Cancer Letters 344 (2014) 147–156

Contents lists available at ScienceDirect

Cancer Letters journal homepage: www.elsevier.com/locate/canlet

Mini-review

Small molecule with big role: MicroRNAs in cancer metastatic microenvironments Yinghan Su a, Xiaoya Li b, Weidan Ji b, Bin Sun b, Can Xu c, Zhaoshen Li c, Guojun Qian d,⇑, Changqing Su b,⇑ a

Department of Biology, Xi’an Jiaotong-Liverpool University, Suzhou 215123, China Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China c Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China d Department of Minimal Invasion Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai 200438, China b

a r t i c l e

i n f o

Article history: Received 25 August 2013 Received in revised form 22 October 2013 Accepted 24 October 2013

Keywords: MicroRNA Cancer metastasis Microenvironment Oncosuppressor gene Oncogene

a b s t r a c t Cancer metastasis is closely related to tumor cell microenvironments. Cancer cells and stromal cells interact with one another through extracellular matrix (ECM) and jointly participate in establishing the microenvironments. However, many questions remain to be addressed, in particular, a crucial question is which messengers mediate the mutual interaction and regulation between cancer cells and stromal cells. MicroRNAs (miRNAs), as oncogenic and oncosuppressor genes, regulate the expression and function of their related target genes to affect the biological behaviors of cancer cells and stromal cells, which may play an important role in cancer metastasis. Many miRNAs associated with cancer metastasis have been identified. The molecules of miRNAs are small and relatively easy to be secreted into extracellular microenvironments and devoured by nearby cells. As the regulatory messengers between cells, the secreted miRNAs function to regulate cancer cell proliferation, migration, intercellular communication and stromal modification, thereby helping cancer cells to establish their microenvironments for metastasis. In conclusion, miRNAs are small molecules, but they play a powerful role in regulating cancer metastatic ability by construction and modification of microenvironments. Ó 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Tumor metastasis is a major factor influencing the prognosis of cancer patients. The happening of tumor metastasis is not only related to the augmented invasive and diminished adhesive capability of cancer cells, but also closely associated with a variety of microenvironment changes, such as angiogenesis, matrix degradation, and stroma remodeling [1]. During the process of metastasis, cancer cells can induce stroma perturbation; conversely, cancer stroma also affects the biological characters of cancer cells. Cancer cells and stromal cells have interaction with one another through extracellular matrix (ECM) to establish microenvironments which are available for cancer metastasis [2]. However, questions remain to be addressed with respect to the underlying mechanisms of cancer cell invasion and metastasis; in particular, a crucial question is which messengers mediate the mutual interaction and regulation between cancer cells and stromal cells. The factors and mechanisms involved in the regulation of cancer metastatic microenvironments are extremely complicated. MicroRNAs (miRNAs) are a kind of non-coding RNA micromolecules of 21–23 nucleotides in length and widespread in the animal ⇑ Corresponding authors. Tel./fax: +86 2181875351. E-mail addresses: [email protected] (G. Qian), [email protected] (C. Su). 0304-3835/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canlet.2013.10.024

and plant cells, which can regulate massive transcriptomes and therefore is essential to the regulation of gene expression and post-transcriptional modifications. miRNAs take part in a series of important cellular events, including embryonic development, cell proliferation and differentiation, cell death and apoptosis, and in vivo biochemical metabolism [3–6]. The processing and expressing of miRNAs go through 3 steps, the transcription of longer primary transcripts (pri-miRNAs, several hundred base pairs in length) in cellular nucleus, cropped by the microprocessor complex (Drosha and Pasha/DGCR8) into short hairpin precursor miRNAs (pre-miRNAs, 60–70 base pairs), finally transported into cytoplasm where they are cleaved by RNAse Dicer to generate mature miRNAs [7]. The mature miRNAs are incorporated into the RNA-induced silencing complex (RISC) and bind to the target mRNAs to result in their degradation or translational repression. MiRNAs, as proto-oncogenes and oncosuppressor genes, regulate the expression and function of their related target genes to affect the functional status of cancer cells, stromal cells and microenvironment, which may play a significant role in cancer metastasis [8,9]. It has been established that miRNAs are closely related with cancer occurrence, development, invasion and metastasis In particular, miRNA abnormalities are widely involved in a plethora of pathophysiological processes of cancer, including cell proliferation, differentiation, metabolism, and apoptosis of cancer

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cells [10–14]. All of these processes are closely related with cancer metastatic capability, and the establishment and modification of cancer microenvironments play an important role in cancer metastasis [10]. Some miRNAs share a common or similar seed region sequence and are predicted to target largely overlapping sets of genes, and they are concluded a family. For example, miR-34 family, which comprises three processed miRNAs (miR34a/b/c), is identified as the mediator of tumor suppression by p53, and contribute to the inhibition of invasion or metastasis in various tumor types [15]. This review will focus on the recent research on the miRNAs in regulating the cancer metastatic microenvironments. 2. Construction of cancer metastatic microenvironment Tumor metastasis refers to a series of events by which cancer cells detach from the primary sites, and subsequently migrate toward the surrounding and distant sites for growth and formation into new lesions, which is an important biological characteristic of malignant tumor and a crucial factor led to tumor recurrence and poor prognosis of cancer patients. Metastasis of tumor is a multi-factor regulated, multi-step, multi-stage, continuous and complex biological process [16]. From the cancer cell proliferation and shedding, penetration through basement membrane into stroma, blood, lymphatic system, and migration into target organs, a variety of parameters regulate the cascade of events in the metastatic processes. Importantly, the microenvironment where cancer cells encounter plays a nonnegligible role in tumor metastatic regulation. During the process of cancer metastasis, cancer cells and stromal cells interact through releasing messenger molecule into ECM [17]. Stromal cells can be recruited and activated by cancer cells. These recruited and modified stromal cells are known as cancer-associated stromal cells (CSCs) [18,19]. CSCs are the most important component of the microenvironment for tumor metastasis, which can excessively secrete cell growth factors, such as the epidermal growth factor (EGF), transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). These growth factors can damage the equilibrium of ECM synthesis and degradation and induce the formation of tumor microvessels. At the same time, those also can affect the biological traits of cancer cells to promote their motility, tropism, and invasiveness. The mutual interaction between cancer cells and stromal cells enable these two types of cells to jointly establish the microenvironment conducive to cancer cell adhesion, growth and formation into new lesions, which accelerates tumor cell invasion and metastasis [20,21]. 3. Impact of miRNAs on cancer cell metastasis 3.1. miRNAs as oncogenic miRNAs (OncomiRs) and oncosuppressors In different kinds of human cancer miRNAs expression profile, high expression of specific miRNAs are found in breast cancer, hepatocellular carcinoma (HCC), lung cancer, colorectal cancer, brain cancer, leukemia and other tumors, these miRNAs are regarded as a type of oncogenes. High expression of miR-155 in chronic lymphocytic leukemia, Hodgkin’s lymphoma and B-cell lymphoma, breast cancer, lung cancer, colon cancer and thyroid carcinoma may indicate that the patients with these diseases are difficult to alleviate after treatment [22–25]. High expression of miR-17-92 cluster (miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19-1, miR-92-1) can be used as a biomarker for prognosis in multiple myeloma patients [26], and can promote the malignant development of B-cell lymphoma [27]. In addition,

downregulation or absence of some miRNAs expression in tumor cells may also lead to carcinogenesis and progression, this kind of miRNAs can be regarded as oncosuppressor genes. For example, downregulated expression of let-7 is associated with tumorigenesis of gastric or lung cancer [28,29], and downregulated expression of miR-15 and miR-16 is associated with chronic lymphocytic leukemia [30]. Low expression of miR-26a, miR-129, miR-143 and miR-145 occurs in breast cancer, prostate cancer, cervical cancer, lymphocytic malignancy and colorectal cancer [31,32], which might enhance cancer stem cell characteristics and promote cancer cell proliferation and migration [33,34]. Moreover, decreased miR122 expression may mediate the carcinogenesis process of primary HCC [35,36]. The miR-34 family, including miR-34a, miR-34b and miR-34c, exhibits abnormal low expression in breast cancer and malignant melanoma, these changes in the expression level of miR-34 family endow cancer cells with high capacity of invasion and metastasis [15,37]. The elevated expression of oncogenic miRNAs and/or the decreased expression of oncosuppressor miRNAs can promote cancer cell proliferation, invasion, and metastasis, which cause cancer cells to exhibit more malignant biological features (Fig. 1) [38,39]. 3.2. miRNAs associated with cancer metastasis Metastasis is a significant biological property of malignant tumors, and miRNAs are widely involved in regulation of gene expression in the process of tumor metastasis. The complementary binding of miRNAs to the genes associated with invasion and metastasis of cancer cells silences gene expression, leads to changes in metastatic activities of cancer cells. In lung, prostate, nasopharyngeal, liver and breast cancers, a large amount of miRNAs associated with metastasis have been identified (Table 1). The upregulation of miR-223 expression and the downregulation of miR-9 expression have been observed in recurrence and metastatic patients of ovarian cancer, both of these two miRNAs may serve as potential molecular markers of ovarian cancer recurrence and metastasis [40]. In breast cancer cell lines with high metastasis ability, the expression of miR-29b, miR-126, miR-206 and miR335 is reduced significantly, and the enhancement expression of miR-126 and miR-335 by retrovirus can inhibit the movement ability of cancer cells and reduce the metastatic activity of cancer cells [41,42]. Through the comparison of miRNAs expression profile in invasive and noninvasive HCC, it was found that 20 miRNAs are associated with cancer metastasis, postoperative recurrence, and patient survival, among which the expression of miR-185, miR-219-1, miR-207 and miR-338 is upregulated, while the expression of let-7g, miR-1-2, miR-122, miR-124a-2, miR-125b2, miR-126, miR-148a, miR-148b, miR-15a, miR-194, miR-19a, miR-30a, miR-30c-1, miR-30e, miR-34a and miR-9-2 is downregulated [43]. 3.3. Molecular mechanisms of miRNAs in the regulation of cancer metastasis Many studies have investigated the molecular mechanisms by which miRNAs regulate the metastatic phenotypes of tumor cells. Some miRNAs regulate the expression of pro-metastatic genes or metastatic suppressor genes to determine the potential of the tumor invasion and metastasis. For example, miR-31 inhibits the migration of MDA-MB-231 breast cancer cells by downregulating the expression of tumor metastatic gene RhoA [44], whereas miR-182 enhances the invasive and metastatic capacity of melanoma cells by decreasing the expression of tumor metastatic suppressor genes, forkhead box O3 (FOXO3) and microphthalmia-associated transcription factor (MITF) [14]. Some other miRNAs regulate the expression of oncogenes and tumor suppressor

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Fig. 1. Expression and function of miRNAs in cancer. In majority of human cancers, miRNA activation and inactivation are frequent molecular events. Upregulation of oncogenic miRNAs (OncomiRs), generally activated by amplification and translocation of oncogenic miRNA genes, reduces the expression of oncosuppressor proteins. Whereas, downregulation of oncosuppressor miRNAs, usually inactivated by homozygous deletion, mutation, promoter methylation and abnormal processing of oncosuppressor miRNA genes, induces an increased production of oncogenic proteins. Both of these two alterations in expression of miRNAs promote cancer development through miRNA post-transcriptional regulation of oncogenes or/and oncosuppressor genes that finally function on cancer hallmarks. The symbol ‘’ represents the promotion effect, and ‘ ’ the suppression effect.

genes to influence the activity of cancer metastasis. The regulation of p53 on miR-34 family (miR-34a/b/c) implements a suppression effect on the expression of multiple proto-oncogenes or cytokine genes, such as E2F transcription factor 3 (E2F3), B-cell CLL/lymphoma 2 (Bcl-2), c-myc, cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, and cyclin E2, and forms a positive feedback loop through E2F3 and sirtuin 1 (SIRT1) with p53, which could strengthen the function of themselves and p53, prevent the cancer cell growth, migration and invasion [39,45,46]. MiR-21 can reduce the expression level of tumor suppressor gene phosphatase and tensin homolog (PTEN) and enhance the invasive capability of HCC cells [47,48]. Recent study also showed that miR-21 not only inhibits the expression of PTEN, but also inhibits the expression and function of human sulfatase 1 (hSulf-1), which can increase the AKT/ERK activity, then enhancing the capacity of HCC cancer cell proliferation, invasion and migration, and promoting tumor growth and metastasis [49]. In cancer cells, changes in adhesive properties are closely related to invasion and metastasis. Declining in cancer cell homogeneous adhesion can promote the detachment of cells from their primary sites, whereas increased heterogeneous adhesion between cancer cells and vascular endothelial cells or the ECM is conducive to cancer cell attachment and colonization at new sites. Certain miRNAs regulate the expression of adhesion-related molecules to change the adhesive and invasive capability of cancer cells, thereby modulating cellular metastatic phenotypes. MiR-200c can inhibit the transcription of zinc finger E-box binding homeobox 1 (ZEB1; also known as TCF8) in A549 lung cancer cells, which increases the expression of TCF8-regulated expression of E-cadherin and enhances the homogeneous adhesion capability among cancer cells, thus inhibiting cancer cell invasion and metastasis [50]. Integrin b3 mediates the heterogeneous adhesion between melanoma cells and the ECM, let-7a can reduce the expression of integrin b3 and

decrease the survival ability of melanoma cells during invasion and metastasis [51]. Epithelial–mesenchymal transition (EMT) is a transforming process of epithelial phenotype to mesenchymal cellular phenotype. EMT is an early step during cancer cell invasion and metastasis, which is characterized by a disassembly of cellular junctions, loss of epithelial polarity, reorganization of cytoskeleton (actin), decrease of epithelial marker expression, and increase of mesenchymal marker expression. Cancer cells undergoing EMT can resist anoikis and acquire stronger capability of invasion and metastasis. There are lots of miRNAs have been found to participate in the EMT process [52–54]. Members of the miR-200 family (miR-200a, miR200b, miR-200c, miR-141 and miR-429) and miR-205 can reduce the expression of ZEB transcription factor proteins that are the downstream molecules in the epidermal growth factor receptor (EGFR) pathway, induce E-cadherin expression and thus inhibit EMT in cancer cells [55–57]. In a variety of cancers occurred EMT, such as breast, colorectal and lung cancers, the expression of miR-200 family members and miR-205 is decreased [58–60]. In ovarian cancer, miR-23b, miR-203 and miR-29e can also inhibit EMT of tumor cells [61]. By contrast, miR-21 activates the transcription factors, such as activator protein-1 (AP-1) and ZEB1 in the downstream of TGF-b signaling pathway, and promotes cancer cell EMT. In addition, through regulating the genes related to cell cycle and cell apoptosis (e.g., TGF-fl receptor type II (TGFfl RII), programmed cell death 4 (PDCD4), cell division cycle 25A (Cdc25A), and PTEN), miR-21 can also influence the capability of cancer cells in invasion, metastasis and anti-apoptosis [62,63]. In SUM149 breast cancer cell line, miR-9 can increase the expression of mesenchymal cell-originated markers (such as Vimentin), reduce the expression of epithelium-originated markers (such as E-cadherin), confirming the EMT phenotypic transformation happened in cancer cells [64]. EMT is a reversible process, once the cancer cells stop

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Table 1 miRNAs involvement in cancer metastasis. Cancer types

Effect on metastasis

miRNAs

References

Breast

Promote

miR-9; miR-10b; miR-17-92; miR-21; miR-27b; miR-29a; miR-103/107; miR-155; miR-210; miR-373/520c; miR378 miR-7; miR-17/20; miR-22; miR-29b; miR-30; miR-31; miR-34a; miR-126; miR-145; miR-146a/b; miR-183; miR193b; miR-205; miR-206; miR-335; miR-339-5p; let-7

[98–108]

Suppress

[109–125]

Colorectal

Promote Suppress

miR-17-92; miR-21; miR-31/196a/373 miR-9; miR-34a; miR-200b/c; miR-126/141/143/195/215/451; let-7

[126–128] [128–132]

Esophageal

Promote Suppress

miR-10b; miR-21 miR-103/130b

[133,134] [135]

Gastric

Promote Suppress

miR-10b; miR-21; miR-27a; miR-107; miR-223 miR-126; miR-146a/b; miR-218; miR-335; let-7

[136–140] [141–145]

Glioblastoma

Promote

miR-9; miR-10b; miR-21; miR-378

Suppress

miR-7; miR-146a/b; miR-205

[108,146– 148] [149–151]

Promote

miR-9; miR-10b; miR-21; miR-30d; miR-143; miR-151-5p

Suppress

miR-23; miR-29b; miR-34a; miR-122; miR-125b; miR-139; miR-194; miR-338; let-7

HNSCCa

Promote Suppress

miR-21 miR-130b; miR-138; miR-204

[165] [166–168]

Lung

Promote Suppress

miR-21; miR-135b miR-126; miR-183; miR-205; miR-206

[169,170] [151,171– 173]

Melanoma

Promote

miR-30b/30d; miR-182; miR-199a-3p/5p; miR-211; miR-214; miR-532; miR-1908

Hepatocellular

[49,152– 156] [45,157– 164]

Suppress

miR-34a/b/c; miR-145; miR-200c

[14,174– 179] [15,180,181]

Nasopharyngeal

Promote Suppress

miR-10b miR-29c

[182] [183]

Ovarian

Promote Suppress

miR-10b; miR-21; miR-223 miR-9; miR-22

[39,184,185] [186,187]

Pancreatic

Promote Suppress

miR-10a; miR-21; miR-224/486 miR-146a/b

[188–190] [191]

Prostate

Promote Suppress

miR-21; miR-125b; miR-183 miR-16; miR-29b; miR-34a; miR-146a/b; miR-221

[192–194] [195–199]

Renal

Promote Suppress

miR-21; miR-210; miR-1260b miR-106b; miR-135a; miR-204; miR-218

[200–202] [203–206]

Note: a HNSCC, head and neck squamous cell carcinoma.

at new metastatic site, E-cadherin is reactivated to express, which leads to cellular mesenchymal–epithelial transition (MET) and restoration of the epithelial phenotype. 4. Function of miRNAs in the construction of cancer microenvironment 4.1. Secretion and transportation of miRNAs Studies have shown that the existence of miRNAs are found not only in cells but also in serum, plasma, saliva, milk, and tears [65– 68]. Even the miRNAs in plants can go through the way of daily food intake into human blood, tissues and organs [68]. Human blood, lymphatic and tissue fluid constitute the liquid environment for cell survival. The continuous exchange of materials and information occurs not only between different liquid environments but also between cells and their surrounding liquids. In human environments, miRNAs can move with the circulatory system into the blood and tissue fluid, and are subsequently transported to their corresponding target organs to participate in the regulation of physiological and pathological processes [69,70]. MiRNAs are secreted into the cellular microenvironment by fission or budding of cell membrane [71]. In the ECM, miRNAs mainly

exist in two forms, 90% of miRNAs are bound to proteins, 10% of miRNAs reside in microvesicles (MVs) or apoptotic bodies [72– 75]. The MVs, apoptotic bodies and other miRNA carriers secreted by various cells migrate to neighboring or distant target cells. By means of the cell-originated membranous structure of carriers, miRNAs may enter the target cells via endocytosis, direct membrane fusion or binding to specific receptors on target cell membrane, and function to regulate gene expression inside the target cells and express the biological effect [76–79]. Cancer cells can change and maintain the microenvironments by autocrine and paracrine of miRNAs for cell survival and development. The secreted miRNAs in the microenvironments function to regulate cancer cell proliferation, migration, intercellular communication and stromal angiogenesis, thereby promoting tumor growth and progression [71,74]. Compared with other biological macromolecules, miRNAs are small and relatively easy to be secreted into extracellular environment, and the miRNAs which are secreted into the ECM exhibit stable function and structure, are easy to be devoured by nearby cells, and induce biological effect similar to those of endogenous miRNAs by silencing target genes [69,80]. In a prostate cancer xenograft model in nude mice, the administration of subcutaneous injections of MVs containing miR-16 allowed miR-16 to enter cancer cells and inhibit the expression of Bcl-2 [81]. The MVs rich in

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miR-21 released by glioma cells can be absorbed by cerebral microvascular endothelial cells [79]. Therefore, miRNA-based posttranscriptional regulation is a very important mechanism by which cancer cells modify their microenvironments.

4.2. miRNAs-mediated interactions between cancer cells and CSCs Cancer cells facilitate their own survival and metastasis by constantly transforming and adapting to their microenvironments. CSCs in the carcinoma stroma are an important part of these microenvironments that are associated with tumor growth, invasion, and metastasis [1,82,83]. Abnormality of gene expression and changes of biological behaviors, happened in CSCs due to the information exchange between CSCs and cancer cells, can affect the metastasis of tumors [84]. In the process of interaction between cancer cells and CSCs, gene mutation is a low-probability event, instead, cancer cells secrete abundant miRNAs that are ubiquitous in the local microenvironment, and these miRNAs are the main factors causing the abnormal gene expression of CSCs [85]. These miRNAs mainly affect the stromal cells, tumor cells and the ECM components for cancer cells to build the microenvironments, thereby influence the tumor invasion and metastasis. Studies found that miR-148a expression is downregulated not only in a wide variety of tumor cells but also in most tumor stromal cells, which is an important marker of tumor metastasis, and its silenced expression in stromal cells is considered to be caused by tumor cells [86,87]. Furthermore, abnomal content of miRNAs in colorectal cancer microenvironment can induce the secretion of cytokines by CSCs into microenvironment, these cytokines promote cancer cell proliferation and metastasis in turn [88]. Similar to the ways by which miRNAs secreted by cancer cells can affect CSCs, CSCs can also secrete miRNAs to affect cancer cells and participate in the microenvironment modification and construction. High expression of miR-221/222 in vascular endothelial cells can promote the proliferation and migration of endothelial cells, directly providing nutritional support for the invasion and metastasis of cancer cells. MiR-122 can also stimulate the synthesis of a large amount of metalloproteinases to degrade the ECM, and the reduction of miR-122 and miR-26a expression is conducive to the activation of hepatic stellate cells (HSCs) [89].

4.3. miRNAs-mediated changes in the ECM function The ECM is a key factor in the regulation of tumor invasion and metastasis. In the ECM, the increase of matrix metalloproteinases (MMPs) and the decrease of tissue inhibitors of MMPs (TIMPs) play significant roles in not only ECM architecture but also tumor invasion and metastasis. In glioma, cholangiocarcinoma and thymic carcinoma, miR-21 expression is enhanced, which targets the inhibitors of MMPs, RECK (reversion-inducing-cysteine-rich protein with Kazal motifs) and TIMP3 (tissue inhibitor of metalloproteinases-3). The downregulation of RECK and TIMP3 controlled by miR-21 increases the activity of MMPs, which enhances the invasive and metastatic capacity of tumor cells [90–93]. In nasopharyngeal carcinomas, the lower miR-29c levels correlated with higher levels of multiple target mRNAs, and most of which were identified to encode extracellular matrix proteins, including multiple collagens and laminin gamma1, that are associated with tumor cell invasiveness and metastatic potential [94]. Although these miRNAs are not secreted to the outside of the cells, the downregulation of their expression can cause intracellular changes in the synthesis and secretion of ECM components. They also can adjust the microenvironment and affect the invasive and metastatic capability of cancer cells.

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5. miRNAs-targeted cancer diagnosis and treatment The differences of miRNA expression profiles between tumor cells and their corresponding normal cells, as well as the specificity of miRNA expression in different tumors, provide valuable indicators for diagnosis and identification of tumors. The secreted miRNAs in blood and other body fluids can resist the digestion of RNase and are highly stable, which makes it possible for the use of blood and body fluid samples to detect specific miRNAs as tumor biological markers. Since the kinds of miRNAs expressed by cells are variable and multiple, single miRNA has little value for tumor diagnosis, and combination of multiple tumor-specific miRNAs that constitutes a miRNA specific expression group may have a great significance in tumor diagnosis. Through examinations of miRNA expression profiles in colon carcinoma, HCC, pancreatic cancer and gastric cancer samples, it is found that the miRNA expression profiles are able to differentiate the benign and malignant cells, or recognize the tumor cells with different differentiation degrees, demonstrating that the miRNA expression profiles are possible to use in cancer diagnosis [95]. Since miRNAs play roles as oncogenes or oncosuppressor genes in cancer occurrence, development, metastasis and recurrence processes, it is feasible to treat cancer by regulating the expression of miRNAs. The miRNAs that are expressed at low levels in cancer cells have functions of tumor suppressor genes, and these miRNAs can be exogenously introduced into cancer cells via vectors to inhibit tumor growth. For example, let-7 was introduced by lentiviral vector into human breast cancer stem cells and significantly reduced not only the ability of cell self-renewal and proliferation in vitro, but also the tumorigenicity and metastatic potential of cells [96]. The miRNAs that are highly expressed in cancer cells have oncogenic functions, and these miRNAs can be downregulated by using antisense oligonucleotides or specific inhibitors to restrain tumor growth. For example, miR-21 is overexpressed in HCC cells, and inhibition of miR-21 expression can suppress the migration and invasion of cancer cells [49]. MiRNAs also can be used as a response indicator for cancer treatment. Low expression of miR-26 plays a key role in hepatitis B virus-related HCC. HCC patients with low expression level of miR-26 could be increased the 5-year survival rate from 30% to 65% after interferon treatment, but this treatment did not significantly improve survival in the patients with high expression of miR-26. Therefore, the miR-26 expression status can be adopted as a screening indicator for determining whether a HCC patient may be successfully treated using interferon therapy [97]. Similar to the use of miRNAs for tumor diagnosis, the intervention of single miRNA expression will produce limited effect in tumor inhibition, whereas the combined intervention of multiple miRNAs has the potential to be significantly more effective.

6. Conclusions During the induction and modification processes of cancer cells on stromal cells, these two cell populations interact with one another and jointly participate in establishing the microenvironments for cancer invasion and metastasis. Many target genes are regulated by a single miRNA, and a single gene may also be controlled by a variety of miRNAs. Compared with normal cells, there are miRNAs expressed differentially in cancer cells and exhibited tremendous diversity and complexity. Construction of cancer metastatic microenvironment is inevitably involved in lots of miRNA molecules that regulate a wide range of target genes and signaling pathways. Many kinds of miRNAs jointly induce more obvious changes in genetic characteristics and biological properties of tumor cells and stromal cells, which help cancer cells to effectively

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modify their microenvironments. The molecular weight of miRNAs is small, but their impact is broad and powerful. Therefore, further study into the regulation functions of miRNAs in constructing cancer metastatic microenvironments would prove helpful for elucidating the molecular mechanisms of cancer metastasis. The findings may provide a basis for screening molecular targets and accordingly establishing targeted intervention strategies for cancer patients. 7. Conflict of Interest The authors declare that they have no conflict of interest. Acknowledgments This work was supported by grants from the Plan Project of Shanghai Outstanding Academic Leaders (13XD1400300), the National Significant Science and Technology Special Projects of New Drugs Creation (2014ZX09101003), and the National Natural Science Foundation of China (81370552 to C. Su, 81372673 to C. Xu). References [1] S. Koontongkaew, The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas, J. Cancer 4 (2013) 66–83. [2] M.L. Taddei, E. Giannoni, G. Comito, P. Chiarugi, Microenvironment and tumor cell plasticity: an easy way out, Cancer Lett. (2013), http://dx.doi.org/ 10.1016/j.canlet.2013.01.042. [3] P. Olson, J. Lu, H. Zhang, A. Shai, M.G. Chun, Y. Wang, S.K. Libutti, E.K. Nakakura, T.R. Golub, D. Hanahan, MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer, Genes Dev. 23 (2009) 2152–2165. [4] L.M. Tsai, D. Yu, MicroRNAs in common diseases and potential therapeutic applications, Clin. Exp. Pharmacol. Physiol. 37 (2010) 102–107. [5] C.H. Lin, A.L. Jackson, J. Guo, P.S. Linsley, R.N. Eisenman, Myc-regulated microRNAs attenuate embryonic stem cell differentiation, EMBO J. 28 (2009) 3157–3170. [6] R.A. Nimmo, F.J. Slack, An elegant miRror: microRNAs in stem cells, developmental timing and cancer, Chromosoma 118 (2009) 405–418. [7] A. Aigner, MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs, J. Mol. Med. (Berl.) 89 (2011) 445–457. [8] J. Chou, Z. Werb, MicroRNAs play a big role in regulating ovarian cancerassociated fibroblasts and the tumor microenvironment, Cancer Discov. 2 (2012) 1078–1080. [9] S.A. Melo, R. Kalluri, MiR-29b moulds the tumour microenvironment to repress metastasis, Nat. Cell Biol. 15 (2013) 139–140. [10] J. Chou, P. Shahi, Z. Werb, MicroRNA-mediated regulation of the tumor microenvironment, Cell Cycle 12 (2013) 1–9. [11] R. Garzon, G.A. Calin, C.M. Croce, MicroRNAs in cancer, Annu. Rev. Med. 60 (2009) 167–179. [12] M. Negrini, M.S. Nicoloso, G.A. Calin, MicroRNAs and cancer – new paradigms in molecular oncology, Curr. Opin. Cell Biol. 21 (2009) 470–479. [13] G. Sotiropoulou, G. Pampalakis, E. Lianidou, Z. Mourelatos, Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell, RNA 15 (2009) 1443–1461. [14] M.F. Segura, D. Hanniford, S. Menendez, L. Reavie, X. Zou, S. Alvarez-Diaz, J. Zakrzewski, E. Blochin, A. Rose, D. Bogunovic, D. Polsky, J. Wei, P. Lee, I. Belitskaya-Levy, N. Bhardwaj, I. Osman, E. Hernando, Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor, Proc. Natl. Acad. Sci. USA 106 (2009) 1814–1819. [15] H. Yamazaki, T. Chijiwa, Y. Inoue, Y. Abe, H. Suemizu, K. Kawai, M. Wakui, D. Furukawa, M. Mukai, S. Kuwao, M. Saegusa, M. Nakamura, Overexpression of the miR-34 family suppresses invasive growth of malignant melanoma with the wild-type p53 gene, Exp. Ther. Med. 3 (2012) 793–796. [16] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) 646–674. [17] J.D. Yang, I. Nakamura, L.R. Roberts, The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets, Semin. Cancer Biol. 21 (2011) 35–43. [18] B. Bozoky, A. Savchenko, P. Csermely, T. Korcsmaros, Z. Dul, F. Ponten, L. Szekely, G. Klein, Novel signatures of cancer-associated fibroblasts, Int. J. Cancer 133 (2013) 286–293. [19] T. Hasebe, Tumor–stromal interactions in breast tumor progression– significance of histological heterogeneity of tumor–stromal fibroblasts, Expert Opin. Ther. Targets 17 (2013) 449–460.

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