Department of Gastroenterology, Linyi People's Hospital, Linyi, China.
J Cell Mol Med. 2021 Mar;25(5):2584-2595. doi: 10.1111/jcmm.16266. Epub 2021 Feb 11.
Oesophageal cancer (EC) represents a significant cause of cancer worldwide. Yes-associated protein (YAP) is reported to correlate with the initiation of multiple cancers including EC, but the underlying mechanism remains elusive. The current study aimed to investigate the molecular mechanism of YAP-TEAD in the occurrence and progression of EC. EC tissues and cells were obtained, followed by determination of the expression of YAP, c-Jun, pc-Jun and IRS2. The effect of YAP-TEAD on the biological EC cell processes was explored through gain- and loss-of-function approaches. The interaction between YAP and TEAD was detected by co-immunoprecipitation. The binding of TEAD to the c-Jun promoter was determined using chromatin immunoprecipitation. Tumour formation in the nude mice was detected in order to ascertain the effect of YAP and IRS2 in vivo. We found elevated YAP in the EC tissues and cells. YAP silencing led to a decrease in EC cell proliferation, invasion and sphere formation. YAP-TEAD complex bound to the promotor of c-Jun, and c-Jun led to an increase in the expression of IRS2 through the JNK/c-Jun pathway. Additionally, pc-Jun and phosphorylated JNK were localized in the nuclear in addition to displaying enhanced expression in the EC tissues. IRS2 overexpression negated the inhibition of cell proliferation, invasion and sphere formation triggering YAP silencing. YAP up-regulated IRS2 and aggravated EC in vivo. Taken together, YAP-TEAD activates the JNK/c-Jun pathway to up-regulate IRS2, ultimately promoting EC progression. Therefore, YAP-TEAD inhibition could be a promising therapeutic approach for EC treatment.
食管癌（EC）是全球范围内癌症的主要病因之一。研究表明，Yes 相关蛋白（YAP）与多种癌症的发生有关，包括 EC，但潜在机制尚不清楚。本研究旨在探讨 YAP-TEAD 在 EC 发生和发展中的分子机制。本研究获取 EC 组织和细胞，检测 YAP、c-Jun、pc-Jun 和 IRS2 的表达。通过增益和失活功能方法探索 YAP-TEAD 对 EC 细胞生物学过程的影响。通过免疫共沉淀检测 YAP 与 TEAD 的相互作用。通过染色质免疫沉淀检测 TEAD 与 c-Jun 启动子的结合。通过裸鼠肿瘤形成实验检测 YAP 和 IRS2 在体内的作用。我们发现 EC 组织和细胞中 YAP 水平升高。YAP 沉默导致 EC 细胞增殖、侵袭和球体形成减少。YAP-TEAD 复合物结合到 c-Jun 的启动子上，c-Jun 通过 JNK/c-Jun 通路增加 IRS2 的表达。此外，pc-Jun 和磷酸化 JNK 定位于核内，并且在 EC 组织中表达增强。IRS2 过表达可抵消 YAP 沉默引起的细胞增殖、侵袭和球体形成抑制。YAP 上调 IRS2 并加重体内 EC。综上所述，YAP-TEAD 通过激活 JNK/c-Jun 通路上调 IRS2，最终促进 EC 的进展。因此，抑制 YAP-TEAD 可能是治疗 EC 的一种有前途的治疗方法。
