肝细胞中 Shp2 的缺失抑制了由癌基因β-Catenin、PIK3CA 和 MET 驱动的肝癌发生。
Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic β-Catenin, PIK3CA and MET.
机构信息
Department of Pathology, and Division of Biological Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA.
Department of Pathology, and Division of Biological Sciences, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Hepatobiliary Surgery, 3rd affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
出版信息
J Hepatol. 2018 Jul;69(1):79-88. doi: 10.1016/j.jhep.2018.02.014. Epub 2018 Mar 2.
BACKGROUND & AIMS: Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogens or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), β-catenin and PIK3CA.
METHODS
We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and ΔN90-β-catenin (MET/CAT), or c-Met and PIK3CA (MET/PIK), into WT and Shp2 mice. We compared liver tumor loads and investigated the pathogenesis and molecular mechanisms involved using multidisciplinary approaches.
RESULTS
Despite the induction of oxidative and metabolic stresses, Shp2 deletion in hepatocytes suppressed hepatocarcinogenesis driven by overexpression of oncoproteins MET/CAT or MET/PIK. Shp2 loss inhibited proliferative signaling from c-Met, Wnt/β-catenin, Ras/Erk and PI3K/Akt pathways, but triggered cell senescence following exogenous expression of the oncogenes.
CONCLUSIONS
Shp2, acting downstream of RTKs, is positively required for hepatocyte-intrinsic tumorigenic signaling from these oncoproteins, even if Shp2 deficiency induces a tumor-promoting hepatic microenvironment. These data suggest a new and more effective therapeutic strategy for HCCs driven by oncogenic RTKs and other upstream molecules, by inhibiting Shp2 and also suppressing any tumor-enhancing stromal factors produced because of Shp2 inhibition.
LAY SUMMARY
Primary liver cancer is a malignant disease with poor prognosis, largely because there are limited systemic therapies available. We show here that a cytoplasmic tyrosine phosphatase Shp2 is required for liver tumorigenesis. This tumorigenesis is driven by two oncoproteins that are implicated in human liver cancer. This, together with our previous studies, uncovers the complexity of liver tumorigenesis, by elucidating the pro- and anti-tumor effects of Shp2 in mouse models. This data can be used to guide new therapies.
背景与目的
Shp2 是一种 SH2 酪氨酸磷酸酶，作用于受体酪氨酸激酶（RTKs）下游。最近的数据表明，Shp2 具有抑制肝脏肿瘤的作用，因为在肝细胞中敲除 Shp2 会加重化学致癌物或 Pten 缺失诱导的肝细胞癌（HCC）。我们进一步研究了 Shp2 缺失对由经典癌蛋白 c-Met（HGF 的受体）、β-catenin 和 PIK3CA 驱动的肝肿瘤发生的影响。
方法
我们通过尾静脉注射两种表达 c-Met 和 ΔN90-β-catenin（MET/CAT）或 c-Met 和 PIK3CA（MET/PIK）的质粒对 WT 和 Shp2 小鼠进行处理。我们比较了肝肿瘤负荷，并使用多学科方法研究了涉及的发病机制和分子机制。
结果
尽管诱导了氧化和代谢应激，肝细胞中 Shp2 的缺失抑制了由癌蛋白 MET/CAT 或 MET/PIK 过表达诱导的肝癌发生。Shp2 缺失抑制了 c-Met、Wnt/β-catenin、Ras/Erk 和 PI3K/Akt 通路的增殖信号，但在外源表达癌基因后触发了细胞衰老。
结论
Shp2 作为 RTKs 的下游分子，正向需要这些癌蛋白的肝实质肿瘤发生信号，即使 Shp2 缺失诱导了促进肿瘤的肝微环境。这些数据为受致癌 RTKs 和其他上游分子驱动的 HCC 提供了一种新的、更有效的治疗策略，通过抑制 Shp2 并抑制因 Shp2 抑制而产生的任何增强肿瘤的基质因子。
概述
原发性肝癌是一种预后不良的恶性疾病，主要是因为目前可用的全身性治疗方法有限。我们在这里表明，一种细胞质酪氨酸磷酸酶 Shp2 是肝肿瘤发生所必需的。这种肿瘤发生是由两种癌蛋白驱动的，这两种癌蛋白与人类肝癌有关。这与我们之前的研究一起，通过阐明 Shp2 在小鼠模型中的促肿瘤和抗肿瘤作用，揭示了肝肿瘤发生的复杂性。这些数据可用于指导新的治疗方法。
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