title: Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy.
abstract: Colorectal cancer (CRC) is the third highest mortality cancer in the United States and frequently metastasizes to liver and lung. Smad2 is a key element downstream of the TGF-β signaling pathway to regulate cancer metastasis by promoting epithelial to mesenchymal transition and maintaining the cancer stem cell (CSC) phenotype. In this study, we show that hsa-miR-140-5p directly targets Smad2 and overexpression of hsa-miR-140-5p in CRC cell lines decreases Smad2 expression levels, leading decreased cell invasion and proliferation, and increasing cell cycle arrest. Ectopic expression of hsa-miR-140-5p in colorectal CSCs inhibited CSC growth and sphere formation in vitro by disrupting autophagy. We have systematically identified targets of hsa-miR-140-5p involved in autophagy. Furthermore, overexpression of hsa-miR-140-5p in CSCs abolished tumor formation and metastasis in vivo. In addition, there is a progressive loss of hsa-miR-140-5p expression from normal colorectal mucosa to primary tumor tissues, with further reduction in liver metastatic tissues. Higher hsa-miR-140 expression is significantly correlated with better survival in stage III and IV colorectal cancer patients.The functional and clinical significance of hsa-miR-140-5p suggests that it is a key regulator in CRC progression and metastasis, and may have potential as a novel therapeutic molecule to treat CRC.
authors.affiliation: Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY 11794 USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhai
authors.affiliation: Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY 11794 USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Fesler
authors.affiliation: Department of Thoracic Surgery, The Cancer Hospital of Henan, Zhengzhou, Henan 450008 China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Ba
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794 USA.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY 11794 USA.
authors.forename: Jingfang
authors.initials: J
authors.lastname: Ju
mesh_terms: D000818:Animals; D001343:Autophagy; D059447:Cell Cycle Checkpoints; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D045325:HCT116 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; C544302:Mirn140 microRNA, human; C497782:SMAD2 protein, human; D051899:Smad2 Protein
keywords: Smad2; autophagy; colon cancer stem cell; hsa-miR-140-5p; metastasis