Abstract
Ovarian cancer is one of the most aggressive female reproductive tract tumors. Paclitaxel (PTX) is widely used for the treatment of ovarian cancer. However, ovarian cancers often acquire chemotherapeutic resistance to this agent. We investigated the mechanism of chemoresistance by analysis of microRNAs using the ovarian cancer cell line KFr13 and its PTX-resistant derivative (KFr13Tx). We found that miR-31 was downregulated in KFr13Tx cells, and that re-introduction of miR31 re-sensitized them to PTX both in vitro and in vivo. miR-31 was found to bind to the 3′-UTR of mRNA of MET, and the decrease in MET correlated to higher sensitivity to PTX. Furthermore, co-treatment of KFr13Tx cells with MET inhibitors sensitized the tumor cells to PTX both in vitro and in vivo. In addition, lower levels of miR31 and higher expression of MET in human ovarian cancer specimens were significantly correlated with PTX chemoresistance and poor prognosis. This study demonstrated miR31-dependent regulation of MET for chemoresistance of ovarian cancer, raising the possibility that combination therapy with a MET inhibitor and PTX will increase PTX efficacy.
Highlights
Ovarian cancer is the leading cause of death among malignancies of the female reproductive system, resulting in B125 000 deaths annually.[1]
To identify miRNAs that potentially cause the resistance to taxanes, such as PTX, we performed microarray analysis of miRNAs in KFr13 and PTX-resistant KFr13 and its PTX-resistant derivative (KFr13Tx) cells
Fifty-five miRNAs were found to be downregulated below the half amount, while two miRNAs were upregulated more than twofold in KFr13Tx cells compared with wild-type KFr13. miRNAs that exhibited remarkable alterations are shown in Supplementary Table 1
Summary
Ovarian cancer is the leading cause of death among malignancies of the female reproductive system, resulting in B125 000 deaths annually.[1]. The current therapy for ovarian cancer is debulking surgery followed by chemotherapy using carboplatin and paclitaxel (PTX).[5] ovarian cancer in advanced stages initially appears to be chemotherapy sensitive as response rates to platinum-based therapy exceed 80%, long-term survival remains poor as a result of recurrence and emergence of drug resistance. Mature form of miRs silence gene expression by binding to the 30-UTR of target mRNAs and initiate translational repression or cleavage of cognate mRNAs.[6] Following the initial demonstration of the important role for miR in human cancer, such as downregulation of miR-15a-miR-16-1 in chronic lymphocytic leukemia,[7] a number of cancers have been shown to exhibit distinct miR expression patterns related to various phenotypes with remarkable cytogenetic abnormalities.[8,9] Implication of miR in chemoresistance was reported in several cancers other than ovarian origin.[10,11] there was a report for correlation of miR, such as let7i, for chemoresistance of ovarian cancer,[12] the precise mechanism underlying the association is unknown
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