Negative regulation of hepatocellular carcinoma cell growth by signal regulatory protein α1

Abstract

Signal regulatory protein (SIRP) ␣1 is a member of the SIRP family that undergoes tyrosine phosphorylation and binds SHP-2 tyrosine phosphatase in response to various mitogens. The expression levels of SIRP␣1 were decreased in HCC tissues, compared with the matched normal tissues. Exogenous expression of wild type SIRP␣1, but not of a mutant SIRP␣1 lacking the tyrosine phosphorylation sites, in SIRP␣1-negative Huh7 human HCC cells resulted in suppression of tumor cell growth both in vitro and in vivo. Treatment of Huh7 transfectants with EGF or HGF induced tyrosine phosphorylation of SIRP␣1 and its association with SHP-2, which were accompanied by reduced ERK1 activation. Expression of SIRP␣1 significantly suppressed activation of NF-B and also sensitized Huh7 cells to TNF␣ or cisplatin-induced cell death. In addition, SIRP␣1-transfected Huh7 cells displayed reduced cell migration and cell spreading in a fashion that was dependent on SIRP␣1/SHP-2 complex formation. In conclusion, a negative regulatory effect of SIRP␣1 on hepatocarcinogenesis is exerted, at least in part, through inhibition of ERK and NF-B pathways. contains 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) with 4 tyrosine residues that are phosphorylated in response to a variety of growth factors and integrin-mediated cell adhesion. [1][2][3] This phosphorylation enables recruitment and activation of Src homology-containing phosphotyrosine phosphatase 2 (SHP-2) that in turn dephosphorylates specific protein substrates involved in mediating various physiological effects.SHP-2, a widely expressed cytoplasmic tyrosine phosphatase with 2 Src homology-2 domains, has been implicated in growth factor-induced cell proliferation probably through activation of the Ras-mitogen-activated protein kinase (MAPK) cascade. 4 SIRP␣1/SHP-2 complex negatively or positively regulates intracellular signaling initiated either by tyrosine kinase-coupled receptors for growth factors or by cell adhesion to extracellular matrix proteins. For example, SIRP␣1 overexpression in NIH3T3 cells inhibited DNA synthesis and MAPK phosphorylation following endothelial growth factor (EGF) or insulin stimulation. 1 In contrast, overexpression of wildtype SHPS-1 (the murine homolog of SIRP␣1) was reported to increase MAPK activity in response to insulin or integrin stimulation. 5 SHPS-1 overexpression suppressed anchorage-independent cell growth and cancer dissemination; however, phosphorylation states of MAPK and c-jun NH2-terminal kinase (JNK) were almost similar. 6 In fibroblasts expressing an SHPS-1 mutant lacking most of the cytoplasmic region, growth factor-induced JNK

SIRPα1 receptors interfere with the EGFRvIII signalosome to inhibit glioblastoma cell transformation and migration

“…The present data strongly support our previous findings and reports from other groups that SIRPa1 is one of the important binding partners of SHP-2 (Wu et al, 2000;Yan et al, 2004;Qin et al, 2006;Eminaga and Bennett, 2008). However, it is unclear how SIRPa1 modulates SHP-2 activity to exert its regulatory effects.…”

“…Our previous study and reports from other groups have shown that SIRPa1 is involved in the regulation of cell migration and motility (Wu et al, 2000;Motegi et al, 2003;Yan et al, 2004). On the basis of these observations, we extended our study to assess the role of SIRPa1 receptor on tumor cell migration mediated by the constitutively active EGFRvIII oncoprotein.…”

Prostate cancer downregulated SIRP-α modulates apoptosis and proliferation through p38-MAPK/NF-κB/COX-2 signaling

“…Previously, decreased SIRP-α expression levels have been reported in various types of cancer, indicating its important role in oncology (9,10). The present study identified that SIRP-α expression tended to be lower in AIPC tissues compared with paired ADPC tissues.…”

“…SIRP-α has been shown to promote cell apoptosis in liver cancer (10) and breast carcinoma (9), but the molecular mechanism remains unclear. The present study confirmed that SIRP-α is involved in the regulation of cellular proliferation and apoptosis in ADPC and AIPC cell lines.…”

SIRPβ1 Is Expressed as a Disulfide-linked Homodimer in Leukocytes and Positively Regulates Neutrophil Transepithelial Migration

“…In addition, SIRPs are expressed in neuronal cells (4 -6) and certain types of cancer cells (7)(8)(9)(10). SIRPs can be divided into two subfamilies, SIRP␣ and SIRP␤, based on the putative structures of their C-terminal intracellular domains (11).…”