Gli1 interacts with YAP1 to promote tumorigenesis in esophageal squamous cell carcinoma
Gli1 interacts with YAP1 to promote tumorigenesis in esophageal squamous cell carcinoma
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DOI：
10.1002/jcp.29477
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发表时间：
2020-01-20
影响因子：
5.6
通讯作者：
Sun, Guoping
中科院分区：
文献类型：
--
作者：
Wang, Chongchong;Cheng, Li;Sun, Guoping
食管鳞状细胞癌是我国食管癌的主要类型。Hedgehog（Hh）信号通路的关键因子胶质瘤相关癌基因同源物1（Gli1）在食管癌中异常激活。此外，作为Hippo信号通路的主要介导物，YAP 1与食管癌的进展有关。然而，Gli1和YAP 1在ESCC中的确切作用和潜在机制尚不清楚。在这里，我们发现Gli1和YAP1在ESCC中过表达，并且与预后不良相关。此外，我们证实，Gli1或YAP 1的敲低抑制ESCC细胞的生长，迁移和ESCC TE1和EC109细胞的侵袭。在ESCC细胞中，Gli1与YAP 1相互作用。Gli1和YAP1蛋白在人食管鳞癌中相互密切相关。从机制上讲，Gli1以LATS 1独立的方式上调YAP 1。相反，YAP 1通过调节磷酸肌醇3-激酶（PI3K）/AKT信号通路诱导Gli1。最重要的是，我们证明了Gli1和YAP 1之间的相互作用促进体外和体内ESCC肿瘤生长。我们的研究结果建立了一种新的信号转导机制，通过这种机制，Gli1和YAP 1之间的相互作用促进ESCC细胞的生长。这种肿瘤发生的信号调节为高致死性ESCC提供了新的治疗策略。
Esophageal squamous cell carcinoma (ESCC) is the predominant esophageal cancer type in China. The aberrant activation of glioma-associated oncogene homolog1 (Gli1), a key factor in Hedgehog (Hh) signaling pathway, has been found in esophageal carcinoma. Moreover, Yes-associated protein 1 (YAP1), the major mediator of Hippo signaling pathway, has been linked to esophageal carcinoma progression. However, the precise roles and the underlying mechanism of both Gli1 and YAP1 in ESCC are unclear. Here, we found that Gli1 and YAP1 are overexpressed in ESCC and are associated with poor prognosis. In addition, we confirmed that knockdown of Gli1 or YAP1 suppresses ESCC cell growth, migration, and invasion in ESCC TE1 and EC109 cells. Significantly, Gli1 interacts with YAP1 in ESCC cells. Both Gli1 and YAP1 proteins are closely correlated with each other in human ESCC samples. Mechanistically, Gli1 upregulates YAP1 in a LATS1-independent manner. Conversely, YAP1 induces Gli1 by regulating phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Most importantly, we demonstrated that the interaction between Gli1 and YAP1 promotes ESCC tumor growth in vitro and in vivo. Our findings established a novel signaling mechanism by which the interaction between Gli1 and YAP1 promotes ESCC cell growth. This signaling regulation of the tumorigenesis provides a new therapeutic strategy for highly lethal ESCC.