Abstract
MicroRNAs (miRNAs) play important roles in the progression of human cancer. Although previous reports have shown that miR-145-5p is down-regulated in esophageal squamous cell carcinoma (ESCC), the roles and mechanisms of down-regulation of miR-145-5p in ESCC are still largely unknown. Using microRNA microarray and Gene Expression Omnibus (GEO) datasets, we confirmed that miR-145-5p was down-regulated in ESCC tissues. In vitro assays revealed that ectopic miR-145-5p expression repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT). miR-145-5p also reduced the expressions of cell cycle genes including cyclin A2 (CCNA2), cyclin D1 (CCND1) and cyclin E1 (CCNE1), the EMT-associated transcription factor Slug, and matrix metalloproteinases (MMPs) including MMP2, MMP7 and MMP13. Furthermore, miR-145-5p mimics reduced candidate target gene specificity protein 1 (Sp1) and nuclear factor κ B (NF-κB) (p65) both in mRNA and protein levels. Knockdown of Sp1 phenocopied the effects of miR-145-5p overexpression on cell cycle regulators, EMT and the expression of NF-κB (p65). Importantly, inhibition of the NF-κB signaling pathway or knockdown of NF-κB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells. In conclusion, our results suggested that miR-145-5p plays tumor-suppressive roles by inhibiting esophageal cancer cell migration, invasion and EMT through regulating the Sp1/NF-κB signaling pathway.
Highlights
Esophageal squamous cell carcinoma (ESCC) is a serious health problem in China, with 375,000 new deaths in 2015 alone [1]
Discussion miR-145-5p is down-regulated in many types of cancer including cervical cancer, non-small cell lung cancer (NSCLC), colorectal cancer and esophageal squamous cell carcinoma (ESCC), and functions as tumor suppressor in carcinogenesis [5,8,20,21,22,23]
Cui et al found that miR-145 directly targeted the 3 untranslated regions (3 UTRs) of phospholipase C epsilon (PLCE1) and inhibited cell proliferation, migration and metastasis, as well as controlling the cytoskeleton dynamics of esophageal cancer [4]
Summary
Esophageal squamous cell carcinoma (ESCC) is a serious health problem in China, with 375,000 new deaths in 2015 alone [1]. Diagnosis and treatment of ESCC have been improved, the five-year survival rate is still less than 15%. Understanding of the molecular mechanisms underlying esophageal carcinogenesis will improve the diagnosis and treatment of ESCC. MicroRNAs (miRNAs) are endogenous, small non-coding RNAs 20–24 nucleotides in length [2]. They bind to the 3 untranslated regions (3 UTRs) of target genes, and regulate the translation and degradation of target mRNAs [3]. IInn EESSCCCC,, ddoowwnn--rreegguullaattiioonn ooff mmiiRR--114455 wwaass commmoonnllyy epigeenneettiiccaallllyy reguullaatteedd by pprroommootteerr hhyyppeerrmmeetthhyyllaattiioonn [[1100]]. HHoowweevveerr,, tthhee ttuummoorriiggeenniicc rroolleess aanndd mmeecchhaanniissmmss uunnddeerrllyyiinngg ddoowwnn--rreegguullaattiioonn ooff mmiiRR--114455 iinn EESSCCCC aarree ssttiillll llaarrggeellyy uunnkknnoowwnn. IInn tthhee pprreesseennttstsutuddyy, ,wweefofuonudndthtahtaotvoevreexrepxrpesrseisosnioonf omfiRm-i1R4-51-455p-5upsinugsinmgimmicims iincshiibnitheidbitthede pthreolpifreoralitfieorna,tiomni,gmraitgiornat,ioinnv, ainsivoansioanndanEdMETMoTf oefseospohpahgaegael aclacnacnecrerceclelsll.s.WWeefufurrththeerr ffoouunndd tthhaatt oovveerreexxpprreessssiioonn ooff mmiiRR--114455--55pp nneeggaattiivveellyy rreegguullaatteedd ttrraannssccrriippttiioonn ffaaccttoorr SSpp aanndd iinnhhiibbiitteedd tthhee NNFF--κκB ssiiggnnaalliinngg ppaatthhwwaayy vviiaa ddeeccrreeaassiinngg tthhee eexxpprreessssiioonn ooff NNFF--κκB ((p65)). IImmppoorrttaannttllyy,, kknnoocckkddoowwnn ooff Sp1 oorr NF-κκB ((p65)) aanndd iinnhhiibbiittiioonn ooff tthhee NF-κκB ssiiggnnaalliinngg ppaatthhwwaayy uussiinngg CCAAPPEE pphheennooccooppiieedd tthhee eeffffeeccttss ooff mmiiRR--114455--55pp oovveerreexxpprreessssiioonn oonn tthhee rreessppeeccttiivvee ttuummoorr cceellll pphheennoottyyppeess
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