Here, we reviewed recent findings on miRNAs and inflammation in colon carcinogenesis and discussed the potential for miRNAs and inflammation-related genes as biomarkers and therapeutic targets in CRC. © 2014 Published by Elsevier Masson SAS.
Introduction Colorectal cancer (CRC) remains an important health problem worldwide. Over 1 million new cases of colon cancer are diagnosed each year and more than 600,000 people die from the disease [1]. In most cases, the occurrence of colorectal cancer is associated with lifestyle and ageing, and only a small number of cases are associated with genetic disorders [2,3]. However, the environmental factors are involved in
∗
Corresponding author. E-mail address: [email protected] (X.-M. Fan).
CRC development and their exact role remains to be elucidated. A link between chronic inflammation and CRC has been suggested by several studies [4,5] and the contribution of gastrointestinal inflammation to the progression of colon cancer has been demonstrated [6]. Anti-inflammatory treatments can reduce colon cancer morbidity. An increased risk of CRC development is observed in patients with long-standing inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease [7,8]. Although patients with IBD account for only a small fraction of CRC cases, they are at the greatest risk for CRC among the general population [6]. Furthermore, non-steroidal anti-inflammatory drugs are considered chemopreventive
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agents and can decrease the risk of CRC [7,8]. Therefore, inflammatory mediators and factors, including cytokines, chemokines, transcription factors, hormones and microRNAs (miRNAs), play crucial roles in the development of colon cancer [5]. MiRNAs are small non-coding RNAs that were discovered in recent years and have shown a promising role in the treatment of immune related diseases [9,10]. By regulating mRNA degradation at the post-transcriptional level, miRNAs can affect signaling pathways and are therefore candidate therapeutic agents. In addition, reliable methods such as quantitative real-time RT-PCR and microarray technologies have been established for the detection of miRNAs [11]. These advances indicate that miRNAs can be potentially used for early diagnosis, prognostic classification and therapeutic decision-making in CRC. The objective of this review is to discuss the role of miRNAs in the development of CRC and suggest possible uses of miRNAs as biomarkers and therapeutic targets.
A link between inflammation, miRNAs and colon carcinogenesis Tumorigenesis in sporadic and colitis-associated cancer CRC is caused by the consecutive accumulation of genetic and epigenetic alterations, driving the initiation and progression of tumor from aberrant crypt foci (ACF) to adenoma and colorectal carcinoma. Fearon and Vogelstein first described this process in a milestone study [12]. Loss of adenomatous polyposis coli (APC), which has 15 exons and encodes a large protein with a molecular weight > 300 kDa, occurs during the initiation of tumorigenesis. Since APC acts as an inhibitor of -catenin, the proteolytic degradation of APC can induce the activation and translocation of -catenin from the cytoplasm to the nucleus [13—15]. Besides APC, mutations in glycogen synthase kinase-3, -catenin itself and other components of the Wnt pathway are found in 10% of colon tumors [16]. Consequently, several additional pathways are involved in the progression from adenoma to carcinoma, including the activation of the oncogenes K-ras and B-Raf, and the inactivation of tumor suppressors such as the TGF- receptor II, p53 and the apoptotic related protein Bax [17—19]. Upregulation of the expression of cyclooxygenase 2 (COX2) is also required for tumor progression [20—22]. In addition, chromosome instability and microsatellite instability (MSI) result in a variety of mutations and are responsible for the aggressiveness of colon cancer [19]. The association of IBD with CRC was first described by Burrill Crohn in 1925 [23]. The process of carcinogenesis in IBD is believed to be similar to that of adenoma-carcinoma transformation in sporadic CRC. However, unlike sporadic CRC, where dysplasia is only presented in one or two focal areas of the colon, dysplastic lesions are usually multifocal in colitis-associated cancer (CAC) [24]. A considerable overlap in the mechanism of pathogenesis exists between CRC and CAC. However, the sequence of molecular events in IBD-related adenocarcinoma differs from that of sporadic CRC in several aspects. For example, inactivation of p53 is
an important early event in CAC development, whereas p53 mutation in sporadic neoplasia usually occurs late in the adenoma-carcinoma transformation [8]. Mutation of APC, which is considered as an early signaling event in sporadic CRC, usually happens late in the sporadic CRC [25]. Recent studies proposed a role for cell senescence in tumor progression, and the p53 and Rb pathways were shown to be involved in these events [26,27]. P53 isoforms expressed during the progression from colon adenoma to carcinoma might act as signaling factors for escaping from the senescence barrier [28]. In UC patients, senescence may also act as a protective factor to prevent the transition from lowgrade to high-grade dysplasia [29]. Chronic inflammation, which is presented in both sporadic CRC and CAC and is characterized by a persistent pro-inflammatory response and tissue destruction, can facilitate tumor progression by promoting the proliferative and anti-apoptotic properties of premalignant cells, as well as tumor progression and metastasis [30]. COX2 and nuclear factor kappa B (NF-B) are two key genes that provide a mechanistic link between inflammation and cancer [31]. Constitutive NF-B activation was observed in 40% of CRC tissues and two thirds of cell lines, and was shown to promote tumor growth [32]. COX2 is normally expressed at low levels in the colonic mucosa, but its expression increases significantly after APC mutation [33]. Popivanova et al. showed that blockade of tumor necrosis factor-␣ (TNF-␣) reduces the formation of colorectal tumors in mice lacking the TNF receptor, p55 (TNF-Rp55 knockout) [34]. Induced expression of TNF-␣ in colon tissues regulates COX2 levels in inflammatory cells. Furthermore, NF-B can be activated by TNF-␣, interleukinL-1 (IL-1) and IL-6 [8,30].
The role of miRNAs in inflammation and colon carcinogenesis Several studies have shown that miRNAs play a role in inflammatory diseases [35—40] including IBD. Wu et al. studied the mucosa of healthy subjects and that of UC patients and found that miR-192 was predominantly expressed in the intestinal epithelial tissues of healthy subjects and significantly downregulated in UC patients [41]. They also found that miR-21 was increased in UC patients compared to healthy subjects. The upregulation of miR-21 expression was confirmed in Crohn’s disease. Furthermore, elevated miR21 level was detected not only at sites of inflammation, including colitis, but also in many types of cancers, including CRC [42], indicating that the upregulation of miR-21 expression may play an important role in inflammation-associated carcinogenesis. MiR-21, the most investigated and welldescribed miRNA, is also known as the ‘‘oncomiR’’ and its clinical potential has been demonstrated [43]. As shown in many studies, miR-21 can promote cell proliferation, inhibit cell death, and enhance invasion and metastasis by interacting with tumor suppressor genes, including phosphatase and tensin homolog (PTEN), programmed cell death 4 (PDCD4), and sprouty 2 (SPRY2) among others [44,45]. Hatley et al. recently showed that miR-21 acted as a negative regulator of the Ras/MEK/ERK pathway, and it was shown to suppress apoptosis in a KRAS-induced lung cancer mouse model [46]. Medina et al. showed that overexpression of miR-21 led to
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microRNA and inflammation in colon cancer the development of pre-B malignant lymphoma, suggesting that miR-21 acts as an oncogene [47]. Consistent with its oncomiR functions, increased expression of miR-21 has been associated with the activity of the epidermal growth factor receptor (EGFR) and KRAS pathways [48]. Oncogenic KRAS can also induce the pro-inflammatory cytokines IL-6 and IL-8 [4]. In addition, miR-21 can be induced by various inflammatory stimuli. Interferon (IFN) and IL-6 induce miR-21 expression via a signal transducer and activator of transcription 3 (STAT3)-dependent pathway [49,50]. In colon cancer, a positive relation between miR-21 and IL6 expression was demonstrated [51]. Iliopoulos et al. proposed a positive-feedback loop involving inflammation and colon cancer [52]. These authors showed that STAT3 induced by IL6 could activate miR-21 and miR-181b-1, leading to NFB activation to sustain the transformed state through the inhibition of PTEN and cylindromatosis (CYLD) expression. Taken together, these findings suggest that miR-21 plays an important role in both IBD and colon cancer. Polycistronic miR-143 and miR-145 on chromosome 5 are downregulated in sporadic colon cancer [53,54]. They can act as tumor suppressors by targeting genes involved in multiple oncogenic pathways, such as KRAS and MYC [53,55]. Pekow et al. showed that miR-143 and miR-145 are downregulated in patients with UC [56]. The let-7 miRNA family is another regulator of KRAS that acts by base-pairing to the 3 untranslated region of KRAS, followed by RAS pathway inhibition and cell growth arrest [44]. Kanaan et al. identified six miRNAs (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, and miR-143) that are upregulated during the progression from non-neoplastic tissues to dysplasia, whereas they are downregulated from dysplasia to cancer. These authors also identified six differentially expressed miRNAs (miR122, miR-214, miR-372, miR-15b, let-7e, miR-17) affected by the TP53 pathway [57]. Strillacci et al. confirmed that miR-101 downregulation is involved in COX2 overexpression in human colon cancer [58]. The oncogenic miR17-92 cluster was shown to modulate c-myc expression in association with colon cancer progression [59], and the miR135 family regulates APC in association with colorectal cancer [60]. Overexpression of miR-155 was found to downregulate the expression of mismatch repair enzymes, including MSH2, MSH6 and MLH1, leading to a mutator phenotype and MSI [61]. In addition, MSH2 expression is negatively regulated by miR-21 [62]. In a recent study, Chen et al. showed that miR-200b was significantly downregulated in the inflamed mucosa of patients with IBD, especially in UC [63]. In their study, Chen et al. suggested that miR-200b could inhibit TGF1-induced epithelial-mesenchymal transition and promote the growth of intestinal epithelial cells. Collectively, miRNAs play important roles in the initiation and progression of CRC (Table 1).
The diagnostic and therapeutic role of miRNAs in IBD
3 examine the effects of consistently dysregulated miRNAs in IBD and their corresponding target genes. The potential clinical use of miR-21, the most investigated and well-described miRNA, has been demonstrated. Overexpression of miR-21 has been reported in many types of human cancer including colorectal cancer. Several studies [41,64,65] have shown that miR-21 is upregulated in inflamed tissues or the serum of IBD patients. Thus, miR21 may serve as a potential biomarker in IBD. Recently, Maharshak et al. showed that miR-132 is upregulated in the inflamed tissues of patients with IBD patients [66], and suggested miR-132 as a novel target for therapeutic interference. Duttagupta et al. proposed platelet-derived miRNA biomarkers for clinical use [67]. Nata et al. showed that miR-146b can improve intestinal inflammation through the upregulation of NF-B, and suggested modulation of the expression of miR-146b as a therapeutic strategy for the treatment of intestinal inflammation [68]. These studies suggest the potential use of miRNAs as biomarkers and diagnostic tools. Although the exact role of miRNAs in IBD remains to be elucidated by functional studies, miRNAs have shown their promise in the treatment of IBD.
MicroRNAs as potential biomarkers for colorectal cancer Circulating miRNAs as early diagnostic biomarkers Early diagnosis can reduce colorectal cancer death by 60% [69]. Screening tests mainly include fecal occult blood testing and colonoscopy [3]. High cost, radiation exposure and invasiveness are the main disadvantages of colonoscopy. The fecal occult blood test is limited by its low sensitivity. Novel non-invasive biomarkers with high sensitivity and specificity are urgently needed for CRC screening in the clinic. MiRNAs are stable and detectable in serum and plasma samples [4] and could therefore be developed as novel non-invasive biomarkers for CRC screening. The oncogenic miR-17-3p and miR-92a, which belong to the miR-17-92 cluster, are upregulated in the plasma of CRC patients [70]. The sensitivity and specificity of these miRNAs to discriminate CRC from control subjects is 89% and 70%, respectively. Reduced plasma levels of miR-17-3p and miR-92a were observed in CRC patients after surgical resection, suggesting that these miRNAs are effective for the detection of CRC recurrence. Huang et al. confirmed the diagnostic value of miR-92a [71], and proposed a second candidate, miR-29a. Circulating miR-221 in plasma was revealed as a potential CRC biomarker [72]. A study that included two independent CRC cohorts proposed that plasma miR-141 could be a prognostic biomarker for advanced CRC [73]. Further studies with large numbers of patients are necessary to confirm the results of these studies.
Prognostic value of miRNAs The involvement of miRNAs in the pathogenesis of IBD makes them promising candidates as biomarkers and therapeutic targets to improve the clinical outcome of patients with IBD. However, the ongoing process of miRNA discovery is associated with several issues. Large cohorts are needed to
Complete surgical removal with adequate margins is the only curative treatment for patients with localized cancer [3]. However, many patients experience CRC recurrence. Postoperative chemotherapy is common as adjuvant treatment
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miRNAs in colon cancer.
Name
Expression
Targets
References
miR-21 miR-181b-1 miR-143 miR-145 miR-101 miR-17-92 miR-155 miR-200b
Overexpressed Overexpressed Downregulated Downregulated Downregulated Oncosuppressor Overexpressed Downregulated
PTEN, PDCD4, SPRY2 CYLD KRAS, MYC, etc. KRAS, MYC, etc. COX2 c-Myc MSH2, MSH6 and MLH1 SMAD2
[43—46] [53] [54,55] [55] [59] [60] [62] [64]
to improve the survival of TNM stage III patients. However, its clinical benefit for stage II patients remains controversial [74]. Therefore, novel prognostic biomarkers capable of identifying CRC patients at high risk of recurrence may help select patients who will benefit from adjuvant chemotherapy. Schetter et al. performed a large-scale analysis of miRNA expression using paired tumor and non-tumor tissues from two independent CRC cohorts. They found five miRNAs (miR21, miR-20a, miR-181b, miR-203 and miR-106a) that were expressed at high levels in tumors associated with poor outcomes in one cohort. The expression of miR-21 was validated in the other cohort and found to be significantly associated with severe cancer-specific mortality after adjustment for other clinical parameters. Increased miR-21 level was also related with poor prognosis in TNM stage II patients. The authors concluded that miR-21 could be a promising prognostic biomarker for early-stage CRC patients [75]. These findings were confirmed by other studies [44]. Therefore, miR-21 is a prognostic factor in different types of cancer and may act as an oncomiR in a broad range of malignancies. A number of miRNAs have been identified as prognostic biomarkers. Decreased levels of miR-320 and miR-498 were associated with poor survival in stage II colon cancer patients [76]. Other studies suggested that increased expression of miR-17, miR-125b, miR-185, miR-200c, and miR-215, and decreased expression of miR-106a and miR-133b were associated with poor prognosis [77—80]. However, these findings are still need to be validated. Compared to a single biomarker, multiple biomarker combinations could be a more accurate prognostic classification strategy. Schetter et al. reported that the combination of miR-21 with the expression of inflammatory-related genes could improve the prognostic prediction of cancer-specific mortality in CRC patients, including those in stage II [51].
Therapeutic outcome prediction value of miRNAs in CRC The efficiency of chemotherapy is often limited by drug resistance and the different genetic backgrounds of patients. Individualized treatment requires accurate biomarkers predictive of therapeutic response. For example, KRAS mutation testing is required before the administration of EGFR targeted therapy [81]. Schetter et al. reported that increased expression of miR-21 is associated with poor therapeutic outcomes in
CRC patients treated with 5-fluorouracil (5-FU) [75]. CRC patients with an MSI phenotype are also resistant to 5-FU [82]. These findings suggest that miR-21 related 5-FU resistance is associated with MSH2, which is involved in the MSI phenotype. The response to therapy can also be affected by singlenucleotide polymorphisms in miRNAs or miRNA-binding sites [4,44]. Zhang et al. identified a let-7 microRNA-binding site polymorphism in the 3 UTR of KRAS that is positively related to anti-EGFR treatment response in patients with metastatic CRC [83]. Single-nucleotide polymorphisms in pri-miR-26a-1 and pri-miR-100 are associated with treatment outcomes in metastatic CRC patients receiving 5-FU and irinotecan [84]. Further investigation is necessary before these discoveries can be translated into the clinic.
Conclusion Increasing attention has been paid to elucidating the role of miRNAs in IBD and CRC. However, further in vivo studies are needed to clarify the role of miRNAs in CRC. In addition, clinical trials are needed to test the therapeutic efficacy of miRNA-based therapies for the management of CRC. Future efforts should be aimed at developing miRNA-based clinical tools for the early detection of CRC and the design of personalized therapeutic strategies. As the most promising candidate miRNA, miR-21 not only plays an important role in the pathogenesis and progression of CRC, but also acts as a CRC biomarker for prognosis and clinical outcome prediction.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements This work was supported by a research grant for key clinical discipline construction of Shanghai Municipality, China, no. ZK2012B20 the Science and Technology Commission of Shanghai Municipality (no. 11ZR1405700) and Phase II Outstanding Young Medical Personnel Training Fund of Jinshan District Health Systems, Shanghai, China, No. JWKJ-RCYQ201207.
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microRNA and inflammation in colon cancer Author contributions: Fan XM conceived the topic and revised the paper, Zhang L reviewed the literature and wrote the paper.
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The pathological role of microRNAs and inflammation in colon carcinogenesis Lin Zhang , Xiao-Ming Fan ∗ Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, 1508, Longhang road, 201508 Shanghai, China
Summary Evidence of an association between inflammation, microRNAs (miRNAs) and tumorigenesis has emerged in recent years. Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer (CRC) development, suggesting that inflammatory mediators play a causative role in colon carcinogenesis. MiRNAs are small (19—22 nucleotides) non-coding RNA molecules that regulate gene expression at the post-transcriptional level by base-pairing to specific messenger RNAs (mRNAs), promoting their degradation or suppressing translation. MiRNAs can act as inflammatory mediators, oncogenes or tumor suppressors in different cellular environments. MiRNAs also serve as biomarkers and therapeutic targets in CRC. The risk of CRC is also influenced by miRNA polymorphisms and binding sites. Their functions as early diagnostic biomarkers or prognostic classifiers has been demonstrated. Here, we reviewed recent findings on miRNAs and inflammation in colon carcinogenesis and discussed the potential for miRNAs and inflammation-related genes as biomarkers and therapeutic targets in CRC. © 2014 Published by Elsevier Masson SAS.
Introduction Colorectal cancer (CRC) remains an important health problem worldwide. Over 1 million new cases of colon cancer are diagnosed each year and more than 600,000 people die from the disease [1]. In most cases, the occurrence of colorectal cancer is associated with lifestyle and ageing, and only a small number of cases are associated with genetic disorders [2,3]. However, the environmental factors are involved in
∗
Corresponding author. E-mail address: [email protected] (X.-M. Fan).
CRC development and their exact role remains to be elucidated. A link between chronic inflammation and CRC has been suggested by several studies [4,5] and the contribution of gastrointestinal inflammation to the progression of colon cancer has been demonstrated [6]. Anti-inflammatory treatments can reduce colon cancer morbidity. An increased risk of CRC development is observed in patients with long-standing inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease [7,8]. Although patients with IBD account for only a small fraction of CRC cases, they are at the greatest risk for CRC among the general population [6]. Furthermore, non-steroidal anti-inflammatory drugs are considered chemopreventive
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agents and can decrease the risk of CRC [7,8]. Therefore, inflammatory mediators and factors, including cytokines, chemokines, transcription factors, hormones and microRNAs (miRNAs), play crucial roles in the development of colon cancer [5]. MiRNAs are small non-coding RNAs that were discovered in recent years and have shown a promising role in the treatment of immune related diseases [9,10]. By regulating mRNA degradation at the post-transcriptional level, miRNAs can affect signaling pathways and are therefore candidate therapeutic agents. In addition, reliable methods such as quantitative real-time RT-PCR and microarray technologies have been established for the detection of miRNAs [11]. These advances indicate that miRNAs can be potentially used for early diagnosis, prognostic classification and therapeutic decision-making in CRC. The objective of this review is to discuss the role of miRNAs in the development of CRC and suggest possible uses of miRNAs as biomarkers and therapeutic targets.
A link between inflammation, miRNAs and colon carcinogenesis Tumorigenesis in sporadic and colitis-associated cancer CRC is caused by the consecutive accumulation of genetic and epigenetic alterations, driving the initiation and progression of tumor from aberrant crypt foci (ACF) to adenoma and colorectal carcinoma. Fearon and Vogelstein first described this process in a milestone study [12]. Loss of adenomatous polyposis coli (APC), which has 15 exons and encodes a large protein with a molecular weight > 300 kDa, occurs during the initiation of tumorigenesis. Since APC acts as an inhibitor of -catenin, the proteolytic degradation of APC can induce the activation and translocation of -catenin from the cytoplasm to the nucleus [13—15]. Besides APC, mutations in glycogen synthase kinase-3, -catenin itself and other components of the Wnt pathway are found in 10% of colon tumors [16]. Consequently, several additional pathways are involved in the progression from adenoma to carcinoma, including the activation of the oncogenes K-ras and B-Raf, and the inactivation of tumor suppressors such as the TGF- receptor II, p53 and the apoptotic related protein Bax [17—19]. Upregulation of the expression of cyclooxygenase 2 (COX2) is also required for tumor progression [20—22]. In addition, chromosome instability and microsatellite instability (MSI) result in a variety of mutations and are responsible for the aggressiveness of colon cancer [19]. The association of IBD with CRC was first described by Burrill Crohn in 1925 [23]. The process of carcinogenesis in IBD is believed to be similar to that of adenoma-carcinoma transformation in sporadic CRC. However, unlike sporadic CRC, where dysplasia is only presented in one or two focal areas of the colon, dysplastic lesions are usually multifocal in colitis-associated cancer (CAC) [24]. A considerable overlap in the mechanism of pathogenesis exists between CRC and CAC. However, the sequence of molecular events in IBD-related adenocarcinoma differs from that of sporadic CRC in several aspects. For example, inactivation of p53 is
an important early event in CAC development, whereas p53 mutation in sporadic neoplasia usually occurs late in the adenoma-carcinoma transformation [8]. Mutation of APC, which is considered as an early signaling event in sporadic CRC, usually happens late in the sporadic CRC [25]. Recent studies proposed a role for cell senescence in tumor progression, and the p53 and Rb pathways were shown to be involved in these events [26,27]. P53 isoforms expressed during the progression from colon adenoma to carcinoma might act as signaling factors for escaping from the senescence barrier [28]. In UC patients, senescence may also act as a protective factor to prevent the transition from lowgrade to high-grade dysplasia [29]. Chronic inflammation, which is presented in both sporadic CRC and CAC and is characterized by a persistent pro-inflammatory response and tissue destruction, can facilitate tumor progression by promoting the proliferative and anti-apoptotic properties of premalignant cells, as well as tumor progression and metastasis [30]. COX2 and nuclear factor kappa B (NF-B) are two key genes that provide a mechanistic link between inflammation and cancer [31]. Constitutive NF-B activation was observed in 40% of CRC tissues and two thirds of cell lines, and was shown to promote tumor growth [32]. COX2 is normally expressed at low levels in the colonic mucosa, but its expression increases significantly after APC mutation [33]. Popivanova et al. showed that blockade of tumor necrosis factor-␣ (TNF-␣) reduces the formation of colorectal tumors in mice lacking the TNF receptor, p55 (TNF-Rp55 knockout) [34]. Induced expression of TNF-␣ in colon tissues regulates COX2 levels in inflammatory cells. Furthermore, NF-B can be activated by TNF-␣, interleukinL-1 (IL-1) and IL-6 [8,30].
The role of miRNAs in inflammation and colon carcinogenesis Several studies have shown that miRNAs play a role in inflammatory diseases [35—40] including IBD. Wu et al. studied the mucosa of healthy subjects and that of UC patients and found that miR-192 was predominantly expressed in the intestinal epithelial tissues of healthy subjects and significantly downregulated in UC patients [41]. They also found that miR-21 was increased in UC patients compared to healthy subjects. The upregulation of miR-21 expression was confirmed in Crohn’s disease. Furthermore, elevated miR21 level was detected not only at sites of inflammation, including colitis, but also in many types of cancers, including CRC [42], indicating that the upregulation of miR-21 expression may play an important role in inflammation-associated carcinogenesis. MiR-21, the most investigated and welldescribed miRNA, is also known as the ‘‘oncomiR’’ and its clinical potential has been demonstrated [43]. As shown in many studies, miR-21 can promote cell proliferation, inhibit cell death, and enhance invasion and metastasis by interacting with tumor suppressor genes, including phosphatase and tensin homolog (PTEN), programmed cell death 4 (PDCD4), and sprouty 2 (SPRY2) among others [44,45]. Hatley et al. recently showed that miR-21 acted as a negative regulator of the Ras/MEK/ERK pathway, and it was shown to suppress apoptosis in a KRAS-induced lung cancer mouse model [46]. Medina et al. showed that overexpression of miR-21 led to
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microRNA and inflammation in colon cancer the development of pre-B malignant lymphoma, suggesting that miR-21 acts as an oncogene [47]. Consistent with its oncomiR functions, increased expression of miR-21 has been associated with the activity of the epidermal growth factor receptor (EGFR) and KRAS pathways [48]. Oncogenic KRAS can also induce the pro-inflammatory cytokines IL-6 and IL-8 [4]. In addition, miR-21 can be induced by various inflammatory stimuli. Interferon (IFN) and IL-6 induce miR-21 expression via a signal transducer and activator of transcription 3 (STAT3)-dependent pathway [49,50]. In colon cancer, a positive relation between miR-21 and IL6 expression was demonstrated [51]. Iliopoulos et al. proposed a positive-feedback loop involving inflammation and colon cancer [52]. These authors showed that STAT3 induced by IL6 could activate miR-21 and miR-181b-1, leading to NFB activation to sustain the transformed state through the inhibition of PTEN and cylindromatosis (CYLD) expression. Taken together, these findings suggest that miR-21 plays an important role in both IBD and colon cancer. Polycistronic miR-143 and miR-145 on chromosome 5 are downregulated in sporadic colon cancer [53,54]. They can act as tumor suppressors by targeting genes involved in multiple oncogenic pathways, such as KRAS and MYC [53,55]. Pekow et al. showed that miR-143 and miR-145 are downregulated in patients with UC [56]. The let-7 miRNA family is another regulator of KRAS that acts by base-pairing to the 3 untranslated region of KRAS, followed by RAS pathway inhibition and cell growth arrest [44]. Kanaan et al. identified six miRNAs (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, and miR-143) that are upregulated during the progression from non-neoplastic tissues to dysplasia, whereas they are downregulated from dysplasia to cancer. These authors also identified six differentially expressed miRNAs (miR122, miR-214, miR-372, miR-15b, let-7e, miR-17) affected by the TP53 pathway [57]. Strillacci et al. confirmed that miR-101 downregulation is involved in COX2 overexpression in human colon cancer [58]. The oncogenic miR17-92 cluster was shown to modulate c-myc expression in association with colon cancer progression [59], and the miR135 family regulates APC in association with colorectal cancer [60]. Overexpression of miR-155 was found to downregulate the expression of mismatch repair enzymes, including MSH2, MSH6 and MLH1, leading to a mutator phenotype and MSI [61]. In addition, MSH2 expression is negatively regulated by miR-21 [62]. In a recent study, Chen et al. showed that miR-200b was significantly downregulated in the inflamed mucosa of patients with IBD, especially in UC [63]. In their study, Chen et al. suggested that miR-200b could inhibit TGF1-induced epithelial-mesenchymal transition and promote the growth of intestinal epithelial cells. Collectively, miRNAs play important roles in the initiation and progression of CRC (Table 1).
The diagnostic and therapeutic role of miRNAs in IBD
3 examine the effects of consistently dysregulated miRNAs in IBD and their corresponding target genes. The potential clinical use of miR-21, the most investigated and well-described miRNA, has been demonstrated. Overexpression of miR-21 has been reported in many types of human cancer including colorectal cancer. Several studies [41,64,65] have shown that miR-21 is upregulated in inflamed tissues or the serum of IBD patients. Thus, miR21 may serve as a potential biomarker in IBD. Recently, Maharshak et al. showed that miR-132 is upregulated in the inflamed tissues of patients with IBD patients [66], and suggested miR-132 as a novel target for therapeutic interference. Duttagupta et al. proposed platelet-derived miRNA biomarkers for clinical use [67]. Nata et al. showed that miR-146b can improve intestinal inflammation through the upregulation of NF-B, and suggested modulation of the expression of miR-146b as a therapeutic strategy for the treatment of intestinal inflammation [68]. These studies suggest the potential use of miRNAs as biomarkers and diagnostic tools. Although the exact role of miRNAs in IBD remains to be elucidated by functional studies, miRNAs have shown their promise in the treatment of IBD.
MicroRNAs as potential biomarkers for colorectal cancer Circulating miRNAs as early diagnostic biomarkers Early diagnosis can reduce colorectal cancer death by 60% [69]. Screening tests mainly include fecal occult blood testing and colonoscopy [3]. High cost, radiation exposure and invasiveness are the main disadvantages of colonoscopy. The fecal occult blood test is limited by its low sensitivity. Novel non-invasive biomarkers with high sensitivity and specificity are urgently needed for CRC screening in the clinic. MiRNAs are stable and detectable in serum and plasma samples [4] and could therefore be developed as novel non-invasive biomarkers for CRC screening. The oncogenic miR-17-3p and miR-92a, which belong to the miR-17-92 cluster, are upregulated in the plasma of CRC patients [70]. The sensitivity and specificity of these miRNAs to discriminate CRC from control subjects is 89% and 70%, respectively. Reduced plasma levels of miR-17-3p and miR-92a were observed in CRC patients after surgical resection, suggesting that these miRNAs are effective for the detection of CRC recurrence. Huang et al. confirmed the diagnostic value of miR-92a [71], and proposed a second candidate, miR-29a. Circulating miR-221 in plasma was revealed as a potential CRC biomarker [72]. A study that included two independent CRC cohorts proposed that plasma miR-141 could be a prognostic biomarker for advanced CRC [73]. Further studies with large numbers of patients are necessary to confirm the results of these studies.
Prognostic value of miRNAs The involvement of miRNAs in the pathogenesis of IBD makes them promising candidates as biomarkers and therapeutic targets to improve the clinical outcome of patients with IBD. However, the ongoing process of miRNA discovery is associated with several issues. Large cohorts are needed to
Complete surgical removal with adequate margins is the only curative treatment for patients with localized cancer [3]. However, many patients experience CRC recurrence. Postoperative chemotherapy is common as adjuvant treatment
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miRNAs in colon cancer.
Name
Expression
Targets
References
miR-21 miR-181b-1 miR-143 miR-145 miR-101 miR-17-92 miR-155 miR-200b
Overexpressed Overexpressed Downregulated Downregulated Downregulated Oncosuppressor Overexpressed Downregulated
PTEN, PDCD4, SPRY2 CYLD KRAS, MYC, etc. KRAS, MYC, etc. COX2 c-Myc MSH2, MSH6 and MLH1 SMAD2
[43—46] [53] [54,55] [55] [59] [60] [62] [64]
to improve the survival of TNM stage III patients. However, its clinical benefit for stage II patients remains controversial [74]. Therefore, novel prognostic biomarkers capable of identifying CRC patients at high risk of recurrence may help select patients who will benefit from adjuvant chemotherapy. Schetter et al. performed a large-scale analysis of miRNA expression using paired tumor and non-tumor tissues from two independent CRC cohorts. They found five miRNAs (miR21, miR-20a, miR-181b, miR-203 and miR-106a) that were expressed at high levels in tumors associated with poor outcomes in one cohort. The expression of miR-21 was validated in the other cohort and found to be significantly associated with severe cancer-specific mortality after adjustment for other clinical parameters. Increased miR-21 level was also related with poor prognosis in TNM stage II patients. The authors concluded that miR-21 could be a promising prognostic biomarker for early-stage CRC patients [75]. These findings were confirmed by other studies [44]. Therefore, miR-21 is a prognostic factor in different types of cancer and may act as an oncomiR in a broad range of malignancies. A number of miRNAs have been identified as prognostic biomarkers. Decreased levels of miR-320 and miR-498 were associated with poor survival in stage II colon cancer patients [76]. Other studies suggested that increased expression of miR-17, miR-125b, miR-185, miR-200c, and miR-215, and decreased expression of miR-106a and miR-133b were associated with poor prognosis [77—80]. However, these findings are still need to be validated. Compared to a single biomarker, multiple biomarker combinations could be a more accurate prognostic classification strategy. Schetter et al. reported that the combination of miR-21 with the expression of inflammatory-related genes could improve the prognostic prediction of cancer-specific mortality in CRC patients, including those in stage II [51].
Therapeutic outcome prediction value of miRNAs in CRC The efficiency of chemotherapy is often limited by drug resistance and the different genetic backgrounds of patients. Individualized treatment requires accurate biomarkers predictive of therapeutic response. For example, KRAS mutation testing is required before the administration of EGFR targeted therapy [81]. Schetter et al. reported that increased expression of miR-21 is associated with poor therapeutic outcomes in
CRC patients treated with 5-fluorouracil (5-FU) [75]. CRC patients with an MSI phenotype are also resistant to 5-FU [82]. These findings suggest that miR-21 related 5-FU resistance is associated with MSH2, which is involved in the MSI phenotype. The response to therapy can also be affected by singlenucleotide polymorphisms in miRNAs or miRNA-binding sites [4,44]. Zhang et al. identified a let-7 microRNA-binding site polymorphism in the 3 UTR of KRAS that is positively related to anti-EGFR treatment response in patients with metastatic CRC [83]. Single-nucleotide polymorphisms in pri-miR-26a-1 and pri-miR-100 are associated with treatment outcomes in metastatic CRC patients receiving 5-FU and irinotecan [84]. Further investigation is necessary before these discoveries can be translated into the clinic.
Conclusion Increasing attention has been paid to elucidating the role of miRNAs in IBD and CRC. However, further in vivo studies are needed to clarify the role of miRNAs in CRC. In addition, clinical trials are needed to test the therapeutic efficacy of miRNA-based therapies for the management of CRC. Future efforts should be aimed at developing miRNA-based clinical tools for the early detection of CRC and the design of personalized therapeutic strategies. As the most promising candidate miRNA, miR-21 not only plays an important role in the pathogenesis and progression of CRC, but also acts as a CRC biomarker for prognosis and clinical outcome prediction.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements This work was supported by a research grant for key clinical discipline construction of Shanghai Municipality, China, no. ZK2012B20 the Science and Technology Commission of Shanghai Municipality (no. 11ZR1405700) and Phase II Outstanding Young Medical Personnel Training Fund of Jinshan District Health Systems, Shanghai, China, No. JWKJ-RCYQ201207.
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microRNA and inflammation in colon cancer Author contributions: Fan XM conceived the topic and revised the paper, Zhang L reviewed the literature and wrote the paper.
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Please cite this article in press as: Zhang L, Fan X-M. The pathological role of microRNAs and inflammation in colon carcinogenesis. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.06.013
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