Effect of midkine on gemcitabine resistance in biliary tract cancer

Abstract

Gemcitabine-based chemotherapy is one of the most effective and commonly used chemotherapeutic regimens for biliary tract cancer (BTC). However, development of resistance to this drug limits its efficacy. The present study aimed to explore the effects of midkine (MDK) on the resistance of BTC cells to gemcitabine. Cell viability and proliferation were measured by a Cell Counting Kit-8 assay and 5-ethynyl-2′-deoxyuridine staining, respectively. Western blot analysis was used to detect the expression of E-cadherin and vimentin. The results indicated that BTC cell lines were more resistant to gemcitabine plus MDK compared with gemcitabine alone. In terms of the underlying mechanism, MDK promoted the epithelial to mesenchymal transition (EMT) of BTC cells and the enhancing effect of MDK on gemcitabine resistance was abrogated when the EMT was blocked with small interfering (si)RNA targeting Twist. In addition, MDK promoted the expression of Notch-1, while knockdown of Notch-1 by siRNA blocked the EMT process in the BTC cell lines. Taken together, these results indicated that MDK promoted gemcitabine resistance of BTC through inducing EMT via upregulating Notch-1. It was suggested that inhibition of the EMT is a promising strategy to overcome MDK-induced drug resistance.

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Moreover, MK engenders a cross-talk between the Notch signaling and JAK2/STAT3 signaling by inducing an interaction between the JAK2/STAT3 complex and Hes1, which is the downstream target of Notch-2 [51,53]. Recent studies have demonstrated that induced MK is significantly associated with chemoresistance in pancreatic cancer via the activation of NF-κB signaling and Hes1-induced JAK2/STAT3 signaling through cleavage and activation of MK-mediated Notch signaling [54,55]. Intriguingly, the binding of estradiol (E2) to ERβ results in the activated ER-β binding to the estrogen response element within the MK promoter, thereby leading to the induction of MK transcription, which enhances the EMT [56].…”

Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives

“…In cholangiocarcinoma, Notch 1-3 expression was associated with lower histological differentiation and poorer survival of patients, and combining gemcitabine and GSI-IX prevented gemcitabine-induced enrichment of CSClike population in in vitro models [584]. Similar to what was described in pancreatic cancer, Midkine-mediated upregulation of Notch1, responsible for Notch2 upregulation, was also reported as a resistance mechanism for biliary tract cancer [585]. In NSCLC, chronic exposure to gemcitabine drastically upregulates Notch3 expression by tumor cells, whereas the addition of DAPT sensitized cell lines to the pyrimidine analogue, affecting pro-and anti-apoptotic protein expression patterns [586].…”

miR-1275 targets MDK/AKT signaling to inhibit breast cancer chemoresistance by lessening the properties of cancer stem cells

“…AS a heparin-binding growth factor, MDK is abnormally high expressed in a variety of human malignancies and serves as an intermediary agent for the acquiring critical features of cancer, such as proliferation, metastasis, chemoresistance, migration, and angiogenesis [35][36][37][38]. Some studies have shown that MDK can be served to monitor the response to tumor treatment, while the secretion and overexpression of MDK in chemoresistant cells can protect themselves from cannabinoid and doxorubicin treatment [39][40][41][42]. Our findings uncovered that miR-1275-reduced chemoresistance was induced by the increase of MDK-mediated population of CSCs and PI3K/AKT phosphorylation and thus restored sensitivity of cells to epirubicin.…”