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RAB20 Promotes Proliferation via G2/M Phase through the Chk1/cdc25c/cdc2-cyclinB1 Pathway in Penile Squamous Cell
Xingliang Tan1,2,3, Gangjun Yuan4,5, Yanjun Wang1,2,3
1Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Abstract:
RAB20, a member of the RAS GTPase oncogene family, is overexpressed in several cancers with poor outcomes, promoting tumorigenesis and inducing genomic instability. Here, we performed comprehensive genomic sequencing on eight penile squamous cell carcinoma (PSCC) and normal tissue pairs and found that RAB20 was upregulated in tumors, especially in metastatic lymph nodes. RAB20 overexpression in tumors was further verified by qPCR, Western blotting, and immunohistochemistry of our newly established PSCC cell lines and paired tissues. The clinical significance of RAB20 was validated in 259 PSCC patients, the largest cohort to date, and high RAB20 expression positively correlated with the T, N, M status, extranodal extension, and clinical stage (all p < 0.01). RAB20 was an unfavorable independent prognostic indicator in the survival analysis (p = 0.011, HR = 2.090; 95% Cl: 1.183−4.692), and PSCC patients with high RAB20 expression experienced shorter 5-year cancer-specific survival times (p < 0.001). Furthermore, tumorigenesis assays demonstrated that RAB20 knockdown inhibited cell proliferation, migration, and colony formation in vitro and tumor growth in vivo. RAB20 depletion also induced PSCC cell cycle arrest at G2/M by increasing Chk1 expression and promoting cdc25c phosphorylation to reduce cdc2-cyclinB1 complex formation. Our study revealed an oncogenic role for RAB20 in promoting PSCC cell proliferation at the G2/M phase via the Chk1/cdc25c/cdc2-cyclinB1 pathway. Thus, RAB20 could be a promising prognostic biomarker of advanced PSCC with poor patient survival outcomes and could be a potential therapeutic target.
Insights
RAS oncogene family member RAB20 is overexpressed in penile squamous cell carcinoma (PSCC), promoting tumor growth and poor survival. Knockdown of RAB20 inhibited PSCC progression, suggesting it as a therapeutic target.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- RAS GTPase oncogene family member RAB20 is linked to poor outcomes in various cancers.
- RAB20 overexpression promotes tumorigenesis and genomic instability.
Purpose of the Study:
- To investigate the role of RAB20 in penile squamous cell carcinoma (PSCC).
- To evaluate RAB20 as a prognostic biomarker and potential therapeutic target in PSCC.
Main Methods:
- Comprehensive genomic sequencing of PSCC and normal tissues.
- Quantitative PCR, Western blotting, and immunohistochemistry for RAB20 expression.
- Clinical validation in a cohort of 259 PSCC patients.
- In vitro and in vivo tumorigenesis assays.
- Analysis of cell cycle regulation pathways.
Main Results:
- RAB20 was significantly upregulated in PSCC tumors, particularly in metastatic lymph nodes.
- High RAB20 expression correlated with advanced T, N, M status, extranodal extension, and clinical stage.
- RAB20 served as an independent unfavorable prognostic indicator, associated with shorter survival.
- RAB20 knockdown inhibited PSCC cell proliferation, migration, and tumor growth.
- RAB20 depletion induced G2/M cell cycle arrest via the Chk1/cdc25c/cdc2-cyclinB1 pathway.
Conclusions:
- RAB20 plays an oncogenic role in PSCC progression by promoting proliferation at the G2/M phase.
- RAB20 is a promising prognostic biomarker for advanced PSCC with poor survival.
- RAB20 represents a potential therapeutic target for PSCC treatment.
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