Retrospective Study
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2014; 20(43): 16258-16267
Published online Nov 21, 2014. doi: 10.3748/wjg.v20.i43.16258
Phosphatidylinositol 3-kinase CB association with preoperative radiotherapy response in rectal adenocarcinoma
Wei-Dong Yu, Yi-Fan Peng, Hong-Da Pan, Lin Wang, Kun Li, Jin Gu
Wei-Dong Yu, Kun Li, Institute of Clinical Molecular Biology, People’s Hospital, Peking University, Beijing 100044, China
Yi-Fan Peng, Hong-Da Pan, Lin Wang, Jin Gu, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Colorectal Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China
Kun Li, Department of Gastroenterology, People’s Hospital, Peking University, Beijing 100044, China
Author contributions: Yu WD and Peng YF contributed equally to this work, performed the majority of experiments, provided financial support, and were also involved in designing the study and writing the manuscript; Pan HD and Li K provided vital reagents and analytical tools, and were also involved in revising the manuscript; Wang L collected all the clinical materials; Gu J designed the study and wrote the manuscript.
Supported by Grants from the National Natural Science Foundation of China No. 30872923 and the Peking University People’s Hospital Research and Development Fund No. RDB2007-47, No. RDK2008-01 and No. RDB2011-25
Correspondence to: Jin Gu, MD, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Colorectal Surgery, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing 100142, China. zlgujin@126.com
Telephone: +86-10-88196086 Fax: +86-10-88196086
Received: June 11, 2014
Revised: July 9, 2014
Accepted: August 13, 2014
Published online: November 21, 2014
Processing time: 161 Days and 23.4 Hours
Abstract

AIM: To examine the correlation of phosphatidylinositol 3-kinase (PIK3) CB expression with preoperative radiotherapy response in patients with stage II/III rectal adenocarcinoma.

METHODS: PIK3CB immunoexpression was retrospectively assessed in pretreatment biopsies from 208 patients with clinical stage II/III rectal adenocarcinoma, who underwent radical surgery after 30-Gy/10-fraction preoperative radiotherapy. The relation between PIK3CB expression and tumor regression grade, clinicopathological characteristics, and survival time was statistically analyzed. Western blotting and in vitro clonogenic formation assay were used to detect PIK3CB expression in four colorectal cancer cell lines (HCT116, HT29, LoVo, and LS174T) treated with 6-Gy ionizing radiation. Pharmacological assays were used to evaluate the therapeutic relevance of TGX-221 (a PIK3CB-specific inhibitor) in the four colorectal cancer cell lines.

RESULTS: Immunohistochemical staining indicated that PIK3CB was more abundant in rectal adenocarcinoma tissues with poor response to preoperative radiotherapy. High expression of PIK3CB was closely correlated with tumor height (P < 0.05), ypT stage (P < 0.05), and high-degree tumor regression grade (P < 0.001). High expression of PIK3CB was a potential prognostic factor for local recurrence-free survival (P < 0.05) and metastasis-free survival (P < 0.05). High expression of PIK3CB was also associated with poor therapeutic response and adverse outcomes in rectal adenocarcinoma patients treated with 30-Gy/10-fraction preoperative radiotherapy. In vitro, PIK3CB expression was upregulated in all four colorectal cancer cell lines concurrently treated with 6-Gy ionizing radiation, and the PIK3CB-specific inhibitor TGX-221 effectively inhibited the clonogenic formation of these four colorectal cancer cell lines.

CONCLUSION: PIK3CB is critically involved in response to preoperative radiotherapy and may serve as a novel target for therapeutic intervention.

Keywords: Phosphatidylinositol 3-kinase CB; Tumor regression grade; ypT stage; Disease-free survival; Therapeutic target; Rectal cancer; Preoperative radiotherapy

Core tip: The response of rectal cancer cells to preoperative radiotherapy may be related to the dysregulation of phosphatidylinositol 3-kinase (PI3K) signaling molecules, in particular high expression of PIK3CB. Therefore, we evaluated whether PIK3CB upregulation was involved in poor response to preoperative radiotherapy in patients with rectal adenocarcinoma. We found that high expression of PIK3CB was indeed involved in poor response to preoperative radiotherapy, as well as being associated with adverse outcomes in rectal adenocarcinoma patients treated with 30-Gy/10-fraction preoperative radiotherapy. Using TGX-221 (PIK3CB-specific inhibitor), we showed that inhibition of PIK3CB expression enhanced the response of colorectal cancer cell lines to radiotherapy.