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Updated: Jan 25, 2026
Establishment of Gastric Cancer Patient-derived Xenograft Models and Primary Cell Lines
Published on: July 19, 2019
c-Met-dependent phosphorylation of RhoA plays a key role in gastric cancer tumorigenesis
Jianjun Liu1,2, Shun Li1,2, Shangxiang Chen1,2
1State Key Laboratory of Oncology in South PR China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
Abstract:
RhoA has been identified as having a gain-of-function mutation in approximately 20% of diffuse gastric cancer patients. However, the carcinogenic role of RhoA mutations in gastric cancer (GC) is unclear. In the present study, we report that RhoA directly interacts with c-Met and can be phosphorylated by c-Met at Y42 before subsequent K48-linked polyubiquitination and proteasome-mediated protein degradation. Y42C-mutated RhoA exhibits higher protein levels and promotes the proliferation and motility of GC cells. Interestingly, a c-Met inhibitor significantly repressed the growth of GC cells transfected with WT RhoA but not RhoA mutated at Y42 in vivo and in vitro. Analyses of human GC tissues showed that the combined levels of p-c-Met and p-RhoA are a better predictor for prognosis than either factor alone. Taken together, our findings unravel the mechanism by which the RhoA Y42 mutant is linked to poor prognosis in GC. Moreover, this study helps to identify a strategy for patient stratification and optimization of targeted c-Met therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Insights
Gain-of-function RhoA mutations drive gastric cancer (GC) by interacting with c-Met. The Y42 mutant RhoA promotes GC cell growth and motility, impacting patient prognosis and targeted therapy strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Gain-of-function mutations in RhoA are found in 20% of diffuse gastric cancer (GC) patients.
- The precise role of RhoA mutations in gastric cancer pathogenesis remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which RhoA mutations contribute to gastric cancer.
- To investigate the interaction between RhoA and c-Met in GC.
- To evaluate the therapeutic potential of targeting the RhoA-c-Met pathway.
Main Methods:
- Investigated RhoA-c-Met interaction and RhoA phosphorylation at Y42.
- Assessed the impact of Y42C-mutated RhoA on GC cell proliferation and motility.
- Utilized c-Met inhibitors in vitro and in vivo models with wild-type (WT) and Y42-mutated RhoA.
- Analyzed RhoA and c-Met phosphorylation levels in human GC tissues.
Main Results:
- RhoA directly interacts with c-Met and is phosphorylated at Y42, leading to its degradation.
- Y42C-mutated RhoA shows increased protein stability, enhancing GC cell proliferation and motility.
- c-Met inhibition effectively reduced tumor growth in WT RhoA-expressing GC cells, but not in Y42-mutated RhoA cells.
- Combined levels of phosphorylated c-Met (p-c-Met) and phosphorylated RhoA (p-RhoA) are superior prognostic markers in GC.
Conclusions:
- The RhoA Y42 mutant is mechanistically linked to poor prognosis in gastric cancer.
- Understanding the RhoA-c-Met pathway offers a strategy for patient stratification.
- Targeted c-Met therapy can be optimized based on RhoA mutation status.
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