Attenuation of MET-mediated migration and invasion in hepatocellular carcinoma cells by SOCS1

Abstract

AIMTo investigate the role of suppressor of cytokine signaling 1 (SOCS1) in regulating MET-mediated invasive potential of hepatocellular carcinoma (HCC) cells.METHODSStable derivatives of mouse (Hepa1-6) and human (hep3B, HepG2) HCC cell lines expressing SOCS1 or control vector were evaluated for their ability to migrate towards hepatocyte growth factor (HGF) in the transwell migration assay, invade extracellular matrix in response to HGF stimulation in a 3-D invasion assay by confocal microscopy, and to undergo anchorage-independent proliferation in semisolid agar. Following intravenous and intrasplenic inoculation into NOD.scid.gamma mice, the ability of Hepa cells to form othotopic tumors was evaluated. Following HGF stimulation of Hepa and Hep3B cells, expression of proteins implicated in epithelial-to-mesenchymal transition was evaluated by western blot and qRT-PCR.RESULTSSOCS1 expression in mouse and human HCC cells inhibited HGF-induced migration through matrigel. In the 3-D invasion assay, HGF stimulation induced invasion of HCC cells across type-I collagen matrix, and SOCS1 expression significantly reduced the depth of invasion. SOCS1 expression also reduced the number and size of colonies formed by anchorage-independent growth in semisolid agar. Following intravenous inoculation, control Hepa cell formed large tumor nodules that obliterated the liver whereas the SOCS1-expressing Hepa cells formed significantly smaller nodules. Tumors formed by SOCS1-expressing cells showed reduced phosphorylation of STAT3 and ERK that was accompanied by reduced levels of MET protein expression. HGF stimulated Hepa cells expressing SOCS1 showed increased expression of E-cadherin and decreased expression of EGR1, SNAI1 and ZEB1. Comparable results were obtained with Hep3B cells. SOCS1 expressing HCC cells also showed reduced levels of EGR1 and SNAI1 transcripts.CONCLUSIONOur findings indicate that loss of SOCS1-dependent control over epithelial-to-mesenchymal transition may contribute to MET-mediated migration, invasion and metastatic growth of HCC.

Exosomes of pasteurized milk: potential pathogens of Western diseases

“…Novel replication-competent circular DNA molecules with potential proliferative activity have been detected in commercial milk of dairy cows [416][417][418][419][420], that via milk exosome transfer may reach distant tissue including the brain. Exosomes and their cargo are also involved in the spread of neurotoxic proteins such as α-syn, amyloid-β and prions [392,393,[421][422][423][424][425]. Therefore, dairy milk-derived exosomes, although representing an easily accessible and abundant source of exosomes, are apparently not suitable for the treatment of human diseases.…”

“…TP53INP1 is a p53-inducible gene that regulates p53-dependent apoptosis, downregulates the expression of SPARC and is repressed by miR-155 [389][390][391]. Recent findings indicate that loss of SOCS1-dependent control over EMT may contribute to MET-mediated migration, invasion and metastatic growth of HCC [392]. Translational evidence indicates that milk-derived exosomes via transfer of onocogenic miR-148a, miR-21, miR-155 and TGF-β may promote the development of HCC (Fig.…”

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Following HGF binding, the docking motif within the C-terminal end of activated c-MET associates with the SH2 domain of STAT3 and phosphorylates STAT3 [57,58]. However, suppressor of cytokine signaling (SOCS)-1 reduces STAT3 activation by proteasomal degradation of c-MET through direct interaction with c-Met [59,60].…”

Proteinase-activated receptor 2 promotes tumor cell proliferation and metastasis by inducing epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma

“…Recently, some growth factors such as HGF were reported to be responsible for EMT in HCC. Whether HGF participates in PAR2-induced EMT could be further investigated based on this study[ 27 , 35 ].…”