SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression - PubMed (original) (raw)

. 2018 Aug 15;78(16):4680-4691.

doi: 10.1158/0008-5472.CAN-17-3896. Epub 2018 May 18.

Kai Ding # 1, Ze-Rui Wang # 1, Chen-Hong Ding 1, Shu-Juan Lei 1, Jin-Pei Liu 1, Chuan Yin 1, Ping-Fang Hu 1, Jin Ding 2, Wan-Sheng Chen 3, Xin Zhang 4 3, Wei-Fen Xie 4 5

Affiliations

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

Liang-Zhi Wen et al. Cancer Res. 2018.

Abstract

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 (P < 0.001) and inversely correlate with tumor diameters (r = -0.4130, P = 0.0002) and serum α-fetoprotein levels (P = 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 Ptpn6 in hepatocytes (Ptpn6 HKO ) 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 Ptpn6HKO 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.Significance: The nonreceptor protein tyrosine phosphatase SHP-1 acts as a tumor suppressor in hepatocellular carcinoma. Cancer Res; 78(16); 4680-91. ©2018 AACR.

©2018 American Association for Cancer Research.

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