title: MiR-135a functions as a tumor suppressor in epithelial ovarian cancer and regulates HOXA10 expression.
abstract: The activation of homeobox A10 (HOXA10) has been proved to be an important event in epithelial ovarian carcinogenesis, yet its regulation in epithelial ovarian cancer (EOC) is still not fully understood. Here, we aimed to reveal the mechanism that a predicted target miRNA regulates HOXA10 expression and the association of its expression with progression of EOC. Here, by using computer-assisted algorithms from PicTar, TargetScan, and miRBase, we identified that the predicted target miRNA of HOXA10 was miR-135a. MiR-135a expression in EOC tissues and controls was measured with quantitative RT-PCR. The role of miR-135a and HOXA10 in the growth and survival of several EOC cell lines was determined with several in vitro approaches. We found that miR-135a expression was downregulated in an EOC patient cohort. Also, patients with low miR-135a expression had shorter overall survival and progression-free survival durations than those with high expression. Functional analysis of three EOC-derived cell lines (SKOV-3, HEY, and OVCAR-3) demonstrated that miR-135a directly regulated HOXA10 expression by targeting its 3'-UTR. Inhibition of HOXA10 expression with miR-135a mimics and HOXA10 siRNA consistently resulted in cell apoptosis with concomitant enhancement of caspase-3, increase of p53 expression and reduction of Bcl-2 expression, and also suppressed cell growth and adhesion. These findings suggest that ubiquitous loss of miR-135a expression is a critical mechanism for the overexpression of HOXA10 in EOC cells, which is implicated in epithelial ovarian carcinogenesis. Furthermore, miR-135a may be predictive of EOC prognosis.
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Gynecology and Obstetrics, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Mu
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Gynecology and Obstetrics, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: chengwenjundoc@163.com.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China. Electronic address: xrwang@njmu.edu.cn.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D053148:Caspase 3 / Q000096:biosynthesis; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C069634:HOXA10 protein, human; D053148:Caspase 3
keywords: Adhesion; Apoptosis; Epithelial ovarian cancer; HOXA10; MiR-135a