title: Identification of characteristic molecular signature of Müllerian inhibiting substance in human HPV-related cervical cancer cells.
abstract: Müllerian inhibiting substance (MIS), also known as anti-Müllerian hormone (AMH), is a member of the transforming growth factor-β (TGF-β) superfamily that plays an important role in the mesenchymal-epithelial interaction, cell growth and proliferation, extracellular matrix production and tissue remodeling. Previously, we demonstrated that MIS suppressed ovarian cancer cell growth and suggested large-scale genetic elements that could be responsible for anti-neoplastic effects of MIS on ovarian cancer cells. In this study, we demonstrated the expression of MIS type II receptor (MISRII) in the human papillomavirus (HPV)-16-related cervical cancer cell lines CaSki and SiHa, and a non-HPV-related cervical cancer cell line, C33A. We also showed that MIS inhibited growth of cervical cancer cells, and induced cellular apoptosis of C33A. In addition, we identified a characteristic molecular signature of MIS in CaSki cells by using whole genome expression analysis. Of the 1,690 genes that showed significant expression changes by MIS, 21 genes were related to cell cycle; 13 genes to apoptosis; and 52 genes to the cancer pathway. On performing a search for cell cycle pathways in the KEGG pathway database, several gene expressions at the G1/S checkpoint were found. In particular, the expression of p16 and p107 increased and that of E2F2 and E2F3 decreased at an early stage, whereas the expression of E2F4 and E2F5 decreased at a later stage after MIS treatment. These data suggest that MIS produces activity against HPV16-related cervical cancers in vitro, and MIS may also be an effective targeted therapy for HPV16-related cervical cancer. Genetic data obtained here could be useful in determining the treatment strategy of MISR-expressing cervical tumors in the future.
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Suh
authors.forename: Joo Hee
authors.initials: JH
authors.lastname: Yoon
authors.forename: Mee Ran
authors.initials: MR
authors.lastname: Kim
authors.forename: Ki Sung
authors.initials: KS
authors.lastname: Ryu
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.forename: David T
authors.initials: DT
authors.lastname: Maclaughlin
authors.forename: Jang Heub
authors.initials: JH
authors.lastname: Kim
mesh_terms: D054304:Anti-Mullerian Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D052162:Human papillomavirus 16 / Q000302:isolation & purification; D006801:Humans; D030361:Papillomavirus Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology*
chemical_list: C493844:RBL1 protein, human; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D050720:Retinoblastoma-Like Protein p107; D014157:Transcription Factors; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone