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TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness.
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2019-12-13 , DOI: 10.1038/s41392-019-0098-x Renle Du 1 , Wenzhi Shen 2 , Yi Liu 1 , Wenjuan Gao 1 , Wei Zhou 1 , Jun Li 1 , Shuangtao Zhao 1 , Chong Chen 3 , Yanan Chen 1, 4, 5 , Yanhua Liu 1, 4, 5 , Peiqing Sun 6 , Rong Xiang 1, 4, 5 , Yi Shi 1, 4, 5 , Yunping Luo 3
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2019-12-13 , DOI: 10.1038/s41392-019-0098-x Renle Du 1 , Wenzhi Shen 2 , Yi Liu 1 , Wenjuan Gao 1 , Wei Zhou 1 , Jun Li 1 , Shuangtao Zhao 1 , Chong Chen 3 , Yanan Chen 1, 4, 5 , Yanhua Liu 1, 4, 5 , Peiqing Sun 6 , Rong Xiang 1, 4, 5 , Yi Shi 1, 4, 5 , Yunping Luo 3
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TGF-β-induced factor homeobox 2 (TGIF2) is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions. Aberrant expression of TGIF family proteins has been observed in several cancers, including ovarian, esophageal, and colorectal cancers. Here, we report that TGIF2 mediates the EGFR-RAS-ERK signaling pathway to enhance the stemness of lung adenocarcinoma (LUAD) cells and, therefore, promote the progression and metastasis of LUAD. We found that high TGIF2 expression was closely correlated with tumor growth, lymph node metastasis, and survival of patients with LUAD. Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases. Importantly, silencing TGIF2 decreased the cancer stem cell (CSC)-like properties in A549 and H1299 cells. Furthermore, we identified that TGIF2 binding to the OCT4 promoter promotes its expression. In both LUAD cells and in vivo LUAD mouse models, we revealed that EGFR-RAS-ERK signaling phosphorylated TGIF2 and increased its stability, which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions. Thus, our study revealed that an important factor, TGIF2, bridges EGFR signaling to the CSC characteristics of LUAD cells, which can be utilized as an effective target for LUAD therapy.
中文翻译：
TGIF2 通过将 EGFR/RAS/ERK 信号传导与癌细胞干性联系起来，促进肺腺癌的进展。
TGF-β 诱导因子同源盒 2 (TGIF2) 是一种转录调节因子，在发育调节和细胞命运决定中发挥重要作用。在多种癌症中观察到 TGIF 家族蛋白的异常表达，包括卵巢癌、食道癌和结直肠癌。在此，我们报道TGIF2介导EGFR-RAS-ERK信号通路以增强肺腺癌细胞（LUAD）细胞的干性，从而促进LUAD的进展和转移。我们发现TGIF2的高表达与LUAD患者的肿瘤生长、淋巴结转移和生存密切相关。携带TGIF2沉默的H1299异种移植物的小鼠产生更小的肿瘤和更少的肺转移。重要的是，沉默 TGIF2 会降低 A549 和 H1299 细胞中的癌症干细胞 (CSC) 样特性。此外，我们发现 TGIF2 与 OCT4 启动子的结合可促进其表达。在 LUAD 细胞和体内 LUAD 小鼠模型中，我们发现 EGFR-RAS-ERK 信号传导磷酸化 TGIF2 并增加其稳定性，这对于 TGIF2 促进的 LUAD 干性非常重要，因为磷酸化缺陷的 TGIF2 突变体失去了这些功能。因此，我们的研究表明，一个重要的因子TGIF2将EGFR信号传导与LUAD细胞的CSC特征联系起来，可以作为LUAD治疗的有效靶点。
更新日期：2019-12-13
中文翻译：
TGIF2 通过将 EGFR/RAS/ERK 信号传导与癌细胞干性联系起来，促进肺腺癌的进展。
TGF-β 诱导因子同源盒 2 (TGIF2) 是一种转录调节因子，在发育调节和细胞命运决定中发挥重要作用。在多种癌症中观察到 TGIF 家族蛋白的异常表达，包括卵巢癌、食道癌和结直肠癌。在此，我们报道TGIF2介导EGFR-RAS-ERK信号通路以增强肺腺癌细胞（LUAD）细胞的干性，从而促进LUAD的进展和转移。我们发现TGIF2的高表达与LUAD患者的肿瘤生长、淋巴结转移和生存密切相关。携带TGIF2沉默的H1299异种移植物的小鼠产生更小的肿瘤和更少的肺转移。重要的是，沉默 TGIF2 会降低 A549 和 H1299 细胞中的癌症干细胞 (CSC) 样特性。此外，我们发现 TGIF2 与 OCT4 启动子的结合可促进其表达。在 LUAD 细胞和体内 LUAD 小鼠模型中，我们发现 EGFR-RAS-ERK 信号传导磷酸化 TGIF2 并增加其稳定性，这对于 TGIF2 促进的 LUAD 干性非常重要，因为磷酸化缺陷的 TGIF2 突变体失去了这些功能。因此，我们的研究表明，一个重要的因子TGIF2将EGFR信号传导与LUAD细胞的CSC特征联系起来，可以作为LUAD治疗的有效靶点。
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