癌变
癌症研究
Wnt信号通路
生物
下调和上调
MAPK/ERK通路
信号转导
肿瘤微环境
肝细胞
细胞
肿瘤进展
细胞生物学
癌症
肿瘤细胞
基因
遗传学
体外
作者
Wendy S. Chen,Yan Liang,Min Zong,Jacey J. Liu,Kota Kaneko,Kaisa L. Hanley,Kun Zhang,Gen–Sheng Feng
出处
期刊:Cell Reports
[Elsevier]
日期:2021-11-01
卷期号:37 (6): 109974-109974
被引量:23
标识
DOI:10.1016/j.celrep.2021.109974
摘要
The mechanisms of Myc-driven liver tumorigenesis are inadequately understood. Herein we show that Myc-driven hepatocellular carcinoma (HCC) is dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion. However, Myc-induced tumors develop selectively from the rare Shp2-positive hepatocytes in Shp2-deficent liver, and Myc-driven oncogenesis depends on an intact Ras-Erk signaling promoted by Shp2 to sustain Myc stability. Despite a stringent requirement of Shp2 cell autonomously, Shp2 deletion induces an immunosuppressive environment, resulting in defective clearance of tumor-initiating cells and aggressive tumor progression. The basal Wnt/β-catenin signaling is upregulated in Shp2-deficient liver, which is further augmented by Myc transfection. Ablating Ctnnb1 suppresses Myc-induced HCC in Shp2-deficient livers, revealing an essential role of β-catenin. Consistently, Myc overexpression and CTNNB1 mutations are frequently co-detected in HCC patients with poor prognosis. These data elucidate complex mechanisms of liver tumorigenesis driven by cell-intrinsic oncogenic signaling in cooperation with a tumor-promoting microenvironment generated by disrupting the specific oncogenic pathway.
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