SNHG10 promotes tumorigenesis through the EGFR/AKT/ERK/mTOR and miR-150-5p/VEGF-A axis, along with gemcitabine resistance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and often fatal cancer with limited treatment options. Small nucleolar RNA host gene 10 (SNHG10) has emerged as a key regulator in the progression and metastasis of human cancers. However, the potential of SNHG10 in PDAC tumorigenesis, gemcitabine resistance, and the underlying molecular mechanisms remains poorly understood. Our data analysis revealed significant upregulation of the SNHG10 transcript in 179 PDAC cases compared with 171 normal pancreatic specimens, with a positive association with clinical stages of PDAC. Further, we confirmed the significant overexpression of the SNHG10 transcript in several PDAC cell lines compared to normal pancreatic cells. Our results revealed that the downregulation of SNHG10 significantly decreased the cellular proliferation, clonogenic ability, cell migration, and the epithelial to mesenchymal transition, leading to the induction of cell cycle arrest and apoptosis of PDAC cells. Mechanistically, the downregulation of SNHG10 significantly inhibited the expression of vimentin, N-cadherin, survivin, CDK4, CDK6, cyclin B1, cyclin D1, aurora kinase A, and aurora kinase B, with an increased expression of E-cadherin and p21. The bioinformatics analysis, RNA Immunoprecipitation, and qRT-PCR results showed the physical interaction among SNHG10, miR-150-5p, and VEGF-A, which are the integral parts of the ternary complex in PDAC cell lines. Interestingly, silencing of SNHG10 led to the significant induction of miR-150-5p, which repressed the expression of VEGF-A in PDAC cells. Moreover, the miR-150-5p rescued the VEGF-A expression in PDAC cells even during the silencing of SNHG10. Interestingly, the downregulation of SNHG10 enhanced gemcitabine sensitivity in gemcitabine-resistant PDAC cells. The depletion of SNHG10 in the PDAC xenograft model significantly reduced tumor growth, volume, and weight. Importantly, downregulation of SNHG10 suppressed the phosphorylation of EGFR, AKT, ERK1/2, mTOR, and c-MET signaling pathways in both in vitro and xenograft models of PDAC. Our study unveils the oncogenic potential of SNHG10 in tumorigenesis through modulation of the EGFR/AKT/ERK/mTOR, and miR-150-5p/VEGF-A axis, as well as gemcitabine resistance of PDAC as a prospective therapeutic strategy. The graphical abstract represented the potential role of SNHG10 and its regulated molecular mechanisms in the tumorigenesis and gemcitabine resistance in PDAC. Silencing of SNHG10 decreases cell survival, proliferation, clonogenicity, EMT tumor growth through the EGFR/AKT/ERK/mTOR axis, and restores the expression of miR-150-5p, which eventually downregulates VEGF-A. SNHG10 downregulation enhanced the gemcitabine sensitivity in gemcitabine-resistant PDAC cells. The graphical abstract represented the potential role of SNHG10 and its regulated molecular mechanisms in the tumorigenesis and gemcitabine resistance in PDAC. Silencing of SNHG10 decreases cell survival, proliferation, clonogenicity, EMT tumor growth through the EGFR/AKT/ERK/mTOR axis, and restores the expression of miR-150-5p, which eventually downregulates VEGF-A. SNHG10 downregulation enhanced the gemcitabine sensitivity in gemcitabine-resistant PDAC cells.