生物
癌症研究
SOX2
下调和上调
癌变
间质细胞
人口
Wnt信号通路
CD44细胞
结直肠癌
细胞生物学
癌症
信号转导
细胞
医学
遗传学
胚胎干细胞
基因
环境卫生
作者
Hiroaki Kasashima,Abraham Madroñal Durán,Anxo Martínez-Ordóñez,Yuki Nakanishi,Hiroto Kinoshita,Juan F. Linares,Miguel Reina‐Campos,Yotaro Kudo,Antoine L’Hermitte,Masakazu Yashiro,Masaichi Ohira,Fei Bao,Daniele V.F. Tauriello,Eduard Batlle,Marı́a T. Diaz-Meco,Jorge Moscat
标识
DOI:10.1016/j.devcel.2020.10.014
摘要
Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. We show that the upregulation of SOX2 is central to this process, which is repressed by protein kinase Cζ (PKCζ). PKCζ deficiency activates the reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF population expressing the WNT regulator Sfrp2 as its top biomarker. SOX2 directly binds the Sfrp1/2 promoters, and the inactivation of Sox2 or Sfrp1/2 in CAFs impaired the induction of migration and invasion of colon cancer cells, as well as their tumorigenicity in vivo. Importantly, recurrence-free and overall survival of colorectal cancer (CRC) patients negatively correlates with stromal PKCζ levels. Also, SOX2 expression in the stroma is associated with CRC T invasion and worse prognosis of recurrence-free survival. Therefore, the PKCζ-SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential.
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