Institutional members access full text with Ovid®

Share this article on:

Downregulation of ATP-Binding Cassette Subfamily C Member 4 Increases Sensitivity to Neoadjuvant Radiotherapy for Locally Advanced Rectal Carcinoma

Yu, Zhi-Qi Ph.D.1; Zhang, Chang Ph.D.1; Wang, Hao M.D.1; Lao, Xin-Yuan Ph.D.1; Chai, Rui Ph.D.1; Gao, Xian-Hua Ph.D.1; Cao, Guang-Wen M.D., Ph.D.2; Fu, Chuan-Gang M.D., Ph.D.1

Diseases of the Colon & Rectum: May 2013 - Volume 56 - Issue 5 - p 600–608
doi: 10.1097/DCR.0b013e31827c2b80
Original Contribution: Colorectal/Anal Neoplasia

OBJECTIVE: This study was designed to verify the effect of ATP-binding cassette subfamily C member 4 on radiosensitivity of locally advanced rectal carcinoma.

SETTING: The expression of ATP-binding cassette subfamily C member 4 protein in 121 pretreatment tissue samples from locally advanced rectal carcinoma patients was detected by immunohistochemistry.

DESIGN: Pathological response to radiotherapy was evaluated according to tumor regression grading by postoperative histological examinations after they received long-course preoperative neoadjuvant radiotherapy, and the association between clinicopathological data and tumor regression grading was analyzed retrospectively. For further validation, short hairpin RNA was constructed and transfected into colorectal carcinoma cell line HT29. The knockdown efficiency was confirmed at both RNA and protein levels. The altered radiosensitivity was evaluated by methylthiazolyl tetrazolium assay, colony formation assay, flow cytometry, and Hoechst 33258 staining.

RESULTS: Univariate analysis revealed that ATP-binding cassette subfamily C member 4 expression (p < 0.001), P53 type (p = 0.069), and CEA (p = 0.100) were possibly associated with tumor regression grading, and multivariate analysis demonstrated that ATP-binding cassette subfamily C member 4 expression (p < 0.001) and P53 type (p = 0.039) were positively correlated with response to neoadjuvant radiotherapy in locally advanced rectal carcinoma patients. Lentiviral vector was successfully introduced into HT29 cells and inhibited ATP-binding cassette subfamily C member 4 expression efficiently and persistently. Downregulation of ATP-binding cassette subfamily C member 4 expression significantly enhanced inhibition of cell proliferation, decreased colony formation capacity, and increased cell apoptosis induced by irradiation, as examined by a series of experiments in vitro. In addition, radiobiological parameters calculated according to the single-hit multitarget model were also decreased significantly.

CONCLUSIONS: Our data indicate that ATP-binding cassette subfamily C member 4 may be a useful molecular marker in predicting radiosensitivity, and a potential target in improving the response to neoadjuvant radiotherapy in locally advanced rectal carcinoma patients.

1Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China

2Department of Epidemiology, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China

This study is supported by grants from the National Natural Science Foundation of China (30973460).

Financial Disclosure: None reported.

Zhi-Qi Yu and Chang Zhang contributed equally to this study.

Presented at the research forum at the annual meeting of The American Society of Colon and Rectal Surgeons, San Antonio, TX, June 2 to 6, 2012.

Correspondence: Chuan-Gang Fu, M.D., Ph.D., Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Rd, Shanghai, China 200433. E-mail: fugang416@126.com; Guang-Wen Cao, M.D., Ph.D., Department of Epidemiology, College of Basic Medical Sciences, Second Military Medical University, 800 Xiangyin Rd, Shanghai, China 200438. E-mail: caoguangwen@yahoo.com

© The ASCRS 2013