Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Int J Oncol. 2011 Oct;39(4):811-20. doi: 10.3892/ijo.2011.1042. Epub 2011 May 13.
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.
苗勒抑制物质（MIS），也称为抗苗勒管激素（AMH），是转化生长因子-β（TGF-β）超家族的成员，在间质-上皮相互作用、细胞生长和增殖、细胞外基质产生和组织重塑中发挥重要作用。此前，我们证明了 MIS 抑制卵巢癌细胞生长，并提出了可能负责 MIS 对卵巢癌细胞抗肿瘤作用的大规模遗传元件。在这项研究中，我们证明了 MIS Ⅱ型受体（MISRII）在人乳头瘤病毒（HPV）-16 相关的宫颈癌细胞系 CaSki 和 SiHa 以及非 HPV 相关的宫颈癌细胞系 C33A 中的表达。我们还表明，MIS 抑制宫颈癌细胞的生长，并诱导 C33A 细胞的细胞凋亡。此外，我们通过全基因组表达分析鉴定了 CaSki 细胞中 MIS 的特征分子特征。在 MIS 引起明显表达变化的 1690 个基因中，有 21 个与细胞周期有关；13 个与凋亡有关；52 个与癌症途径有关。在 KEGG 途径数据库中进行细胞周期途径搜索时，发现了几个 G1/S 检查点的基因表达。特别是，p16 和 p107 的表达在早期增加，E2F2 和 E2F3 的表达减少，而 E2F4 和 E2F5 的表达在 MIS 处理后晚期减少。这些数据表明，MIS 在体外对 HPV16 相关宫颈癌具有活性，MIS 也可能是 HPV16 相关宫颈癌的有效靶向治疗药物。这里获得的遗传数据可能有助于确定未来表达 MISR 的宫颈肿瘤的治疗策略。
