Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo.
Hypoxia-mediated translational activation of ITGB3 in breast cancer cells enhances TGF-β signaling and malignant features in vitro and in vivo.
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乳腺癌细胞中ITGB3的低氧介导的转化激活增强了TGF-β信号传导和体内的恶性特征。
DOI：
10.18632/oncotarget.23145
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发表时间：
2017-12-29
期刊：
影响因子：
--
通讯作者：
Ramón Y Cajal S
中科院分区：
文献类型：
--
作者：
Sesé M;Fuentes P;Esteve-Codina A;Béjar E;McGrail K;Thomas G;Aasen T;Ramón Y Cajal S
乳腺癌是女性最常见的恶性肿瘤，迫切需要针对侵袭性和转移性亚型的新的治疗药物，如激素不敏感的三阴性乳腺癌(TNBC)。控制蛋白质合成对细胞生长和肿瘤进展至关重要，并允许增加对治疗和细胞压力的抵抗力。低氧癌细胞具有侵袭性和转移性，并对化疗耐药，但蛋白质合成在这一环境中的调节和作用尚不清楚。我们在非恶性乳腺上皮(MCF10A)和TNBC(MDA-MB-231)细胞中进行了多聚体RNA-Seq筛选，这些细胞暴露在常氧或低氧条件下和/或用mTOR途径抑制剂处理。对转录组和翻译组的分析发现，在低氧条件下，转录产物以mTOR依赖或非依赖的方式被激活或抑制。整合素β3(ITGB3)在低氧条件下被翻译激活，它的敲除增加了细胞的凋亡，减少了存活和迁移，特别是在低氧条件下。此外，ITGB3是持续激活转化生长因子-β途径和诱导Snail及其相关的上皮-间充质转化标志物所必需的。ITGB3的下调显著减少了小鼠的肺转移，并提高了小鼠的总存活率。总之，这些数据表明，ITGB3在低氧条件下被翻译激活，并通过转化生长因子-β途径调节恶性特征，包括上皮-间充质转化和细胞迁移，为治疗耐药缺氧肿瘤提供了一个新的角度。
Breast cancer is the most prevalent malignancy in women and there is an urgent need for new therapeutic drugs targeting aggressive and metastatic subtypes, such as hormone-refractory triple-negative breast cancer (TNBC). Control of protein synthesis is vital to cell growth and tumour progression and permits increased resistance to therapy and cellular stress. Hypoxic cancer cells attain invasive and metastatic properties and chemotherapy resistance, but the regulation and role of protein synthesis in this setting is poorly understood. We performed a polysomal RNA-Seq screen in non-malignant breast epithelial (MCF10A) and TNBC (MDA-MB-231) cells exposed to normoxic or hypoxic conditions and/or treated with an mTOR pathway inhibitor. Analysis of both the transcriptome and the translatome identified mRNA transcripts translationally activated or repressed by hypoxia in an mTOR-dependent or -independent manner. Integrin beta 3 (ITGB3) was translationally activated in hypoxia and its knockdown increased apoptosis and reduced survival and migration, particularly under hypoxic conditions. Moreover, ITGB3 was required for sustained TGF-β pathway activation and for the induction of Snail and associated epithelial-mesenchymal transition markers. ITGB3 downregulation significantly reduced lung metastasis and improved overall survival in mice. Collectively, these data suggest that ITGB3 is translationally activated in hypoxia and regulates malignant features, including epithelial-mesenchymal transition and cell migration, through the TGF-β pathway, revealing a novel angle for the treatment of therapy-resistant hypoxic tumours.
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影响因子：
64.5
作者：
BROOKS, PC;MONTGOMERY, AMP;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
8.4
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Brooks, PC
通讯作者：
Brooks, PC
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
5.3
作者：
Blais, JD;Filipenko, V;Bell, JC
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Bell, JC
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide