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Open Access Research article

Genetic and bioinformatic analyses of the expression and function of PI3K regulatory subunit PIK3R3 in an Asian patient gastric cancer library

Jin Zhou1, Geng Bo Chen3, Yew Chung Tang4, Rohit Anthony Sinha1, Yonghui Wu8, Chui Sun Yap1, Guihua Wang5, Junbo Hu5, Xianmin Xia5, Patrick Tan10289, Liang Kee Goh367 and Paul Michael Yen1*

Author Affiliations

1 Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore

2 Laboratory of Genomic Oncology, Cancer and Stem Cell Program, Duke-National University of Singapore Graduate Medical School, Singapore

3 Laboratory of Computational Biology, Cancer and Stem Cell Program, Duke-National University of Singapore Graduate Medical School, Singapore

4 Laboratory of Computational Systems Biology and Human Genetics, Neuroscience and Behavioral Disorder Program, Duke-National University of Singapore Graduate Medical School, Singapore

5 Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China

6 Department of Medical Oncology, National Cancer Centre, Singapore

7 Saw Swee Hock School of Public Health, National University of Singapore, Singapore

8 Cellular and Molecular Research, National Cancer Centre, Singapore

9 Cancer Science Institute of Singapore, National University of Singapore, Singapore

10 Genome Institute of Singapore, Singapore

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BMC Medical Genomics 2012, 5:34  doi:10.1186/1755-8794-5-34

Published: 9 August 2012

Abstract

Background

While there is strong evidence for phosphatidylinositol 3-kinase (PI3K) involvement in cancer development, there is limited information about the role of PI3K regulatory subunits. PIK3R3, the gene that encodes the PI3K regulatory subunit p55γ, is over-expressed in glioblastoma and ovarian cancers, but its expression in gastric cancer (GC) is not known. We thus used genetic and bioinformatic approaches to examine PIK3R3 expression and function in GC, the second leading cause of cancer mortality world-wide and highly prevalent among Asians.

Methods

Primary GC and matched non-neoplastic mucosa tissue specimens from a unique Asian patient gastric cancer library were comprehensively profiled with platforms that measured genome-wide mRNA expression, DNA copy number variation, and DNA methylation status. Function of PIK3R3 was predicted by IPA pathway analysis of co-regulated genes with PIK3R3, and further investigated by siRNA knockdown studies. Cell proliferation was estimated by crystal violet dye elution and BrdU incorporation assay. Cell cycle distribution was analysed by FACS.

Results

PIK3R3 was significantly up-regulated in GC specimens (n = 126, p < 0.05), and 9.5 to 15% tumors showed more than 2 fold increase compare to the paired mucosa tissues. IPA pathway analysis showed that PIK3R3 promoted cellular growth and proliferation. Knockdown of PIK3R3 decreased the growth of GC cells, induced G0/G1 cell cycle arrest, decreased retinoblastoma protein (Rb) phosphorylation, cyclin D1, and PCNA expression.

Conclusion

Using a combination of genetic, bioinformatic, and molecular biological approaches, we showed that PIK3R3 was up-regulated in GC and promoted cell cycle progression and proliferation; and thus may be a potential new therapeutic target for GC.