Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2 0 -deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.
This study investigates the correlation between the oncoprotein Bmi-1 and telomerase activity in ovarian cancer. A real-time polymerase chain reaction (PCR) method is used to detect the messenger RNA (mRNA) expression of Bmi-1 protein in 47 ovarian epithelial cancer cases, and immunohistochemistry is used to detect Bmi-1 protein expression in the tissues. A modified telomeric repeat amplification protocol (TRAP) is used to detect telomerase activity. Western blotting is used to detect the expression of telomerase hTERT in the tissues studied. Compared to normal ovarian epithelial tissue, Bmi-1 protein in the 47 ovarian epithelial cancer cases showed higher expression and was related to pathological grade and clinical stage. Significantly higher Bmi-1 levels were found among different clinocopathological types of the cancer (P<0.05). Grade G3 cases expressed Bmi-1 at a higher rate (93.10%) than did grade G2 cases (61.11%). Expression in phase II and phase III cases was lower (66.67%) than in phase IV (92.31%). In ovarian epithelial cancer tissues, 87.23% (41/47) cases demonstrated positive telomerase activity, whereas no activity was observed in normal tissues. The majority (90.24%) of specimens with positive telomerase activity showed high Bmi-1 expression levels. Spearman correlation analysis indicated that expression of Bmi-1 protein correlated positively with elevated telomerase activity. Bmi-1 protein is highly expressed in ovarian epithelial cancer tissues, and expression correlates with histological grade and clinical phase. Elevated Bmi-1 expression correlates closely with increased telomerase activity and plays a significant role in the pathogenesis of ovarian cancer.
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