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Down-Regulation of PIK3CG, a Catalytic Subunit of Phosphatidylinositol 3-OH Kinase, by CpG Hypermethylation in Human Colorectal Carcinoma¹

First Department of Pathology [S. S., N. I., M. I., M. H, M. Y.] and First Department of Surgery [T. M., W. K.], Yamagata University School of Medicine, Yamagata, 990-9585, Japan, and Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [E. M. Y.]

Purpose: Premature death associated with colorectal adenocarcinoma occurs in PIK3CG^-/- mice and overexpression of PIK3CG in colon cancer cells suppresses cell proliferation. We examined expression levels of PIK3CG, a catalytic subunit of phosphatidylinositide 3-OH kinase (PI3K), in colon cancer cells to investigate the hypothesis that PIK3CG might contribute to the growth and progression of colorectal cancers.

Experimental Design: The effects of LY294002, a PI3K inhibitor, on cell growth were examined to elucidate the role of the PI3K-Akt/protein kinase B (PKB) pathway in colon cancer. We used reverse transcription-PCR, Western blotting, and immunohistochemical analyses to examine PIK3CG mRNA and protein expression levels in colon cancer cells and primary colorectal cancers. To clarify the mechanism responsible for the silencing of this gene in colon cancers, we performed methylation-sensitive PCR analysis of DNA digested with HpaII and MspI and analyzed PI3KCG expression in DLD-1 and LoVo cells treated with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza).

Results: LY294002 suppressed growth and decreased expression of Akt (Ser⁴⁷³) expression in cancer cells. Three (60%) of 5 colon cancer cell lines did not express PIK3CG, but hypermethylation at CpG sites of the promoter regions of this gene was detected. However, 5-Aza-treated DLD-1 and LoVo cells did express PIK3CG. Reduction of PIK3CG expression was detected immunohistochemically in 85% of human colorectal cancers and was closely associated with invasion, metastasis, and poor differentiation. Down-regulation of PIK3CG expression and hypermethylation of promoter regions were also detected in primary colon cancers.

Conclusions: Our findings suggest that the silencing of the PIK3CG gene plays an important role in inhibiting the PI3K-Akt/PKB signaling system responsible for tumorigenesis and the progression of colorectal cancers.

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