Evolution Of MicroRNA Expression During Human Esophageal Squamous Carcinogenesis

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer related deaths worldwide. The incidence of esophageal squamous cell carcinoma (ESCC) is more frequent in China. ESCC has a very poor prognosis, with an overall 5-year survival rate of about 20% after surgery, which is largely due to late diagnosis. Detection an earlier stage can dramatically improve prognosis. Yet the molecular mechanism during human esophageal squamous carcinogenesis remains unclear.miRNAs are 19-24nt in length, highly conserved noncoding RNAs that control gene expression post-transcriptionally. miRNAs play important roles in cell proliferation, differentiation, and apoptosis. Recent cumulative evidences suggested that miRNAs play important roles in carcinogenesis.In present study. we analyzed the miRNA expression profile of disease /normal-paired tissues from 3 carcinoma in situ (CIS) and 3 ESCC patients with TaqMan human microRNA arrays. Four miRNAs (miR-133a, miR-143, miR-145 and miR-375) were found to be decreased in CIS and ESCC compared to paired normal tissues. We further detected the expression of the 4 miRNAs in disease /normal -paired tissues from 14 mild and moderate dysplasia.26 CIS (severe dysplasia also included) and 29 ESCC patients with qRT-PCR. Relative expression of 3 miRNAs (miR-133a. miR-143 and miR-145) were observed to be downregulated significantly in CIS and ESCC, but not in mild and moderate dysplasia. Among the 4 miRNAs, miR-375 showed a linear evolution of its relative expression, whose expression progressively decreased from mild and moderate dysplasia to ESCC.Further investigation displayed that overexpression of miR-375 in ESCC cell lines could induce cell cycle arrest and inhibit cell proliferation in vitro and in vivo. miR-375 directly binds to PDK1 3'UTR and represses PDK1 expression. Reconstitution of miR-375-resistant PDK1 reverses the cell cycle arrest of miR-375 in ESCC cells.Taken together, microRNAs are involved in esophageal carcinogenesis from the early steps of this process, thus, could provide potential biomarkers for early detection of ESCC.