Abstract
Gallbladder cancer represents the most common malignancy of the biliary tract and is highly lethal with less than 5% overall 5-year survival rate. Chemotherapy remains the major treatment for late-stage patients. However, insensitivity to these chemotherapeutic agents including cisplatin is common. MicroRNAs (miRNAs) have been shown as modulators of drug resistance in many cancer types. We used genome-wide gene expression analysis in clinical samples to identify miR-125b-5p down-regulated in gallbladder cancer. miR-125b-5p up-regulation promoted cell death in gallbladder cancer cells in the presence of cisplatin. In contrast, knockdown of miR-125b-5p reduced cell death in gallbladder cancer cells treated with cisplatin. Up-regulation of miR-125b-5p significantly decreased tumor growth in combination with cisplatin in a mouse model. We identified Bcl2 as a direct target of miR-125b-5p which mediates the function of miR-125b-5p in gallbladder cancer. In clinical samples, miR-125b-5p was down-regulated in gallbladder cancer whereas Bcl2 was up-regulated and their expression was inversely correlated. Moreover, low miR-125b-5p expression or high expression of Bcl2 is correlated with poor prognosis in gallbladder cancer. Taken together, our findings indicate that miR-125b-5p is a potent chemotherapy sensitizer and may function as a new biomarker for the prognosis of gallbladder cancer patients.
Highlights
Gallbladder cancer represents the most common malignancy of the biliary tract and is highly lethal with less than 5% overall 5-year survival rate
We recently found that miR-125b-5p is significantly down-regulated in gallbladder cancer from genome-wide microRNA expression profiling in Gallbladder cancer (GBC) and neighboring normal tissues. miR-125b-5p directly suppresses Bcl[2] expression and increases the sensitivity of cisplatin treatment in gallbladder cancer cells and mouse models
To determine whether the expression of microRNA candidates is correlated with prognosis, we selected two most down-regulated microRNAs, miR-125b-5p and miR-376a-3p (Fig. 1A), and two most up-regulated microRNAs, miR-3145-5p and miR-3174 (Fig. 1A), in gallbladder cancer to determine the correlation of their expressions and survival in clinical gallbladder cancer samples
Summary
Gallbladder cancer represents the most common malignancy of the biliary tract and is highly lethal with less than 5% overall 5-year survival rate. Chemotherapy remains the major treatment for late-stage patients Insensitivity to these chemotherapeutic agents including cisplatin is common. Gallbladder cancer (GBC) is the most common biliary tract cancer in clinic worldwide[1] Chemotherapies such as cisplatin (CDDP) remain the major treatment for patients with gallbladder cancer or cholangiocarcinoma[2]. The overall survival is less than 12 months even with the combination of cisplatin and gemcitabine[4] It is crucial for an extensive and thorough understanding of the molecular mechanisms of chemotherapy resistance in GBC. MicroRNAs have been shown to play important roles in cancer development including gallbladder cancer[5,6,7] Their functions in chemotherapy resistance are not well studied. Because miR-125b-5p was identified in clinical samples prior to adjuvant therapy, it contributes to intrinsic www.nature.com/scientificreports/
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