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miR-145 sensitizes gallbladder cancer to cisplatin by regulating multidrug resistance associated protein 1
Ming Zhan1, Xiaonan Zhao1, Hui Wang1
1Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China.
Abstract:
Gallbladder cancer (GBC) is the most common malignancy in biliary tract with poor prognosis. Due to its high chemoresistance, systemic chemotherapies have had limited success in treating GBC patients. MicroRNAs (miRNAs) are emerging novel regulators of chemoresistance, which modulate the expression of drug resistance-related genes. In this study, we investigated the association between miR-145 expression and cisplatin sensitivity by both in vivo and in vitro analysis. Quantitative PCR (q-PCR) analysis indicated an increased miR-145 expression in GBC tissues. In addition, studies on GBC cell lines suggested an increased cisplatin efficacy with miR-145 overexpression, whereas decreasing miR-145 expression reduced cisplatin sensitivity. Further, we found that miR-145 accelerated MRP1 mRNA degradation by directly targeting its 3'-UTR and therefore caused increased cisplatin toxicity in GBC cells. Moreover, lower miR-145 and higher MRP1 expression levels predicted poor prognosis in GBC patients who received chemotherapy. Collectively, our findings established a rationale for using miR-145 expression as a biomarker to identify cisplatin-resistant GBC patients and propose that treatment strategies increasing the expression of miR-145 could be a new therapeutic approach for GBC patients.
Insights
MicroRNA-145 (miR-145) enhances cisplatin sensitivity in gallbladder cancer (GBC) by targeting MRP1. Increased miR-145 expression predicts better outcomes for GBC patients receiving chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Gallbladder cancer (GBC) is a prevalent biliary tract malignancy with a poor prognosis.
- Chemoresistance significantly limits the efficacy of systemic chemotherapies for GBC.
- MicroRNAs (miRNAs) are key regulators of chemoresistance, influencing drug resistance gene expression.
Purpose of the Study:
- To investigate the role of miR-145 in modulating cisplatin sensitivity in GBC.
- To determine the association between miR-145 expression levels and patient prognosis in GBC.
Main Methods:
- Quantitative PCR (q-PCR) to assess miR-145 expression in GBC tissues and cell lines.
- In vitro and in vivo experiments to evaluate the effect of miR-145 modulation on cisplatin efficacy.
- Analysis of miR-145 targeting of MRP1 mRNA via its 3'-UTR.
- Correlation analysis of miR-145 and MRP1 expression with patient survival data.
Main Results:
- miR-145 expression was elevated in GBC tissues.
- Overexpression of miR-145 increased cisplatin sensitivity, while its downregulation decreased sensitivity in GBC cell lines.
- miR-145 directly targets MRP1 mRNA, leading to its degradation and enhanced cisplatin toxicity.
- Low miR-145 and high MRP1 expression correlated with poor prognosis in chemotherapy-treated GBC patients.
Conclusions:
- miR-145 acts as a crucial determinant of cisplatin sensitivity in GBC.
- miR-145 can serve as a predictive biomarker for identifying cisplatin-resistant GBC.
- Therapeutic strategies aimed at increasing miR-145 expression represent a potential novel treatment approach for GBC.
