MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma

Abstract

The cancer drug gemcitabine (GEM) is a key drug for treating pancreatic ductal adenocarcinoma (PDAC), but PDAC cells develop chemoresistance after long-term administration. Since the tolerance was immediately spread to every PDAC tissue in a patient, it is assumed that some certain efficient mechanisms underlay in the development of chemoresistance. Changes in the levels of particular microRNAs or alterations in intercellular communication play a dominant role in chemoresistance development, and recent data also suggest that exosomes play an important role in this process. In this study, we revealed that the loop conferred chemoresistance in PDAC cells. The loop was as follows; 1, The long-term exposure of GEM increased miR-155 expression in PDAC cells. 2, The increase of miR-155 induced two different functions; exosome secretion and chemoresistance ability via facilitating the anti-apoptotic activity. 3, Exosome deliver the miR-155 into the other PDAC cells and induce the following function. The target therapy to miR-155 or the exosome secretion effectively attenuated the chemoresistance, and these results were validated with both clinical samples and in vivo experiments. This mechanism represents a novel therapeutic target in GEM treatment to PDAC.

Five key lncRNAs considered as prognostic targets for predicting pancreatic ductal adenocarcinoma

“…Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal commonly diagnosed cancers worldwide by complex molecular and cellular heterogeneity . In the past, great efforts have been made to provide novel insights into the molecular mechanisms underlying PDCA, but the focus has been on protein‐coding genes or miRNA . PDAC is the most common form of pancreatic cancer and its incidence is rising every year .…”

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

“…EVs have also been shown to modulate the anti-tumoral response by affecting the immune response, T-cell activation and natural killer cell induction (30)(31)(32)(33). EVs can also contribute to drug resistance via various mechanisms, including the sequestration of drugs (34,35) and the transfer of proteins or RNA (36)(37)(38)(39) (40)(41)(42)(43)(44)(45). The morphology and the proteomic profile of EVs from multi-drug resistant tumours has been shown to be different from those from sensitive tumours (46) and EVs could be used as prognostic and diagnostic biomarkers in cancer (47).…”

The cancer exosomes: Clinical implications, applications and challenges

“…Tumor‐associated macrophage (TAM) is another crucial part contributing to poor tumor therapy efficacy and chemo‐resistant phenotype. Mikamori et al . analyzed and further assumed that it was miR‐155 from TAM‐derived exosomes that elevated the anti‐apoptotic of gemcitabine‐tolerant pancreatic ductal adenocarcinoma (PDAC), which provided a therapeutic miRNA target in promoting gemcitabine efficacy of PDAC (Table ).…”