title: IFN-γ-mediated IRF1/miR-29b feedback loop suppresses colorectal cancer cell growth and metastasis by repressing IGF1.
abstract: To investigate the clinicopathological significance and underlying mechanism of microRNA-29b (miR-29b) in colorectal cancer (CRC), the role of miR-29b was investigated using in vivo and in vitro assays. Luciferase reporter assays were conducted to determine the association between miR-29b and the insulin-like growth factor 1 (IGF1) 3' untranslated region (3'UTR). Chromatin immunoprecipitation (ChIP) assays were employed to assess the direct binding of interferon regulatory factor 1 (IRF1) to miR-29b. We found that interferon (IFN)-γ could induce miR-29b by recruiting IRF1 to binding sites in the miR-29b promoter. A low level of miR-29b was significantly associated with an aggressive phenotype. MiR-29b inhibited CRC cell growth and invasion. IGF1, an activator of PI3K/Akt signaling, was confirmed as a novel target of miR-29b. Moreover, miR-29b increased IRF1 expression, and the inhibition of miR-29b suppressed IFN-γ-induced apoptosis. We elucidated the potential signaling pathway, IFN-γ/IRF1/miR-29b/IGF1, and its implication for CRC tumorigenesis. A positive feedback loop between IRF1 and miR-29b may contribute to the sensitivity of CRC cells to IFN-γ. Targeting miR-29b may provide a strategy for blocking CRC growth and metastasis.
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Anatomy and Histology, Guangdong Pharmaceutical University, No. 280 Outer Ring East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China.
authors.forename: Min
authors.initials: M
authors.lastname: Hong
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China.
authors.forename: Zuoyang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China.
authors.forename: Zheying
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Southern Medical University, NO.1838 Guangzhou Road, Guangzhou 510515, China. Electronic address: nfydlxn@126.com.
authors.forename: Xuenong
authors.initials: X
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C583557:IGF1 protein, human; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; Colorectal cancer; IFN-γ; IRF1; Metastasis; miR-29b