title: Downregulated miR329 and miR410 promote the proliferation and invasion of oral squamous cell carcinoma by targeting Wnt-7b.
abstract: microRNA (miRNA) dysregulation contributes widely to human cancer but has not been fully assessed in oral cancers. In this study, we conducted a global microarray analysis of miRNA expression in 40 pairs of betel quid-associated oral squamous cell carcinoma (OSCC) specimens and their matched nontumorous epithelial counterparts. Eighty-four miRNAs were differentially expressed in the OSCC specimens compared with the matched tissue. Among these downregulated miRNAs, 19 miRNAs were found and mapped to the chromosome 14q32.2 miRNA cluster region, which resides within a parentally imprinted region designated as Dlk-Dio3 and known to be important in development and growth. Bioinformatic analysis predicted two miRNAs from the cluster region, miR329 and miR410, which could potentially target Wnt-7b, an activator of the Wnt-β-catenin pathway, thereby attenuating the Wnt-β-catenin signaling pathway in OSCC. Stable ectopic expression of Wnt-7b in OSCC cells overexpressing miR329 or miR410 restored proliferation and invasion capabilities abolished by these miRNA. Combining a demethylation agent and a histone deacetylase inhibitor was sufficient to reexpress miR329, miR410, and Meg3, consistent with epigenetic regulation of these miRNA in human OSCC. Specifically, arecoline, a major betel nut alkaloid, reduced miR329, miR410, and Meg3 gene expression. Overall, our results provide novel molecular insights into how betel quid contributes to oral carcinogenesis through epigenetic silencing of tumor-suppressor miRNA that targets Wnt-β-catenin signaling.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Shine-Gwo
authors.initials: SG
authors.lastname: Shiah
authors.affiliation: Department of Otolaryngology, Head and Neck Collaborative Oncology Group, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jenn-Ren
authors.initials: JR
authors.lastname: Hsiao
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Department of Pathology, Taiwan Adventis Hospital, Taipei, Taiwan.
authors.forename: Ying-Tai
authors.initials: YT
authors.lastname: Jin
authors.affiliation: Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tung-Yiu
authors.initials: TY
authors.lastname: Wong
authors.affiliation: Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jehn-Shyun
authors.initials: JS
authors.lastname: Huang
authors.affiliation: Department of Otolaryngology, Head and Neck Collaborative Oncology Group, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Sen-Tien
authors.initials: ST
authors.lastname: Tsai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yuan-Ming
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Sung-Tau
authors.initials: ST
authors.lastname: Chou
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Yen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Shih Sheng
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, Taipei, Taiwan.
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Shieh
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: I-Shou
authors.initials: IS
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. jychang@nhri.org.tw.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D046228:Microarray Analysis; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics*; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays
chemical_list: C584396:MIRN329 microRNA, human; C568527:MIRN410 microRNA, human; D035683:MicroRNAs; C490675:WNT7B protein, human; D051153:Wnt Proteins