Activin-A signaling promotes epithelial-mesenchymal transition, invasion, and metastatic growth of breast cancer.
Activin-A signaling promotes epithelial-mesenchymal transition, invasion, and metastatic growth of breast cancer.
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DOI：
10.1038/npjbcancer.2015.7
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发表时间：
2015
影响因子：
5.9
通讯作者：
Kondaiah P
中科院分区：
文献类型：
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作者：
Bashir M;Damineni S;Mukherjee G;Kondaiah P
激活素属于转化生长因子-β(转化生长因子-β)超家族细胞因子。尽管转化生长因子-β在肿瘤进展中的作用得到了高度的提倡，但激活素信号在癌症中的作用还不是很清楚。然而，已经观察到激活素-A在几种癌症中过表达。基因表达谱显示激活素-A在乳腺肿瘤中有较高的表达。因此，本研究的目的是评估激活素信号通路在这些肿瘤中的地位和作用。微阵列分析揭示乳腺肿瘤中基因表达的变化。在两组独立的正常和肿瘤样本中，通过定量聚合酶链式反应和免疫组织化学分析验证了结果。此外，激活素的表达与生存期和远处转移的相关性被用来评估其在肿瘤进展中的可能作用。我们使用重组激活素-A、抑制剂、过表达和体内敲除策略，来了解这一信号通路在促肿瘤发生中的作用机制。我们报告激活素-A信号在乳腺癌中被过度激活，在晚期乳腺癌中激活素-A、磷酸化SMAD2和磷酸化SMAD3水平较高。参与这一信号通路的骨形态发生蛋白和分子表达下调，提示其在乳腺癌中受到抑制。激活素-A的表达与晚期乳腺癌的生存和转移呈负相关。此外，激活素-A还能促进乳腺癌细胞的非贴壁生长、上皮-间充质转化、侵袭、血管生成和干细胞分化。我们证明激活素-A诱导的表型是由SMAD信号通路介导的。此外，激活素-A的表达影响肿瘤细胞在裸鼠体内的成瘤能力和转移定植。这些结果表明激活素-A在乳腺癌的进展中起着关键作用，因此，针对这一途径可能是治疗乳腺癌患者的一种有价值的策略。
Activins belong to the transforming growth factor-β (TGF-β) superfamily of cytokines. Although the role of TGF-β in cancer progression has been highly advocated, the role of activin signaling in cancer is not well known. However, overexpression of activin-A has been observed in several cancers. The gene expression profile indicated higher expression of Activin-A in breast tumors. Hence the aim of this study was to evaluate the status and role of Activin signaling pathway in these tumors. Microarray analysis was performed to reveal gene expression changes in breast tumors. The results were validated by quantitative PCR and immunohistochemical analysis in two independent sets of normal and tumor samples. Further, correlation of activin expression with survival and distant metastasis was performed to evaluate its possible role in tumor progression. We used recombinant activin-A, inhibitors, overexpression, and knockdown strategies both in vitro and in vivo, to understand the mechanism underlying the protumorigenic role of this signaling pathway. We report that activin-A signaling is hyperactivated in breast cancers as indicated by higher activin-A, phosphoSMAD2, and phosphoSMAD3 levels in advanced breast cancers. Bone morphogenetic proteins and molecules involved in this signaling pathway were downregulated, suggesting its suppression in breast cancers. Activin-A expression correlates inversely with survival and metastasis in advanced breast cancers. Further, activin-A promotes anchorage-independent growth, epithelial–mesenchymal transition, invasion, angiogenesis, and stemness of breast cancer cells. We show that activin-A-induced phenotype is mediated by SMAD signaling pathway. In addition, activin-A expression affects the tumor-forming ability and metastatic colonization of cancer cells in nude mice. These results suggest that activin-A has a critical role in breast cancer progression and, hence, targeting this pathway can be a valuable strategy in treating breast cancer patients.