Brief Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jul 28, 2012; 18(28): 3745-3751
Published online Jul 28, 2012. doi: 10.3748/wjg.v18.i28.3745
PI3K expression and PIK3CA mutations are related to colorectal cancer metastases
Yu-Fen Zhu, Bao-Hua Yu, Da-Li Li, Hong-Lin Ke, Xian-Zhi Guo, Xiu-Ying Xiao
Yu-Fen Zhu, Hong-Lin Ke, Xian-Zhi Guo, Xiu-Ying Xiao, Department of Oncology, Shanghai Xuhui District Center Hospital, Shanghai 200031, China
Bao-Hua Yu, Da-Li Li, Department of Pathology, Fudan University, Shanghai Cancer Center, Shanghai 200032, China
Author contributions: Zhu YF and Yu BH performed most of the experiments and the analysis; Ke HL and Guo XZ sorted out the materials; Li DL assisted with analysis of the results; and Xiao XY directed most experiments and wrote and modified the manuscript.
Supported by Youth Foundation of Shanghai Municipal Health Bureau, No. 2008Y087; Jiangsu University Clinical Medicine Science and Technology Development Fund, No. JLY20080090
Correspondence to: Xiu-Ying Xiao, MD, PhD, Department of Oncology, Shanghai Xuhui District Center Hospital, Shanghai 200031, China. xiaoxiuying2002@163.com
Telephone: +86-21-31270810 Fax: +86-21-54039762
Received: July 29, 2011
Revised: September 26, 2011
Accepted: April 12, 2012
Published online: July 28, 2012
Abstract

AIM: To assess the significance of phosphatidylinositol 3-kinase (PI3K) in colorectal cancer (CRC) and toxicity of LY294002 in CRC cells with different metastatic abilities.

METHODS: Sixty formalin-fixed and paraffin-embedded CRC tumor specimens were investigated. Adjacent normal colonic mucosa specimens from 10 of these cases were selected as controls. PI3K protein was detected by immunohistochemistry and PIK3CA mutations were investigated by gene sequencing analysis. A flow-cytometry-based apoptosis detection kit was used to determine PI3K inhibitor-induced apoptosis in CRC cell lines SW480 and SW620. Expression of phosphorylated protein kinase B in CRC cell lines was detected by Western blotting.

RESULTS: There was a significant difference in the proportion of primary lesions (30%, 18/60) vs metastatic lesions (46.7%, 28/60) that were positive for PI3K (P < 0.05). Mutations were detected in exon 9 (13.3%) and exon 20 (8.3%). Out of 60 cases, seven mutations were identified: two hotspot mutations, C.1633G>A resulting in E545A, and C.3140A>G resulting in H1047R; two novel missense mutations C.1624G>A and C.3079G>A; and three synonymous mutations (C.1641G>A, C.1581C>T and C.3027T>A). Exposure of SW480 cells to PI3K inhibitor for 48 h resulted in a significant increase of apoptotic cells in a dose-dependent manner [3.2% apoptotic cells in 0 μmol/L, 4.3% in 5 μmol/L, 6.3% in 10 μmol/L (P < 0.05), and 6.7% in 20 μmol/L (P < 0.05)]. Moreover, PI3K inhibitor induced a similar significant increase of apoptotic cells in the SW620 cell line for 48 h [3.3% apoptotic cells in 0 μmol/L, 13.3% in 5 μmol/L (P < 0.01), 19.2% in 10 μmol/L (P < 0.01), and 21.3% in 20 μmol/L (P < 0.01)].

CONCLUSION: High PI3K expression is associated with CRC metastasis. PI3K inhibitor induced apoptosis in CRC cells and displayed strong cytotoxicity for highly metastatic cells. PI3K inhibition may be an effective treatment for CRC.

Keywords: Colorectal cancer, PI3K, PIK3CA, Metastasis