Abstract
BackgroundMechanism 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.MethodsThe 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.ResultsHigh 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.ConclusionsOur 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.
Highlights
Treatment of locally advanced rectal carcinoma (LARC, T3-4 or/and N1-2 lesions) remains to be a challenge [1]
We aimed to evaluate the long-term prognostic significance of ATP-binding cassette subfamily C member 4 (ABCC4) in this group of LARC patients treated with neoadjuvant radiotherapy (nRT)
We carefully collected 2–3 biopsy tissue specimens from each case for HE examination to confirm the diagnosis of rectal adenocarcinoma, used the remaining tissues for immunohistochemical analyses to detect the expression and subcellular localization of ABCC4 and p53
Summary
Treatment of locally advanced rectal carcinoma (LARC, T3-4 or/and N1-2 lesions) remains to be a challenge [1]. The current multidisciplinary treatment strategy recommends preoperative neoadjuvant radiotherapy (nRT) because of its significant benefits in decreasing tumor stage, increasing the opportunities of curative resection and sphincter preservation, improving the local control, and even achieving clinical or pathological complete regression in the short term [2], there is no enough evidence to support that nRT significantly prolong the long-term survival rate in LARC patients, which largely restricts its clinical use [3]. Our previous studies have demonstrated a combined predictive value of p53 and p21 for tumor regression after preoperative nRT in rectal carcinoma patients and identified that ATP-binding cassette subfamily C member 4 (ABCC4) may play a role in response to irradiation of CRC cell line HT29 in vitro [4,5]. 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
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