Abstract
The expression of miR-638 was found downregulated in colorectal carcinoma (CRC) in our previous study. However, the role of miR-638 in CRC remains unknown. The aim of this study was to determine the function and mechanism of miR-638 in CRC. Here, we verified that miR-638 was frequently downregulated in CRC tissues compared with corresponding noncancerous tissues (NCTs) in an expanded CRC cohort, and survival analysis showed that the downregulation of miR-638 in CRC was associated with poor prognoses. The ectopic expression of miR-638 inhibited CRC cell proliferation, invasion and arrest the cell cycle in G1 phase, whereas the repression of miR-638 significantly promoted CRC cell growth, invasion and cell cycle G1/S transition. Subsequent mechanism analyses revealed that miR-638 inhibited CRC cell growth, invasion and cell cycle progression by targeting TSPAN1. TSPAN1 protein levels were upregulated in CRC samples and were inversely correlated with miR-638 levels. More importantly, high TSPAN1 expression levels in CRC tissues predicted poor overall survival, and appears to be an independent prognostic factor for CRC survival. Furthermore, CpG island methylation analyses revealed that the miR-638 promoter was hypermethylated in CRC and that attenuating promoter methylation was sufficient to restore miR-638 expression in CRC cells. Taken together, our current data demonstrate that miR-638 functions as a tumor suppressor in human CRC by inhibiting TSPAN1, and that TSPAN1 is a potential prognostic factor for CRC.
Highlights
MicroRNAs, a class of small non-coding RNAs, play a pivotal role in many biological processes, ranging from development and differentiation to apoptosis and proliferation, by downregulating endogenous genes
After adjustment for age, gender, tumor size, TNM stage and grading, a Cox multivariate analysis indicated that miR-638 expression is a potential prognostic factor for survival
Of the 146 cases, 100 tumors showed increased TSPAN1 expression compared to the paired noncancerous tissues (NCTs) (Figure 4A and B). Both miR-638 and TSPAN1 expression data were available for a total of 103 paired tumors and NCTs, and the results showed that the protein levels of TAPAN1 in the CRC tissues were inversely correlated with the miR-638 levels (Spearman r = −0.341, p < 0.0001; Figure 4C), suggesting that the increased TSPAN1 expression in CRC might due to miR638 underexpression
Summary
MicroRNAs (miRNAs), a class of small non-coding RNAs, play a pivotal role in many biological processes, ranging from development and differentiation to apoptosis and proliferation, by downregulating endogenous genes. Recent data show that miRNAs critically regulate tumorigenesis and progression by targeting oncogenes, tumor suppressors, or genes related to proliferation, angiogenesis, and apoptosis [2]. We and other groups found that miRNAs appear to be potential biomarkers for the early detection of CRC [4,5,6, 17, 18]. All of these studies provide a strong theoretical basis for the key role of miRNA in CRC tumorigenesis, and highlight the promising implication of miRNA in the diagnosis and prognosis of CRC
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