Tumor suppressive microRNA-133a regulates novel molecular networks in lung squamous cell carcinoma

Abstract

Analysis of the microRNA (miRNA) expression signature of lung squamous cell carcinoma (lung-SCC) revealed that the expression levels of miR-133a were significantly reduced in cancer tissues compared with normal tissues. In this study, we focused on the functional significance of miR-133a in cancer cell lines derived from lung-SCC and the identification of miR133a-regulated novel cancer networks in lung-SCC. Restoration of miR-133a expression in PC10 and H157 cell lines resulted in significant inhibition of cell proliferation, suggesting that miR-133a functions as a tumor suppressor. We used genome-wide gene expression analysis to identify the molecular targets of miR-133a regulation. Gene expression data and web-based searching revealed several candidate genes, including transgelin 2 (TAGLN2), actin-related protein2/3 complex, subunit 5, 16kDa (ARPC5), LAG1 homolog, ceramide synthase 2 (LASS2) and glutathione S-transferase pi 1 (GSTP1). ARPC5 and GSTP1 likely represent bona fide targets as their expression is elevated in lung-SCC clinical specimens. Furthermore, transient transfection of miR-133a, repressed ARPC5 and GSTP1 mRNA and protein levels. As cell proliferation was significantly inhibited in lung-SCC cells following RNAi knock down of either gene, ARPC5 and GSTP1 may function as oncogenes in the development of lung-SCC. The identification of a tumor suppressive miRNA and the novel cancer pathways it regulates could provide new insights into potential molecular mechanisms of lung-SCC carcinogenesis.

Identification and characterization of tumor suppressor and oncogenic miRNAs in gastric cancer

“…However, a more recent study demonstrated that miR-133 is aberrantly expressed in tumors, and that miR-133a/b can inhibit the proliferation, and metastasis of bladder and prostate cancer by regulating the expression of the epidermal growth factor receptor (20,21). In addition, previous studies have observed a significant downregulation of miR-133a/b in head and neck neoplasms, lung cancer, esophageal cancer, colon cancer, renal carcinoma, prostate cancer, and other malignancies (22)(23)(24)(25). The present study indicated that miR-133b may act as a tumor suppressor while regulating the invasion and metastasis of cancer cells.…”

Key Role of MicroRNA in the Regulation of Granulocyte Macrophage Colony-stimulating Factor Expression in Murine Alveolar Epithelial Cells during Oxidative Stress

“…A recent report concerning non-small cell lung cancer describes a relationship between the tumor stage and expression of miR133b (49,50). Acting through effects on epidermal growth factor receptor, miR133b appears to limit proliferation and invasion of cancer cells.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…In HNSCC cells both miR133a/133b target moesin specifically, and restoration of miR-133b levels in HNSCC cells, as well as in PC10 and H157 lung SCC cell lines, reduces moesin expression, inhibits cell proliferation, cell migration and invasion [143] . The phenotype is also associated with elevation of other miR133 targets such as ARPC5 and GSTP1 [115] . Both ARPC5 and GSTP1 levels are elevated in lungSCC and elevated GSTP1 is seen in bladder cancer (TCC) associated with reduced levels of miR133a [144] .…”

“…Muscle microRNAs in development and disease [102,106] , metastatic lung tumors [107] , proliferating breast cancer [108] , ERαpositive breast cancer [109] , EEC [110] , NSCLC [85] , TSCC [111,112] , laryngeal SCC [113] , and HNSCC [114] (Table 3). Many of the reports identify reduction in a single myomiR, but in case studies of particular cancers often the different myomiRs have been identified as downregulated, for example in NSCLC tumor samples, miR1 [100] , 133a [85,115] , 133b [85,115] , 206 [107] or miR1/206 [99] have been reported, by implication dysregulation of all of the myomiRs. Si milarly, for colorectal cancer, downregulated miR1 [101] , 133a [104] , or 133b [86] , or upregulated miR206 [116] , while in prostate cancer downregulated miR1 [101,102] and miR206 [102] , miR133a [97,102] and miR133b [95,96] have been variously reported (Table 3).…”