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Original Articles
- RASSF4 Suppresses Gastric Tumor Growth through Activation of Chk2-p53 Signaling Axis
- Soon-Ki Park, Min-Ju Kang, Kyung-Phil Ko, Sung-Gil Chi
- Received February 5, 2025 Accepted April 17, 2025 Published online April 18, 2025
- DOI: https://doi.org/10.4143/crt.2025.135 [Accepted]
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Abstract
PDF - Purpose
Ras association domain family 4 (RASSF4) is a putative tumor suppressor that is frequently inactivated in multiple human cancers. However, its candidacy as a suppressor in gastric tumorigenesis remains undefined. To understand the role for RASSF4 in gastric tumorigenesis, we investigated its expression status in cancer cell lines and tissues and regulatory role in tumor growth.
Materials and Method
RASSF4 expression was analyzed in 13 cancer cell lines and 20 carcinoma tissues using PCR and immunoblot assays. RASSF4 effect on cell proliferation and apoptosis was examined by flow cytometry, colony formation, and [3H]thymidine incorporation assays and its regulation of p53 was determined using cycloheximide chase, promoter reporter, and immunoprecipitation assays. Mouse xenograft assay was performed to verify RASSF4 effect on tumor growth and therapeutic response.
Results
RASSF4 expression is epigenetically inactivated in 8 of 13 (61.5%) cancer cell lines and 15 of 20 (75%) primary carcinomas. RASSF4 suppresses cell proliferation by inducing a G2/M cell-cycle arrest and enhances apoptotic response to therapeutic drugs. RASSF4 is induced in response to genotoxic agents to facilitate stress-induced apoptosis in a highly p53-dependent fashion. Mechanistically, RASSF4 stabilizes p53 through Chk2 activation and its apoptotic function is profoundly impaired by depletion of either p53 or Chk2. RASSF4 attenuates xenograft tumor growth and enhances tumor response to 5-FU. Clinically, RASSF4 expression correlates strongly with the overall survival of gastric cancer patients.
Conclusion
RASSF4 suppresses gastric tumor growth through the activation of the Chk2-p53 axis, illuminating the mechanistic consequence of its inactivation in gastric tumorigenesis.
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- AKAP12α is Associated with Promoter Methylation in Lung Cancer
- Ukhyun Jo, Young Mi Whang, Han Kyeom Kim, Yeul Hong Kim
- Cancer Res Treat. 2006;38(3):144-151. Published online June 30, 2006
- DOI: https://doi.org/10.4143/crt.2006.38.3.144
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Abstract
PDF
PubReader
ePub Purpose Promoter methylation is an important mechanism for silencing tumor-suppressor genes in cancer and it is a promising tool for the development of molecular biomarkers. The purpose of the present study was to investigate whether inactivation of the A Kinase Anchoring Protein 12 (AKAP12) gene is assoCiated with promoter methylation in lung cancer.
Materials and Methods The AKAP12 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) in ten lung cancer cell lines. The methylation status of the AKAP12α promoter was analyzed by performing bisulfite sequencing analysis in ten lung cancer cell lines, twenty four lung tissues and matched normal tissues.
Results The AKAP12α expression was reduced in 6 of 10 (60%) lung cancer cell lines, whereas the AKAP12β expression was absent in 1 of 10 (10%) lung cancer cell lines. The AKAP12α expression was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine in three lung cancer cell lines. Methylation of CpG island 1 in the AKAP12α promoter was detected in 30% of the lung cancer cell lines, whereas methylation of CpG island 2 in the AKAP12α promoter was observed in the immortalized bronchial cell line and in all the lung cancer cell lines. In lung tumors, the CpG island 1 in the AKAP12α promoter was infrequently methylated. However, CpG island 2 in the AKAP12α promoter was highly methylated in lung tumors compared with the surrounding normal tissues, and this was statistically significant (p=0.0001).
Conclusion Our results suggest that inactivation of the AKAP12α expression is assoCiated with DNA methylation of the promoter region in lung cancer, and that AKAP12α may play an important role in lung cancer carcinogenesis.
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Citations
Citations to this article as recorded by
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- AKAP12 promotes cancer stem cell-like phenotypes and activates STAT3 in colorectal cancer
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