PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients

Han, Tao; Xiang, Di; Sun, Wen; Liu, Na; Sun, Huanlin; Wen, Wen; Shi, Weifeng; Wang, Ruo–Yu; Chen, Cheng; Wang, Xue; Cheng, Zhuo; Li, Hengyu; Wu, Mengchao; Wang, Cong; Feng, Gen‐Sheng; Ding, Jin; Wang, Hongyang

doi:10.1016/j.jhep.2015.03.036

Cited by 129 publications

(115 citation statements)

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“…This phenomenon has been observed for a large number of growth factors signaling through receptor tyrosine kinases, such as hepatocyte growth factor and FGFs that are produced in excess by the cirrhotic tissue adjacent to tumor tissue [28, 118–120]. Secondly, EGFR stimulates the PI3K/Akt and Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular-signal-regulated kinase (ERK) cascades that both can promote β-catenin signaling through inhibition of GSK3β activity [121–125] (Fig. 3).…”

Section: Wnt/β-catenin Signaling Paves the Way For Progression Of Chrmentioning

confidence: 99%

Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

et al. 2016

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Hepatitis C virus (HCV) infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide but the mechanistic basis as to how chronic HCV infection furthers the HCC process remains only poorly understood. Accumulating evidence indicates that HCV core and nonstructural proteins provoke activation of the Wnt/β-catenin signaling pathway, and the evidence supporting a role of Wnt/β-catenin signaling in the onset and progression of HCC is compelling. Convincing molecular explanations as to how expression of viral effectors translates into increased activity of the Wnt/β-catenin signaling machinery are still largely lacking, hampering the design of rational strategies aimed at preventing HCC. Furthermore, how such increased signaling is especially associated with HCC oncogenesis in the context of HCV infection remains obscure as well. Here we review the body of contemporary biomedical knowledge on the role of the Wnt/β-catenin pathway in the progression from chronic hepatitis C to cirrhosis and HCC and explore potential hypotheses as to the mechanisms involved.

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Section: Wnt/β-catenin Signaling Paves the Way For Progression Of Chrmentioning

confidence: 99%

Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

et al. 2016

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“…In a recent report (Jiang et al, 2012), the authors screened 333 human HCC samples and detected significantly decreased expression of SHP2 in 235 tumors in correlation with poor prognosis. Analysis of a different cohort of HCC samples detected over-expression of SHP2 in association with HCC progression and poor prognosis (Han et al, 2015). The complexity of big patients’ data is expected and likely represents the diverse age, sex, and disease backgrounds, compared to the mouse models with clean genetic background and targeted deletion of specific genes.…”

Section: Discussionmentioning

confidence: 99%

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

et al. 2016

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SUMMARY The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells, and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH), and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation, and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

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“…Studies [65] have demonstrated that Shp2 promotes HCC growth and metastasis by coordinately activating the Ras/Raf/Erk pathway and PI3K/Akt/mTOR cascade. Moreover, downregulation of Shp2 enhanced the sensitivity of hepatoma cells to sorafenib treatment, and patients with low Shp2 expression exhibited a superior response to sorafenib' treatment, implying that Shp2 might be a potential biomarker for sorafenib response.…”

Section: Other Possible Mechanismsmentioning

confidence: 99%

New knowledge of the mechanisms of sorafenib resistance in liver cancer

et al. 2017

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Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.

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PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients

Cited by 129 publications

References 50 publications

Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

New knowledge of the mechanisms of sorafenib resistance in liver cancer

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