Prognostic Significance and Molecular Mechanism of ATP-Binding Cassette Subfamily C Member 4 in Resistance to Neoadjuvant Radiotherapy of Locally Advanced Rectal Carcinoma

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.

Biomarkers and Molecular Imaging as Predictors of Response to Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

“…49 The significant association observed between sensitivity to neoadjuvant RT and downregulation of ABCC4 (MRP4) indicates a possible role of this protein as a predictive biomarker, 50 and the correlation between high ABCC4 expression and shorter DFS makes it a good biomarker of poor outcome in LARC. 51 Finally, the negative effect on pathological response of aberrant expression of MRP3, another member of this family, was recently shown by Yu et al in 144 pretreatment rectal biopsies from patients treated with NCRT. 52 With regard to protein microarray technologies, Mammano et al published an interesting report in 2012 based on a new method for quantitative multiplexed analysis of protein signaling activation.…”

Dual Role of cAMP in the Transcriptional Regulation of Multidrug Resistance-Associated Protein 4 (MRP4) in Pancreatic Adenocarcinoma Cell Lines

“…This study provided the first experimental evidence that MRP4 and cAMP extrusion may represent a new potential target for differentiation therapy. Moreover, several clinical studies using tumor genome sequencing showed MRP4 expression as a prognosis marker in esophageal [ 15 ], gastric [ 16 ], rectal [ 17 ], lung [ 18 ], ovarian [ 19 ] and prostate [ 20 ] cancer as well as in neuroblastoma [ 21 ]. Furthermore, current evidence also supports that MRP4 expression may represent a relevant pharmacological target [ 22 ].…”

A polymorphism in ABCC4 is related to efficacy of 5-FU/capecitabine-based chemotherapy in colorectal cancer patients

“…ABCC4 confers cells resistance to cytotoxic complexes, protects important tissues from aberrant biological damage and at the same time affects drug metabolism in cells, resulting in drug resistance. Significant association between downregulation of ABCC4 and sensitivity to neoadjuvant chemo-radiotherapy, as well as between low ABCC4 expression and longer disease-free survival in rectal cancer patients has been demonstrated 18 , 19 , indicating that ABCC4 might be a possible predictive biomarker for the efficacy of chemotherapy in CRC. Recent reports demonstrate that the expression of ABCC4 can be attenuated by miR-124a, miR-125a, miR-125b, miR-143, and miR-506 13 , 20 .…”