title: miR-135a leads to cervical cancer cell transformation through regulation of β-catenin via a SIAH1-dependent ubiquitin proteosomal pathway.
abstract: Human papillomaviruses (HPVs) is the principal etiological agent of cervical cancer (CC). However, exposure to the high-risk type HPV alone is insufficient for tumor formation, and additional factors are required for the HPV-infected cells to become tumorigenic. Dysregulated microRNAs (miRNAs) expression is frequently observed in cancer but their roles in the formation of CC have not been fully revealed. In this study, we compared the expression of miR-135a in laser capture microdissected cervical specimens and confirmed overexpression of the miRNA in malignant cervical squamous cell carcinoma compared with precancerous lesions. Transient force-expression of miR-135a induced growth in low-density culture, anchorage-independent growth, proliferation and invasion of a HPV-16 E6/E7-immortalized cervical epithelial cell line, NC104-E6/E7. The observed effects were due to the inhibitory action of miR-135a on its direct target seven in absentia homolog 1 (SIAH1) leading to upregulation of β-catenin/T cell factor signaling. miR-135a force-expression enhanced the growth of HeLa- and NC104-E6/E7-derived tumor in vivo. The effect of miR-135a could be partially nullified by SIAH1 force-expression. More importantly, the expression of SIAH1 and β-catenin correlated with that of miR-135a in precancerous and cancerous lesions of cervical biopsies. By comparing the tumorigenic activities of miR-135a in E6/E7 positive/negative cell lines and in NC104-E6/E7 with or without E6/E7 knockdown, we demonstrated that HPV E6/E7 proteins are prerequisite for miR-135a as an oncomiR. Taken together, miR-135a/SIAH1/β-catenin signaling is important in the transformation and progression of cervical carcinoma.
authors: Department of Obstetrics and Gynaecology.
authors: Carmen O N
authors: CO
authors: Leung
authors: Department of Anatomy.
authors: Wen
authors: W
authors: Deng
authors: Department of Obstetrics and Gynaecology.
authors: Tian-Min
authors: TM
authors: Ye
authors: Department of Obstetrics and Gynaecology.
authors: Hextan Y S
authors: HY
authors: Ngan
authors: Department of Anatomy.
authors: Sai Wah
authors: SW
authors: Tsao
authors: Department of Pathology and.
authors: Annie N Y
authors: AN
authors: Cheung
authors: Department of Obstetrics and Gynaecology, Centre for Reproduction, Development and Growth, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region rtkpang@hku.hk.
authors: Ronald T K
authors: RT
authors: Pang
authors: Department of Obstetrics and Gynaecology, Centre for Reproduction, Development and Growth, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region.
authors: William S B
authors: WS
authors: Yeung
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D000098563:Seven in Absentia Proteins
chemical_list: C495270:CTNNB1 protein, human; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D046988:Proteasome Endopeptidase Complex