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CD81 is a candidate tumor suppressor gene in human gastric cancer
Tae-Hyoung Yoo1, Byung-Kyu Ryu, Min-Goo Lee
1School of Life Sciences and Biotechnology, Korea University, 136-701, Seoul, Republic of Korea.
Background:
CD81 is a transmembrane protein that serves as a putative receptor for hepatitis C virus. In addition, CD81 has been suggested to be involved in a broad range of other cellular functions. Its putative implication in tumorigenesis has so far, however, remained largely unexplored. To assess the candidacy of CD81 as a tumor suppressor in gastric cancer development, we investigated its expression and function in a series of primary gastric tumors and gastric tumor-derived cell lines.
Methods:
The expression and concomitant methylation status of the CD81 gene and its effect on tumor development and cellular signaling were evaluated.
Results:
CD81 mRNA levels were found to be low in 16 of 40 (40 %) primary tumors and 9 of 14 (64.2 %) cell lines, and these low expression levels were found to correlate with the stage and grade of the tumors. Genomic alterations of CD81 were not encountered, whereas its expression could be re-activated in low expressing cells upon 5-aza-dC treatment. Bisulfite DNA sequencing analysis of 10 CpG sites within the 5' proximal region of the CD81 gene promoter revealed that the observed transcriptional silencing was tightly associated with aberrant hypermethylation. Subsequent restoration of CD81 expression induced a G1 cell cycle arrest and apoptosis, whereas siRNA-mediated CD81 down-regulation promoted cell proliferation and attenuated cellular responses to various apoptotic stress stimuli. Also the colony-forming ability of the tumor cells could be inhibited and enhanced through CD81 up- and down-regulation, respectively. CD81 was found to inhibit p38 (but not ERK, JNK and AKT) phosphorylation and its growth suppressive effect could be abolished through p38 up- and down-regulation.
Conclusion:
From our data we conclude that epigenetic inactivation of CD81 is a common feature of gastric tumors and that this inactivation may render growth and survival advantages to the tumor cells, at least partially through p38 signaling.
Insights
Epigenetic silencing of CD81, a tumor suppressor, is common in gastric cancer. Reactivating CD81 inhibits tumor growth and promotes apoptosis, partly via p38 signaling.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- CD81 is a transmembrane protein implicated in various cellular functions.
- Its role in tumorigenesis, particularly gastric cancer, remains under-explored.
Purpose of the Study:
- To investigate the expression and function of CD81 in gastric cancer.
- To assess CD81's potential as a tumor suppressor in gastric cancer development.
Main Methods:
- Evaluated CD81 gene expression and methylation status in primary gastric tumors and cell lines.
- Assessed the impact of CD81 modulation on cell cycle, apoptosis, and proliferation.
- Investigated the role of p38 signaling in CD81's tumor-suppressive effects.
Main Results:
- CD81 expression was frequently downregulated in gastric tumors, correlating with advanced stage and grade.
- Transcriptional silencing was linked to promoter hypermethylation, reversible with 5-aza-dC treatment.
- Restoring CD81 induced G1 cell cycle arrest and apoptosis, inhibited colony formation, and suppressed p38 phosphorylation.
Conclusions:
- Epigenetic inactivation of CD81 is a frequent event in gastric tumors.
- CD81 inactivation confers growth and survival advantages to tumor cells, partly through p38 signaling.
- CD81 acts as a tumor suppressor in gastric cancer, with its silencing representing a potential therapeutic target.
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