The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

Background/Aim: MicroRNAs (miRNAs) play regulatory roles in pancreatic ductal adenocarcinoma (PDAC). However, it is still required to identify the function of miRNA-301-3p in pancreatic cancer cells. Materials and Methods: Effects of luteolin on cell growth, TRAIL cytotoxicity, and miR-301-3p levels were evaluated. The role of miRNA-301-3p in regulating cell proliferation, target gene expression, and TRAIL cytotoxicity were studied. Results: The levels of miR-301-3p were down-regulated in PANC-1 cells exposed to luteolin, which inhibits the growth of PANC-1 cells and sensitizes cells to TRAIL. The knockdown of miR-301-3p attenuates cell proliferation and enhances TRAIL cytotoxicity. In addition, caspase-8 was directly targeted by miR-301-3p. Conclusion: Our findings unveil a critical biological function of miR-301-3p in regulating cell proliferation and elevating an antiproliferative effect of TRAIL on cancer cells. Our observation of miR-301-3p/caspase-8 relationship can also serve to clarify the role of miR-301-3p in other cancer types and related diseases.Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and a highly fatal malignancy with lymph node or distant metastases upon diagnosis. PDAC is predicted to be the second principal cause of cancer-related deaths by the year 2030 (1). Despite much progress on pancreatic cancer research over the past decades, surgery is the only attempt towards a curative outcome (2). Insufficient clinical efficacy of chemotherapy and radiation therapy has been reported and attributed to drug resistance in PDAC (3-6). Several signaling pathways, including nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) signaling, are activated, leading to cell growth and metastasis in PDAC. Mutations in tumor suppressor genes are also detected in PDAC (5, 7-9). A better understanding of the molecular characteristics of PDAC can lead to development of novel treatment strategies to combat PDAC.Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL has been known to inhibit cell growth by inducing cell-cycle arrest (10,11). In addition, anticancer effects of TRAIL can occur through death receptors 4 and 5, which generally regulate the activation of caspases, a family of cysteine proteases (12-14). Upon TRAIL binding, activation of caspase-8 cleaves executioner caspases, such as caspase-3 and -7, by which effective caspases contribute to chromatin condensation and nuclear fragmentation with the formation of apoptotic bodies (12-15). Indeed, TRAIL-induced apoptosis is impeded by the low expression of death receptors and caspases (16-18). Moreover, TRAIL resistance is associated with FADD-like ICE inhibitory proteins (FLIP) and inhibitor of apoptosis (IAP) family, such as cIAP, XIAP, and survivin, which inhibit the activation of caspases (19). Accumulating evidence has shown that combination of TRAIL with cancer therapeutic agents is effective to subdue TRAIL resistance. For instance, trea...

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Background/Aim: Patients with advanced non-small cell lung cancer (NSCLC) frequently face a dismal prognosis because of lack of curative therapies. We, therefore, conducted a preclinical investigation of the therapeutic efficacy of microRNA-107 (miR-107). Materials and Methods: The effects of miR-107 on cell proliferation and target gene expression were studied. Combinatorial effects of miR-107 and parthenolide were evaluated. Results: Cell proliferation was repressed in A549 NSCLC cells transfected with miR-107. Inhibitor of nuclear factor kappa B kinase subunit gamma was directly targeted by miR-107. Overexpression of miR-107 in A549 cells sensitized them to parthenolide along with a marked reduction of cyclindependent kinase 2. Conclusion: Our findings unveil an important biological function of miR-107 in regulating lung cancer cell proliferation and elevating an antiproliferative effect of parthenolide on lung cancer cells, suggesting that miR-107 could be beneficial benefit treatment for advanced NSCLC.