Hypoxia-induced MIR31HG expression promotes partial EMT and basal-like phenotype in pancreatic ductal adenocarcinoma based on data mining and experimental analyses.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer, with a five-year survival rate below 8%. Its high mortality is largely due to late diagnosis, metastatic potential, and resistance to therapy. Epithelial-mesenchymal transition (EMT) plays a key role in metastasis, enabling cancer cells to become mobile. Partial EMT, where cells maintain both epithelial and mesenchymal traits, is more frequent in tumors than complete EMT and contributes to cancer progression. The long non-coding RNA MIR31 host gene (MIR31HG) has recently emerged as a critical factor in PDAC oncogenesis. This study aimed to investigate MIR31HG's role in partial EMT and its association with the basal-like PDAC subtype.

Methods: We analyzed the relationship between MIR31HG expression, partial EMT, and the basal-like subtype of PDAC by integrating data from public databases. We reanalyzed public data from PDAC patient-derived organoids to assess MIR31HG expression and gene signatures under hypoxic and normoxic conditions. RNA sequencing and bioinformatics analyses, including gene set enrichment analysis (GSEA), were used to investigate differentially expressed genes and pathway enrichments. EMT, partial EMT, and hypoxia scores were calculated based on the expression levels of specific gene sets.

Results: We observed that MIR31HG overexpression strongly correlates with higher partial EMT scores and the stabilization of the epithelial phenotype in PDAC. MIR31HG is highly expressed in the basal-like subtype of PDAC, which exhibits partial EMT traits. Hypoxia, a hallmark of basal-like PDAC, was shown to significantly induce MIR31HG expression, thereby promoting the basal-like phenotype and partial EMT. In patient-derived organoids, hypoxic conditions increased MIR31HG expression and enhanced basal-like and partial EMT gene signatures, while normoxia reduced these expressions. These findings suggest that hypoxia-induced MIR31HG expression plays a crucial role in driving the aggressive basal-like subtype of PDAC.

Conclusions: Our results indicate that MIR31HG is crucial in regulating PDAC progression, particularly in the aggressive basal-like subtype associated with hypoxia and partial EMT. Targeting the MIR31HG-mediated network may offer a novel therapeutic approach to combat hypoxia-driven PDAC.