title: Epigenetic silencing of miR-490-3p promotes development of an aggressive colorectal cancer phenotype through activation of the Wnt/β-catenin signaling pathway.
abstract: The Wnt/β-catenin pathway is known to contribute to colorectal cancer (CRC) progression, although little is known about the contribution of β-catenin on this process. We investigated the role of miR-490-3p, which was recently reported to suppress tumorigenesis through its effect on Wnt/β-catenin signaling. We found that hypermethylation of the miR-490-3p promoter down-regulates miR-490-3p expression in CRC tissue. Gain- and loss-of-function assays in vitro and in vivo reveal that miR-490-3p suppresses cancer cell proliferation by inducing apoptosis and inhibits cell invasiveness by repressing the initiation of epithelial-to-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. The frequently rearranged in advanced T-cell lymphomas (FRAT1) protein was identified as a direct target of miR-490-3p and contributes to its tumor-suppressing effects. miR-490-3p appears to have an inhibitory effect on β-catenin expression in nuclear fractions of CRC cells, whereas FRAT1 expression is associated with the accumulation of β-catenin in the nucleus of cells, which could be weakened by transfection with miR-490-3p. Our findings suggest that the miR-490-3p/FRAT1/β-catenin axis is important in CRC progression and provides new insight into the molecular mechanisms underlying CRC. They may help to confirm the pathway driving CRC aggressiveness and serve for the development of a novel miRNA-targeting anticancer therapy.
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Kehong
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Radiotherapy Department, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zetao
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Cui
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Dachuan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China. Electronic address: drhuangzh@163.com.
authors.forename: Zonghai
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. Electronic address: liangsmu@foxmail.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; C491819:FRAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C574862:MIRN490 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D051176:beta Catenin
keywords: Colorectal cancer (CRC); Epithelial–mesenchymal transition (EMT); Frequently rearranged in advanced T-cell lymphomas protein (FRAT1); Wnt signaling pathway; miR-490-3p