MicroRNA‐181b‐5p, ETS1, and the c‐Met pathway exacerbate the prognosis of pancreatic ductal adenocarcinoma after radiation therapy

Abstract

Preoperative chemoradiation therapy (CRT) for pancreatic ductal adenocarcinoma (PDAC) has emerged as a reasonable strategy that shows good prognostic impact. However, after preoperative CRT, resected specimens show remnant tumor cells, which indicate that some tumor cells had acquired or were selected for resistance to CRT. Recently, two oncological mechanisms, the EMT and the presence of CSCs, were reported to be associated with resistance in various cancers. Previous reports showed that HGF could induce EMT in PDAC cells; moreover, the HGF receptor, c‐Met, was identified as a dominant pancreatic CSC marker. However, the clinical significance of c‐Met expression remains unclear. So, we hypothesized that remnant PDAC tissue after CRT might harbor cells with high c‐Met expression, and these cells may exacerbate patients’ prognosis. In the immunohistochemical analysis, we showed that preoperative CRT was significantly associated with high c‐Met expression; moreover, high c‐Met expression was a significant marker of a dismal prognosis. Next, we investigated mechanisms of c‐Met upregulation in PDAC cells. We established GEM‐resistant and radioresistant PDAC cells to analyze the transcriptome involved in c‐Met expression. The microarray data for the established radiation‐resistant PDAC cells indicated miR‐181b‐5p downregulation, which targets ETS1, one of the transcription factors for c‐Met, and it was shown that radiation exposure induced c‐Met expression through ETS1 increase by the suppression of miR‐181b‐5p. These results suggested that targeting these mechanisms may promote the development of a novel multidisciplinary treatment strategy for improving preoperative CRT efficiency.

Identification of novel genes associated with a poor prognosis in pancreatic ductal adenocarcinoma via a bioinformatics analysis

“…MET, the receptor of hepatocyte growth factor, was identified as a cancer stem cell marker in PDAC. Tomihara et al (2017) [62] also revealed that patients with high Met expression experienced a markedly shorter survival time than those with low Met expression, consistent with the current research. Altogether, these data support that the DEmiRNAs and hub genes shed light on the clinical utility of prognostic values in PDAC.…”

Exosome Release of Drugs: Coupling with Epithelial-Mesenchymal Transition

“…For example, activating mutations in PIK3CA have been often detected in HNC [107]. Resistance Class III consists of stromal signals, including HGF-high stroma that activates HGF-MET signaling [108][109][110]. The HGF-MET signaling pathway is driven by the HSF1-HSP stress response system in triple-negative breast cancer (TNBC) [40].…”

“…HGF-high stroma activates HGF-MET signaling, which is driven by HSF1-HSP stress signaling. [40,108,110 ] Class IV…”

Role of histone deacetylase 1 in distant metastasis of pancreatic ductal cancer

“…16 We also used radio-resistant cell clones established from Panc1 and MiaPaCa2 cells by fractionated irradiation and named them Panc1-RR and MiaPaCa2-RR cells, respectively, as reported previously. 17 In the experiment with the histone deacety-…”