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Attenuation of MET-mediated migration and invasion in hepatocellular carcinoma cells by SOCS1
Yirui Gui1, Md Gulam Musawwir Khan1, Diwakar Bobbala1
1Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
Aim:
To investigate the role of suppressor of cytokine signaling 1 (SOCS1) in regulating MET-mediated invasive potential of hepatocellular carcinoma (HCC) cells.
Methods:
Stable 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.
Results:
SOCS1 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.
Conclusion:
Our 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.
Insights
Suppressor of cytokine signaling 1 (SOCS1) inhibits hepatocellular carcinoma (HCC) cell invasion and metastasis by regulating MET signaling. Loss of SOCS1 promotes HCC cell migration, invasion, and tumor growth, indicating its critical role in controlling HCC progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Hepatocellular carcinoma (HCC) is a major global health concern with limited treatment options.
- The MET signaling pathway plays a crucial role in HCC progression, including migration, invasion, and metastasis.
- Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of cytokine signaling, but its role in HCC remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of SOCS1 in regulating MET-mediated invasive potential of hepatocellular carcinoma (HCC) cells.
- To determine how SOCS1 expression affects HCC cell migration, invasion, proliferation, and tumor formation in vivo.
- To elucidate the molecular mechanisms by which SOCS1 influences epithelial-to-mesenchymal transition (EMT) in HCC cells.
Main Methods:
- Stable SOCS1-expressing and control HCC cell lines (mouse Hepa1-6, human Hep3B, HepG2) were generated.
- Transwell migration, 3-D invasion, and anchorage-independent proliferation assays were performed.
- Orthotopic tumor formation was evaluated in NOD.scid.gamma mice.
- Protein and gene expression related to EMT, STAT3, ERK, and MET were analyzed by western blot and qRT-PCR.
Main Results:
- SOCS1 expression inhibited HGF-induced migration and invasion of HCC cells in vitro.
- SOCS1 reduced anchorage-independent proliferation and orthotopic tumor formation in vivo.
- SOCS1 expression decreased MET protein levels and STAT3/ERK phosphorylation.
- SOCS1 promoted E-cadherin expression while reducing EGR1, SNAI1, and ZEB1, key EMT markers.
Conclusions:
- SOCS1 acts as a tumor suppressor in HCC by inhibiting MET-mediated invasion and metastasis.
- Loss of SOCS1-dependent control over EMT contributes to HCC progression.
- SOCS1 represents a potential therapeutic target for HCC treatment.
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