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KMID : 0988920070050020131
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Intestinal Research
2007 Volume.5 No. 2 p.131 ~ p.143
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Molecular Characterization of hSRBC, a Candidate Tumor Suppressor Gene anda Upstream Regulator of p53 in Human Colon Cancer
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Kim Wan-Jung
Kim Hyo-Jong
Kim Jin-Oh
Cho Joo-Young
Shim Chan-Sup
Chi Sung-Gil
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Abstract
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Background: hSRBC [human Serum deprivation response (sdr)-Related gene product that Binds to c-kinase] was identified using PKCδ or BRCA1 as a probe and located at 11p15.5-p15.4 region. Expression of hSRBC protein was also decreased in a number of breast, lung, and ovarian cancer cell lines, suggesting that hSRBC might be a putative tumor suppressor gene.
Method:The expression status of hSRBC was analyzed in 50 primary colon tumors and their adjacent 50 normal tissues, and 20 colon cancer cell lines. Transcript and protein expression of hSRBC was studied by quantitative RT-PCR and Western blot, respectively. siRNA-mediated knockdown of hSRBC expression was utilized to investigate its association with p53.
Results: The mRNA expression of hSRBC was decreased in 60% (12/20) of colon cancer cell lines and 44% (22/50) of patient’s colon cancer tissues. Expression of hSRBC mRNA was significantly decreased in tumors compared to non-cancerous cells, while genomic level of hSRBC was not decreased in tumors. hSRBC expression was increased by 5-aza-2’-deoxycytidine treatment and hypermethylation of CpG sites was strongly associated with decreased expression. Ectopic transfection of hSRBC suppressed RKO cell count and hSRBC knockdown by siRNA augmented HCT116 cell numbers. Flow cytometry showed G1 arrest and apoptosis of colon cancer cells by restoration of hSRBC expression in RKO cells. Both basal and etoposide-mediated p53 expression was decreased when hSRBC expression was knockdowned with siRNA.
Conclusions: hSRBC expression is frequently decreased by promoter CpG site hypermethylation. hSRBC down-regulates p53 expression in G1 phase and might be a novel upstream regulator of p53.
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KEYWORD
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Genes, Tumor Suppressor, PRKCDBP Protein, Human, p53, Gene Silencing, Colorectal Neoplasms
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