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Comparative Study
. 2011 Feb 15;104(4):707-13.
doi: 10.1038/sj.bjc.6606071. Epub 2011 Jan 4.

Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma

M Yamasaki  1 , T Makino, T Masuzawa, Y Kurokawa, H Miyata, S Takiguchi, K Nakajima, Y Fujiwara, N Matsuura, M Mori, Y Doki
Affiliations
Comparative Study

Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma

M Yamasaki et al. Br J Cancer. .

Abstract

Background: Although multidrug resistance protein 2 (MRP2) confers chemoresistance in some cancer types, its implication on oesophageal squamous cell carcinoma (ESCC) remains unclear.

Methods: We evaluated MRP2 expression by immunohistochemistry and RT-PCR using 81 resected specimens from ESCC patients who did or did not receive neo-adjuvant chemotherapy (NACT), including 5-fluorouracil, doxorubicin, and cisplatin (CDDP). Correlation between MRP2 expression and response to chemotherapy was also examined in 42 pre-therapeutic biopsy samples and eight ESCC cell lines.

Results: MRP2-positive immunostaining was more frequently observed in ESCCs with NACT than in those without NACT (27.3 vs 5.4%). The MRP2-positive patients showed poorer prognosis than MRP2-negative patients (5-year survival rate, 25.6 vs 55.7%). Concordantly, ESCC with NACT showed 2.1-fold higher mRNA expression of MRP2 than those without NACT (P=0.0350). In pre-therapeutic biopsy samples of patients with NACT, non-responders showed 2.9-fold higher mRNA expression of MRP2 than responders (P=0.0035). Among the panel of ESCC cell lines, TE14 showed the highest MRP2 mRNA expression along with the strongest resistance to CDDP. Inhibition of MRP2 expression by small-interfering RNA reduced chemoresistance to CDDP.

Conclusion: Our data suggested that MRP2 is one of molecules, which regulate the sensitivity to chemotherapy including CDDP in advanced ESCC patients.

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Figures

Figure 1
Figure 1
MRP2 expression by immunohistochemistry. (A) Strong MRP2 expression in liver tissue as a positive control (magnification, × 400). (B) Representative normal squamous epithelium negative for MRP2 expression (magnification, × 200). (C) Representative MRP2-positive ESCC showing staining mainly in the membrane and cytoplasm of tumour cells (magnification, × 200). (D) Representative MRP2-negative oesophageal squamous cell carcinoma with no appreciable staining of tumour cells (magnification, × 200).
Figure 2
Figure 2
Survival curves according to MRP2 expression. Overall survival curve classified according to MRP2 expression for all patients were plotted by Kaplan–Meier method. Differences between two groups were evaluated by log–rank test. Ordinate: overall survival rate, abscissa: time after surgery (years).
Figure 3
Figure 3
Differences in MRP2 mRNA expression between patients with and without neo-adjuvant chemotherapy in resected specimens (A), and between responders and non-responders at biopsy (B). (A) The relative ratio of MRP2 mRNA expression in resected tumours treated with neo-adjuvant chemotherapy (n=16) was significantly higher than in untreated cancers (n=10). (B) In endoscopy biopsy samples, the relative ratios of MRP2 mRNA expression in responders (n=22) were significantly higher than those in non-responders (n=20). Data are shown as mean±s.d. (log2 values).
Figure 4
Figure 4
Correlation between MRP2 mRNA expression and CDDP-resistance (IC50) in eight cell lines of ESCC. Relatively high MRP2 expression was observed in TE14 and TE5 cell lines, both of which displayed strong resistance to CDDP. Black bar: the relative ratio of MRP2 mRNA expression, grey bar: IC50 values against CDDP.
See this image and copyright information in PMC

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