Mechanism study of tyrosine phosphatase shp-1 in inhibiting hepatocellular carcinoma progression by regulating the SHP2/GM-CSF pathway in TAMs.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Macrophage-mediated innate immune responses play a crucial role in tumor development. This study revealed the mechanism of SHP-1 in regulating HCC progression. SHP-1 inhibits tumour development in vivo. Increasing SHP-1 expression in macrophages promotes the expression of p-SHP-1, SHP2, and p-SHP-2. In macrophages GM-CSF recruits SHP-2 to the GM-CSF receptor GM-CSFR induces p-SHP-2 dephosphorylation. GM-CSF recruits p-SHP-2 for dephosphorylation by up-regulating HoxA10HOXA10 activates the transcription of TGFβ2 by interacting with tandem cis-elements in the promoter thereby regulating the proliferation and migration of liver cancer cells. GM-CSF inhibits SHP-1 regulation of p-SHP-1, SHP2, and p-SHP-2 in macrophages. Detailed studies have shown that SHP-1 regulates SHP2 expression, and SHP-1 and SHP2 are involved in macrophage M2 polarisation. SHP-1 inhibits HOXA10 and TGFβ2 which in turn regulates the expression of the migration-associated proteins, MMP2/9, and the migration of hepatocellular carcinoma cells. Overexpression of SHP-1 inhibits macrophage M2 polarisation via the p-STAT3/6 signalling pathway Classical markers arginase-1, CD206, CD163 and regulate the expression of M2 polarisation cytokines IL-4 and IL-10. In addition, hypoxia-induced ROS inhibited SHP-1 regulation by suppressing the expression of p-SHP-1. The combined effect of GM-CSF and ROS significantly increased p-HOXA10/TGFβ2 and macrophage M2 polarisation, and the regulatory effect of ROS was significantly suppressed by GM-CSF knockdown. These findings suggest that increasing the expression of tyrosine phosphatase SHP-1 can inhibit hepatocellular carcinoma progression by modulating the SHP2/GM-CSF pathway in TAM and thus inhibit the progression of hepatocellular carcinoma.

Wei Q ，Luo S ，He G 《Scientific Reports》

HoxA10 Facilitates SHP-1-Catalyzed Dephosphorylation of p38 MAPK/STAT3 To Repress Hepatitis B Virus Replication by a Feedback Regulatory Mechanism.

Hepatitis B virus (HBV) infection is the leading cause of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study reveals a distinct mechanism underlying the regulation of HBV replication. HBV activates homeobox A10 (HoxA10) in human hepatocytes, leukocytes, peripheral blood mononuclear cells (PBMCs), HepG2-NTCP cells, leukocytes isolated from CHB patients, and HBV-associated HCC tissues. HoxA10 in turn represses HBV replication in human hepatocytes, HepG2-NTCP cells, and BALB/c mice. Interestingly, we show that during early HBV infection, p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were activated to facilitate HBV replication; however, during late HBV infection, HoxA10 was induced to attenuate HBV replication. Detailed studies reveal that HoxA10 binds to p38 MAPK, recruits SH2-containing protein tyrosine phosphatase 1 (SHP-1) to facilitate SHP-1 in catalyzing dephosphorylation of p38 MAPK/STAT3, and thereby attenuates p38 MAPK/STAT3 activation and HBV replication. Furthermore, HoxA10 binds to the HBV enhancer element I (EnhI)/X promoter, competes with STAT3 for binding of the promoter, and thereby represses HBV transcription. Taken together, these results show that HoxA10 attenuates HBV replication through repressing the p38 MAPK/STAT3 pathway by two approaches: HoxA10 interacts with p38 MAPK and recruits SHP-1 to repress HBV replication, and HoxA10 binds to the EnhI/X promoter and competes with STAT3 to attenuate HBV transcription. Thus, the function of HoxA10 is similar to the action of interferon (IFN) in terms of inhibition of HBV infection; however, the mechanism of HoxA10-mediated repression of HBV replication is different from the mechanism underlying IFN-induced inhibition of HBV infection.IMPORTANCE Two billion people have been infected with HBV worldwide; about 240 million infected patients developed chronic hepatitis B (CHB), and 650,000 die each year from liver cirrhosis (LC) or hepatocellular carcinoma (HCC). This work elucidates a mechanism underlying the control of HBV replication. HBV infection activates HoxA10, a regulator of cell differentiation and cancer progression, in human cells and patients with CHB and HCC. HoxA10 subsequently inhibits HBV replication in human tissue culture cells and mice. Additionally, HoxA10 interacts with p38 MAPK to repress the activation of p38 MAPK and STAT3 and recruits and facilitates SHP-1 to catalyze the dephosphorylation of p38 MAPK and STAT3. Moreover, HoxA10 competes with STAT3 for binding of the HBV X promoter to repress HBV transcription. Thus, this work reveals a negative regulatory mechanism underlying the control of HBV replication and provides new insights into the development of potential agents to control HBV infection.

Yang Q ，Zhang Q ，Zhang X ，You L ，Wang W ，Liu W ，Han Y ，Ma C ，Xu W ，Chen J ，Yang H ，Wan P ，Zhou Y ，Liu Y ，Wu K ，Yang Z ，Wu J ... -  《-》

M-CSF secreted by gastric cancer cells exacerbates the progression of gastric cancer by increasing the expression of SHP2 in tumor-associated macrophages.

Zhang S ，Ren D ，Hou H ，Yao L ，Yuan H ... -  《Aging-US》

RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells.

Regulatory factor X-1 (RFX-1) is a transcription factor that has been linked to negative regulation of tumor progression; however, its biological function and signaling cascades are unknown. Here, we performed several studies to elucidate the roles of RFX-1 in the regulation of SHP-1 in hepatocellular carcinoma (HCC) cells. Overexpression of RFX-1 resulted in the activation of SHP-1 and repressed colony formation of HCC cells. In addition, by a mouse xenograft model, we demonstrated that RFX-1 overexpression also inhibited the tumor growth of HCC cells in vivo, suggesting that RFX-1 is of potential interest for small-molecule-targeted therapy. We also found that SC-2001, a bipyrrole molecule, induced apoptosis in HCC cells through activating RFX-1 expression. SC-2001 induced RFX-1 translocation from the cytosol to nucleus, bound to the SHP-1 promoter, and activated SHP-1 transcription. In a xenograft model, knockdown of RFX-1 reversed the antitumor effect of SC-2001. Notably, SC-2001 is much more potent than sorafenib, a clinically approved drug for HCC, in in vitro and in vivo assays. Our study confirmed that RFX-1 acts as a tumor suppressor in HCC and might be a new target for HCC therapy. The findings of this study also provide a new lead compound for targeted therapy via the activation of the RFX-1/SHP-1 pathway.

Su JC ，Chiang HC ，Tseng PH ，Tai WT ，Hsu CY ，Li YS ，Huang JW ，Ko CH ，Lin MW ，Chu PY ，Liu CY ，Chen KF ，Shiau CW ... -  《-》

Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells.

Kim H ，Baumann H 《-》