Abstract
Gastric cancer (GC) is a biologically heterogeneous disease accompanying various genetic and epigenetic alterations, and the molecular mechanisms underlying this disease are complex and not completely understood. Increasing evidence shows that abnormal microRNA (miRNA) expression is involved in GC tumorigenesis, but the role of specific miRNAs involved in this disease remains elusive. MiR-141 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here we found that the expression of miR-141 was significantly reduced in GC compared with paired adjacent normal tissues and was significantly correlated with a more aggressive phenotype of GC in patients. Ectopic expression of miR-141 mimics in GC cell lines resulted in reduced proliferation, invasion and migration, and inhibition of miR-141 in GC cell lines promoted cell proliferation, invasion and migration in vitro. We further demonstrated that miR-141 acted as tumor suppressors through targeting transcriptional co-activator with PDZ-binding motif (TAZ) in GC. Moreover, the inverse relationship between miR-141 and its target was verified in patients and xenograft mice. Finally, overexpression of miR-141 suppressed tumor growth and pulmonary metastasis in nude mice. Take together, we identified that miR-141 is a potent tumor suppressor in the stomach, and its growth inhibitory effects are, in part, mediated through its downstream target gene, TAZ. These findings implied that miR-141 might be employed as novel prognostic markers and therapeutic targets of GC.
Highlights
Recent discoveries have shed new light on the involvement of a class of non-coding RNA known as microRNA in Gastric cancer (GC)
The quantitative real-time PCR analyses showed that miR-141 levels were attenuated in GC cell lines (BGC-823, HGC-27 and SGC7901), compared with normal gastric mucosa (Figure 1b), and revealed that miR-141 expression was significantly downregulated in GC tissues, compared with paired normal mucosa (NM) tissues (Po0.001; Figure 1c)
No significant differences were observed in age, gender, tumor location or histology. These results suggest that miR-141 is consistently downregulated in GCs, and may serve as tumor suppressor in this disease, and miR-141 correlates inversely with metastatic capacity in GC tissues
Summary
Recent discoveries have shed new light on the involvement of a class of non-coding RNA known as microRNA (miRNA) in GC. 22 nt in length) RNAs that have important roles in the pathogenesis of human diseases by modulating the activity of specific mRNA targets.[8] This large family of highly conserved small non-coding RNAs may regulate a vast number of proteincoding genes, including oncogenes and tumor-suppressor genes, which suggest that miRNAs can function as tumor suppressors or oncogenes.[9,10] There are an increasing number of studies showing the overexpression or downregulation of specific miRNA in GC.[11] MicroRNA-21 promotes tumor proliferation and invasion in GC by targeting phosphatase and tensin homolog and is a new marker of circulating tumor cells in GC patients.[12] MiRNA-223 promotes GC invasion and metastasis by targeting tumor-suppressor erythrocyte membrane protein band 4.1-like 3.13 MiR-29c acts as a tumor suppressor in GC by directly targeting integrin beta-1. We showed that miR-141 may function as a tumor suppressor by directly targeting TAZ
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