title: Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma.
abstract: Cholangiocarcinoma (CCA), which is a poor prognosis malignancy that arises from the malignant transformation of cholangiocytes, is associated with chronic inflammation of the biliary epithelium. Thus far, the molecular mechanisms of the origin and neoplastic processes of CCA that are promoted by inflammation are still unclear and need to be fully elucidated. Here using small RNA sequencing to determine the microRNA (miRNA) expression profiles in CCA, we found that let-7c, miR-99a and miR-125b, which are three miRNAs of the same cluster, were downregulated in CCA and targeted interleukin 6 (IL-6), IL-6R and type 1 insulin-like growth factor, which are important cytokines and receptors of the IL-6/signal transducer and activator 3 (STAT3) pathway and have key roles in inflammation and CCA initiation. We also found that enforced expression of let-7c, miR-99a or miR-125b could reduce the activity of STAT3 and further suppress CCA tumorigenicity in vivo and inhibit the migration and invasion of CCA cells in vitro. Surprisingly, let-7c/miR-99a/miR-125b cluster also significantly decreased the ability of CCA cells for cancer stem cell-like mammosphere generation by downregulating CD133 and CD44, which suggests the pivotal roles of let-7c, miR-99a and miR-125b in CCA by regulating both inflammation and stem-like properties. Our findings showed potential links between miRNAs and inflammation, and provide a potential treatment strategy for developing an miRNA-based therapy via IL-6/STAT3 targeting for CCA.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Science, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Lin
authors.affiliation: Department of Hepatobiliary, and Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Ye
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Science, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: B-W
authors.initials: BW
authors.lastname: Han
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Science, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: W-T
authors.initials: WT
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Science, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: P-P
authors.initials: PP
authors.lastname: Wei
authors.affiliation: Department of Hepatobiliary, and Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: He
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Science, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Science, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: C000597236:IGF1R protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; C531888:MIRN125 microRNA, human; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D019947:Receptors, Interleukin-6; D017451:Receptors, Somatomedin; D050796:STAT3 Transcription Factor; C487931:mirnlet7 microRNA, human; D017526:Receptor, IGF Type 1