miRNA control of tumor cell invasion and metastasis

Abstract

MicroRNAs have emerged as a novel class of noncoding RNAs that regulate gene expression at the post-translational level in almost every biological event. A large body of evidence indicates that microRNAs regulate the expression of different genes that play an important role in cancer cell invasion, migration and metastasis. In this review, we briefly describe the role of various miRNAs in invasion, migration and metastasis which are essential steps during cancer progression.

Figure 1. Schematic illustration of role of miRNAs in regulation of tumor cell invasion and migration

miR-21 is upregulated in cancer, and represses the expression of various tumor suppressor proteins such as PDCD4, TIMP1, MARCK5, BMD6, RACK, TIMP3 and PTEN. Also, miR-21 upregulates the expression of HER2, MMP2 and MMP9. MiR-205 is downregulated in several cancers, and it represses kinases such as ErbB3, VEGF and PKC epsilon. miR-146b modulates MMP16 in glioblastoma migration. miR-1 is downregulated in lung cancer, and targets of miR-1 are MET, Pim-1 and FoxP1. Ezrin is a target for miR-183 and Crk is a target for miR-126. miR-182 is upregulated in melanoma, and it promotes migration through its effects on Factor-M and FOXO-3. miR-29c is downregulated in nasopharyngeal carcinoma, and it regulates the expression of collagen and laminin. Arrows in the upper part of the figure represents upregulation (↑) and downregulation (↓) of respective miRNAs in cancer. Also shown in the lower part of the figure are the targets of those miRNAs which are either repressed (shown by reverse T) or upregulated (↓).

Figure 2. Role of miRNAs in metastasis

(A) EMT regulation by miRNAs: miRNAs such as miR-200 and miR-205, modulate the ZEB family of transcription factors and regulate epithelial-mesenchymal transition. miR-101 modulates E-cadherin expression epigenetically via targeting Zeste Homolog 2 (EZH2) in prostate cancer. miR-155 modulates TGFβ pathway, which plays an important role in cancer metastasis. (B) Suppression of metastasis by miRNAs:. miR-10b is the first miRNA identified to be upregulated in breast cancer that is mediated by Twist1, MMPs, urokinase plasminogen activator(uPA), and various integrins. miR-373 and miR-520c are pro-metastatic miRNAs that serve as metastasis promoters (partly mediated by modulation of CD44). miR-335, miR-206 and miR-31 are identified as antimetastatic miRNAs that target RhoA, Fzd3, RDX, and integrin α₅. miR-146 and miR-98/let-7 are shown to be upregulated in response to metastatic suppressor proteins BRMS-1 and RKIP respectively. miR-10b, miR-373, miR-520c and miR-21 are pro-metastatic miRNAs, while miRNAs such as miR-335, miR-206 and miR-31 are anti-metastatic. Prometastatic miRNAs are depicted pink, dark green and red, while anti-metastatic ones are shown in violet, red and light green.