Prognostic significance and molecular mechanism of ATP-binding cassette subfamily C member 4 in resistance to neoadjuvant radiotherapy of locally advanced rectal carcinoma.
BACKGROUND
Mechanism of radioresistance in rectal carcinoma remains largely unknown. We aimed to evaluate the predictive role of ATP-binding cassette subfamily C member 4 (ABCC4) in locally advanced rectal carcinoma and explore possible molecular mechanisms by which ABCC4 confers the resistance to neoadjuvant radiotherapy.


METHODS
The expression of ABCC4 and P53 mutant in biopsy tissue specimens from 121 locally advanced rectal carcinoma patients was examined using immunohistochemistry. The factors contributing to 3-year overall survival and disease-free survival were evaluated using the Kaplan-Meier method and Cox proportional hazard model. Lentivirus-mediated small hairpin RNA was applied to inhibit ABCC4 expression in colorectal carcinoma cell line RKO, and investigate the radiosensitivity in xenograft model. Intracellular cyclic adenosine monophosphate concentration and cell cycle distribution following irradiation were detected.


RESULTS
High expression of ABCC4 and p53 mutant in pretreated tumors, poor pathological response, and high final tumor staging were significant factors independently predicted an unfavorable prognosis of locally advanced rectal carcinoma patients after neoadjuvant radiotherapy. Down-regulation of ABCC4 expression significantly enhanced irradiation-induced suppression of tumor growth in xenograft model. Furthermore, down-regulation of ABCC4 expression enhanced intracellular cyclic adenosine monophosphate production and noticeable deficiency of G1-S phase checkpoint in cell cycle following irradiation.


CONCLUSIONS
Our study suggests that ABCC4 serves as a novel predictive biomarker that is responsible for the radioresistance and predicts a poor prognosis for locally advanced rectal carcinoma after neoadjuvant radiotherapy.
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Zhiqi
Z
Yu
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Chang
C
Zhang
Department of Colorectal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
Rui
R
Chai
Department of Epidemiology, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
Yan
Y
Du
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Xianhua
X
Gao
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Junjie
J
Xing
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Enda
E
Yu
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Wei
W
Zhang
Department of Radiotherapy, Changhai Hospital, Second Military Medical University, Shanghai, China.
Xiaoqing
X
Zhang
Department of Epidemiology, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
Guangwen
G
Cao
Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Chuangang
C
Fu
D000818:Animals; D002455:Cell Division; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D012004:Rectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*
D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human