The stabilization of yes-associated protein by TGFβ-activated kinase 1 regulates the self-renewal and oncogenesis of gastric cancer stem cells.
The stabilization of yes-associated protein by TGFβ-activated kinase 1 regulates the self-renewal and oncogenesis of gastric cancer stem cells.
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DOI：
10.1111/jcmm.16660
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发表时间：
2021-07
影响因子：
5.3
通讯作者：
Xu A
中科院分区：
文献类型：
--
作者：
Wang G;Sun Q;Zhu H;Bi Y;Zhu H;Xu A
胃癌（GC）是全球最常见的消化系统恶性肿瘤，也是全球第二大癌症死亡原因。癌症干细胞（CSC）是实体瘤中一小部分具有分化、自我更新和致瘤能力的癌细胞。它们积极参与肿瘤的发生、发展、转移、复发和对化疗和放疗的抵抗。胃癌干细胞（GCSCs）与胃癌的发生和转移密切相关。在本研究中，我们通过RT-qPCR、Western blot和免疫组化发现，与癌旁组织相比，胃癌组织中的TAK 1表达水平显著升高。TAK 1已被鉴定为在体内和体外促进多种恶性GC表型并促进GCSC自我更新的关键分子。从机制上讲，TAK 1被IL-6上调，并通过与雅普结合阻止细胞质中yes相关蛋白（雅普）的降解。因此，TAK 1促进了GCSC的SOX 2和SOX 9转录以及自我更新和肿瘤发生。我们的研究结果为GCSC中TAK 1的自我更新和肿瘤发生机制提供了见解，并对临床治疗具有广泛的意义。
Gastric cancer (GC) is the most frequent digestive system malignant tumour and the second most common cause of cancer death globally. Cancer stem cell (CSC) is a small percentage of cancer cells in solid tumours that have differentiation, self‐renewal and tumorigenic capabilities. They have an active participation in the initiation, development, metastasis, recurrence and resistance of tumours to chemotherapy and radiotherapy. Gastric cancer stem cells (GCSCs) have been shown to be correlated with GC initiation and metastasis. In this study, we found that TAK1 expression level in GC tissues was significantly increased compared to the adjacent non‐cancerous tissues by RT‐qPCR, Western blot and immunohistochemistry. TAK1 has been identified as a critical molecule that promoted a variety of malignant GC phenotypes both in vivo and in vitro and promoted the self‐renewal of GCSCs. Mechanistically, TAK1 was up‐regulated by IL‐6 and prevented the degradation of yes‐associated protein (YAP) in the cytoplasm by binding to YAP. Thus, TAK1 promoted the SOX2 and SOX9 transcription and the self‐renewal and oncogenesis of GCSCs. Our findings provide insights into the mechanism of self‐renewal and tumorigenesis of TAK1 in GCSCs and have broad implications for clinical therapies.
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