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

Luo, Xiaolin; Liao, Rui; Hanley, Kaisa L.; Zhu, Helen He; Malo, Kirsten; Hernandez, Carolyn; Wei, Xufu; Varki, Nissi; Alderson, Nazilla; Chu, Catherine; Li, Shuangwei; Fan, Jia; Loomba, Rohit; Qiu, Shuang–Jian; Feng, Gen‐Sheng

doi:10.1016/j.celrep.2016.11.048

Cited by 45 publications

(40 citation statements)

References 54 publications

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“…Both of SHP-1 and SHP-2 govern a host of cellular functions with similar or parallel signal pathways (10). Previous studies reported that SHP-2 suppresses tumorigenesis, but promotes the progression of HCC, suggesting that SHP-2 plays bidirectional roles in HCC (47). However, our present data demonstrate that SHP-1 acted as a suppressor in initiation and progression of HCC in mice.…”

Section: Discussioncontrasting

confidence: 75%

SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression

et al. 2018

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Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1, also known as PTPN6) is a nonreceptor protein tyrosine phosphatase that acts as a negative regulator of inflammation. Emerging evidence indicates that SHP-1 plays a role in inhibiting the progression of hepatocellular carcinoma (HCC). However, the role of SHP-1 in hepatocarcinogenesis remains unknown. Here, we find that levels of SHP-1 are significantly downregulated in human HCC tissues compared with those in noncancerous tissues ( < 0.001) and inversely correlate with tumor diameters ( = -0.4130, = 0.0002) and serum α-fetoprotein levels ( = 0.047). Reduced SHP-1 expression was associated with shorter overall survival of patients with HCC with HBV infection. Overexpression of SHP-1 suppressed proliferation, migration, invasion, and tumorigenicity of HCC cells, whereas knockdown of SHP-1 enhanced the malignant phenotype. Moreover, knockout of in hepatocytes ( ) enhanced hepatocarcinogenesis induced by diethylnitrosamine (DEN) as well as metastasis of primary liver cancer in mice. Furthermore, systemic delivery of SHP-1 by an adenovirus expression vector exerted a therapeutic effect in an orthotopic model of HCC in NOD/SCID mice and DEN-induced primary liver cancers in mice. In addition, SHP-1 inhibited the activation of JAK/STAT, NF-κB, and AKT signaling pathways, but not the MAPK pathway in primary hepatocytes from DEN-treated mice and human HCC cells. Together, our data implicate SHP-1 as a tumor suppressor of hepatocarcinogenesis and HCC progression and propose it as a novel prognostic biomarker and therapeutic target of HCC. The nonreceptor protein tyrosine phosphatase SHP-1 acts as a tumor suppressor in hepatocellular carcinoma. .

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Section: Discussioncontrasting

confidence: 75%

SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression

et al. 2018

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“…The effects of TAZ on inflammation were recently implicated in the progression of NASH (44). Luo et al suggested that the liver microenvironment is a key factor for NASH-derived cancer development in Pten and Shp2 DKO mice (45). Here, we found that the increased levels of TAZ in DKO livers were associated with enhanced immune cell infiltration and increased levels of inflammatory cytokines in the liver ( Figure 1D, Figure 2G, and Table 1), as well as with the rapid development of NASH.…”

Section: Generation Of Liversupporting

confidence: 67%

Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

Jeong

Kim

et al. 2018

Journal of Clinical Investigation

149

102

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IntroductionNAFLD is characterized by an excessive accumulation of fat in the liver. The most severe form of NAFLD, NASH, often progresses to liver cancer (1-3). Tracking with the increasing prevalence of general obesity, 30% of the US population is now estimated to have NAFLD, and 25% of these individuals will develop NASH (1, 3). Currently, there are no effective therapies to prevent the incidence and progression of NAFLD or NASH (4). This makes clarification of the detailed mechanisms of disease progression using appropriate animal models that much more urgent.Insulin signaling begins with the binding of insulin to the insulin receptor (IR). This then phosphorylates insulin receptor substrates (IRSs) and subsequently triggers the recruitment of PI3K and the activation of AKT (5-9). Deletion of IRS1 and IRS2 in the mouse liver reduces AKT activity and gives rise to insulin resistance (10). Excessive AKT activation leads to the development of NAFLD by promoting the maturation of the transcription factor SREBP1c (11,12). In its mature form, SREBP1c contributes to the induction of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), which are key enzymes in de novo lipogenesis (13). Phosphatase and tensin homolog (PTEN) is a negative regulator of AKT signaling, and several human cancers are associated with mutations or downregulation of the PTEN gene (14-16). Liver-specific PTEN-knockout mice progressively develop NAFLD, NASH, and HCC (17, 18) as a result of increased AKT signaling (19).The Hippo signaling pathway has been implicated in the suppression of tissue regeneration, the proliferation of stem cells, and the development of cancer by inhibiting the oncogenic activity of the transcriptional coactivators YAP and TAZ (20,21). In mice, liverspecific knockout of the Hippo pathway components MST1/2, SAV1, or NF2 induces the expansion of hepatic progenitor cells via YAP/TAZ activation and leads eventually to the development of liver cancer (HCC, cholangiocarcinoma [CC], or both) (22)(23)(24)(25). Despite its importance in tumorigenesis, the role of Hippo signaling in the metabolic dysregulation that precedes the development of liver cancer remains unclear.Previous studies have suggested that YAP regulates components of the AKT pathway (i.e., PI3K, PTEN, and AKT) and that the Drosophila Hippo ortholog MST1 binds and inhibits AKT directly (26)(27)(28)(29). Increased YAP expression in human liver tumors is associated with high levels of p- AKT (30,31). This suggests that crosstalk between the Hippo and AKT pathways may be important in the maintenance of functional liver homeostasis. The molecular coordination of these 2 pathways in liver tumorigenesis, however, has not been revealed. Using several mouse models, we now show Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transc...

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“…Immunostaining demonstrated significant decrease of CD44v6 + , SOX9 + , EpCam + and V6 + cell numbers in Pten Δ H and DEN-treated Shp2 Δ H liver sections 7 days following pIC treatment (Figure S7H–L). These markers have been previously shown to be associated with liver TICs by a number of groups (Liu et al, 2016; Luo et al, 2016; Yamashita and Wang, 2013). Of note, pIC injection did not cause severe hepatotoxicity, as reflected by serum ALT levels (Figure S7M).…”

Section: Resultsmentioning

confidence: 96%

Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions

et al. 2017

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Summary Liver cancer has become the second most deadly malignant disease, with no efficient targeted or immune therapeutics available yet. In dissecting roles of cytoplasmic signaling molecules in hepatocarcinogenesis using an inducible mouse gene targeting system, Mx1-cre, we identified a potent liver tumor-inhibitory effect of synthetic double-stranded RNA (dsRNA), polyinosinic-polycytidylic acid (pIC), an inducer of the Mx1-cre system. Injection of pIC at the pre-cancer stage robustly suppressed liver tumorigenesis either induced by chemical carcinogen or by Pten loss and associated hepatosteatosis. The immunostimulatory dsRNA inhibited liver cancer initiation, apparently by boosting multiple anti-tumor activities of innate immunity, including induction of immunoregulatory cytokines, activation of NK cells and dendritic cells, and reprogramming macrophage polarization. This study paves a way for development of preventive and early interfering strategies for liver cancer, to reduce the rapidly increasing incidences of liver cancer in an ever-growing population with chronic liver disorders.

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

Cited by 45 publications

References 54 publications

SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression

SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression

Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions

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