Unbalanced YAP-SOX9 circuit drives stemness and malignant progression in esophageal squamous cell carcinoma.
Unbalanced YAP-SOX9 circuit drives stemness and malignant progression in esophageal squamous cell carcinoma.
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不平衡的 YAP-SOX9 回路驱动食管鳞状细胞癌的干细胞性和恶性进展
DOI：
10.1038/s41388-018-0476-9
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Wang L;Zhang Z;Yu X;Huang X;Liu Z;Chai Y;Yang L;Wang Q;Li M;Zhao J;Hou J;Li F
是相关蛋白（雅普）已被确定为组织稳态的关键调节因子。然而，雅普在食管鳞状细胞癌（ESCC）中的确切作用和调控机制尚不清楚。在这里，我们报告说，遗传或药理学抑制雅普阻遏癌症干细胞（CSC）样的属性，包括肿瘤球形成的潜力，细胞运动性，和体外化疗耐药性，并足以减弱肿瘤生长和CSC标志物表达ESCC异种移植。从机制上讲，雅普通过TEAD 1介导的结合转录激活其下游靶标SOX 9。我们还在两个独立的临床队列中观察到雅普信号传导和SOX 9表达之间的正相关性。有趣的是，靶向YAP的microRNA，包括由SOX 9诱导的miR-506- 3 p，转录后抑制雅普表达，有助于负反馈机制。雅普和SOX 9的双重抑制稳健地抑制恶性表型。值得注意的是，来自癌症基因组图谱（TCGA）数据集的ESCC样品具有频繁（44%）的雅普基因扩增和Hippo途径调节剂的遗传失活的实例。在中国人群的197例食管鳞癌组织中，核雅普表达升高。总之，我们的研究结果提供的证据表明，遗传超激活的雅普不平衡的YAP-SOX 9反馈回路，并赋予CSC样功能的ESCC，这表明，这个YAP-SOX 9电路代表一个潜在的治疗靶点。
Yes-associated protein (YAP) has been identified as a key regulator of tissue homeostasis. However, the precise role and regulatory mechanism of YAP in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we report that the genetic or pharmacological inhibition of YAP repressed cancer stem cell (CSC)-like properties, including tumorsphere-forming potential, cell motility, and chemoresistance in vitro, and was sufficient to attenuate tumor growth and CSC marker expression in ESCC xenografts. Mechanistically, YAP transcriptionally activated its downstream target SOX9 via TEAD1-mediated binding. We also observed a positive correlation between YAP signaling and SOX9 expression in two independent clinical cohorts. Intriguingly, YAP-targeting microRNAs, including miR-506-3p, which were induced by SOX9, post-transcriptionally repressed YAP expression, contributing to a negative feedback mechanism. Dual inhibition of YAP and SOX9 robustly suppressed malignant phenotypes. Notably, ESCC samples from The Cancer Genome Atlas (TCGA) dataset had frequent (44%) instances of YAP gene amplification and genetic inactivation of Hippo pathway regulators. Nuclear YAP expression was elevated in 197 ESCC tissues from a Chinese cohort. Together, our findings provide evidence that genetic hyperactivation of YAP unbalances the YAP–SOX9 feedback loop and confers CSC-like features in ESCC, suggesting that this YAP–SOX9 circuit represents a potential therapeutic target.
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影响因子：
8
作者：
He C;Lv X;Hua G;Lele SM;Remmenga S;Dong J;Davis JS;Wang C
通讯作者：
Wang C
影响因子：
8
作者：
Ciamporcero E;Shen H;Ramakrishnan S;Yu Ku S;Chintala S;Shen L;Adelaiye R;Miles KM;Ullio C;Pizzimenti S;Daga M;Azabdaftari G;Attwood K;Johnson C;Zhang J;Barrera G;Pili R
通讯作者：
Pili R
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
15.9
作者：
Ma, Fen;Ye, Huihui;Yuan, Xin
通讯作者：
Yuan, Xin
影响因子：
14.9
作者：
Mathelier A;Fornes O;Arenillas DJ;Chen CY;Denay G;Lee J;Shi W;Shyr C;Tan G;Worsley-Hunt R;Zhang AW;Parcy F;Lenhard B;Sandelin A;Wasserman WW
通讯作者：
Wasserman WW