title: miR-106a represses the Rb tumor suppressor p130 to regulate cellular proliferation and differentiation in high-grade serous ovarian carcinoma.
abstract: The degree of differentiation in human cancers generally reflects the degree of malignancy, with the most undifferentiated cancer being also the highest grade and the most aggressive. High-grade serous ovarian carcinomas (HGSOC) are poorly differentiated and fast-growing malignancies. The molecular mechanisms underlying the poor differentiation of HGSOC has not been completely characterized. Evidence suggests that miRNA, miR are dysregulated in HGSOC. Therefore, we focused on those miRNAs that are relevant to tumor differentiation. Expression profiling of miRNAs in HGSOC, indicated miR-106a and its family members were significantly upregulated. Upregulation of miR-106a was further validated by real-time reverse transcriptase PCR (qRT-PCR) and miRNA in situ hybridization in a large cohort of HGSOC specimens. Overexpression of miR-106a in benign and malignant ovarian cells significantly increased the cellular proliferation rate and expanded the side-population fraction. In particular, SKOV3 cells with miR-106a overexpression had significantly higher tumor initial/stem cell population (CD24- and CD133-positive cells) than control SKOV3 cells. Among many miR-106a predicated target genes, p130 (RBL2), an retinoblastoma (Rb) tumor suppressor family member, was not only confirmed as a specific target of miR-106a but also related to tumor growth and differentiation. The importance of mir-106a and RBL2 was further demonstrated in vivo, in which, SKOV3 cells overexpressing miR-106a formed poorly differentiated carcinomas and had reduced RBL2 levels. To our knowledge, this is the first study of miR-106a mediating proliferation and tumor differentiation in HGSOC.
  
  
  CONCLUSIONS
  The current study suggests that the RB tumor suppressor pathway is a critical regulator of growth and differentiation in HGSOC.
authors.affiliation: Department of Pathology, Northwestern University School of Medicine, Feinberg 7-334, 251 East Huron Street, Chicago, IL 60611. jianjun-wei@northwestern.edu.
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gersbach
authors.forename: Xiyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Xu
authors.forename: Ruifen
authors.initials: R
authors.lastname: Dong
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Beihua
authors.initials: B
authors.lastname: Kong
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: C542541:MIRN106 microRNA, human; D035683:MicroRNAs; C493837:RBL2 protein, human; D050717:Retinoblastoma-Like Protein p130
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