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

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.

• Authors: Jin Zhou, Geng Bo Chen, Yew Chung Tang, Rohit Anthony Sinha, Yonghui Wu, Chui Sun Yap, Guihua Wang, Junbo Hu, Xianmin Xia, Patrick Tan, Liang Kee Goh, Paul Michael Yen
• Journal: BMC medical genomics (BMC Med Genomics) Vol. 5 Pg. 34 (Aug 09 2012) ISSN: 1755-8794 [Electronic] England
• PMID: 22876838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCND1 protein, human
• Phosphoinositide-3 Kinase Inhibitors
• Protein Subunits
• RNA, Messenger
• RNA, Small Interfering
• Retinoblastoma Protein
• Cyclin D1
• PIK3R3 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Asian People (genetics)
• Cell Proliferation
• Computational Biology (methods)
• Cyclin D1 (genetics, metabolism)
• G1 Phase Cell Cycle Checkpoints (genetics)
• Gastric Mucosa (metabolism, pathology)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Protein Subunits (genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Resting Phase, Cell Cycle (genetics)
• Retinoblastoma Protein (metabolism)
• Signal Transduction (genetics)
• Stomach Neoplasms (enzymology, genetics, pathology)