Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation
Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation
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DOI：
10.1093/carcin/bgn230
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发表时间：
2009-01-01
期刊：
影响因子：
4.7
通讯作者：
Cheung, Annie N. Y.
中科院分区：
文献类型：
--
作者：
Liao, Xiaoyun;Siu, Michelle K. Y.;Cheung, Annie N. Y.
hedgehog （HH）通路的异常激活与人类恶性肿瘤的发展有关。本研究旨在探讨HH分子在人卵巢癌发生中的作用。检测HH分子在卵巢肿瘤样本和卵巢癌细胞系中的表达谱，评估HH分子在体外对细胞增殖、凋亡、迁移、侵袭、细胞分化及相关下游靶基因的影响。卵巢癌中补丁蛋白和Gli1蛋白的过表达与患者生存不良相关（P = 0.008; P = 0.004）。与正常组织和良性卵巢肿瘤相比，Sonic hedgehog信使RNA在卵巢癌中的表达显著升高，且这种差异表达具有组织学类型特异性（P < 0.05）。Gli1在卵巢癌细胞中的异位过表达与E-cadherin、vimentin、Bcl-2、caspases以及β 1整合素、膜型基质金属蛋白酶（MT1-MMP）和血管内皮生长因子（VEGF）的表达增加有关，可促进细胞增殖、细胞移动性、侵袭性和分化变化。3-酮- n -（氨基乙基-氨基丙基-二氢肉桂基）-环巴胺可诱导癌细胞凋亡，抑制细胞生长、迁移和侵袭性，诱导癌细胞去分化，降低E-cadherin、细胞角蛋白7、Snail、calretinin、vimentin、Bcl-2、caspases、β 1整合素、MT1-MMP和VEGF的表达。我们的数据表明异常HH信号激活在卵巢癌的发生和发展中起着重要作用。Gli1表达是一个独立的预后指标。抑制HH通路分子可能是卵巢癌的有效治疗策略。
Aberrant activation of hedgehog (HH) pathway has been implicated in the development of human malignancies. This study aimed at investigating the role of HH molecules in human ovarian carcinogenesis. The expression profiles of HH molecules were examined in ovarian tumor samples and ovarian cancer cell lines and the in vitro effects of HH molecules on cell proliferation, apoptosis, migration, invasion and cell differentiation as well as related downstream target genes were assessed. Overexpression of Patched and Gli1 protein in ovarian cancers correlated with poor survival of the patients (P = 0.008; P = 0.004). Significantly elevated expression of Sonic hedgehog messenger RNA was observed in ovarian cancers compared with normal tissues and benign ovarian tumors and such differential expression was specific to histological types (P < 0.05). Ectopic Gli1 overexpression in ovarian cancer cells conferred increased cell proliferation, cell mobility, invasiveness and change in differentiation in association with increased expression of E-cadherin, vimentin, Bcl-2, caspases as well as beta 1 integrin, membrane type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF). Treatment with 3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)-cyclopamine induced cancer cell apoptosis, suppressed cell growth, mobility and invasiveness and induced cancer cell dedifferentiation with decreased expression of E-cadherin, cytokeratin 7, Snail, calretinin, vimentin, Bcl-2, caspases, beta 1 integrin, MT1-MMP and VEGF. Our data suggested that abnormal HH signaling activation plays important roles in the development and progression of ovarian cancers. Gli1 expression is an independent prognostic marker. Inhibition of the HH pathway molecules might be a valid therapeutic strategy for ovarian cancers.