LncRNA ROR1-AS1 Stimulates Epithelial-Mesenchymal Transition and Chemoresistance of Pancreatic Cancer by Upregulating HMGB1 Through miR-33a-5p Adsorption

Abstract

The work aimed at exploring the potential mechanism of Long noncoding RNA tyrosine protein kinase transmembrane receptor 1 antisense RNA 1 (ROR1-AS1) in the process of epithelial-mesenchymal transition (EMT) of pancreatic cancer (PC) cells resistant to Gemcitabine (GEM). ROR1-AS1 expression was analyzed in PC tissues, cells, PANC-1/GEM-resistant cell lines, and its correlation with PC clinicopathological features was determined. The proliferation ability, invasive and migratory properties of PC cells were evaluated, and the apoptotic rate was measured. EMT process of E-cadherin, N-cadherin, and Snail were analyzed. The direct molecular interactions within the ROR1-AS1/miR-33a-5p/HMGB1 axis were confirmed using dual-luciferase reporter and RNA immunoprecipitation assays. ROR1-AS1 expression was elevated in PC tissues, cells, and PANC-1/GEM cells. The survival rate of patients with higher ROR1-AS1 levels was lower, and expression was correlated with tumor node metastasis stage and lymph node metastasis. Silencing ROR1-AS1 supressed cell growth and EMT process, whilst overexpressing ROR1-AS1 was the opposite. ROR1-AS1 could bind miR-33a-5p to target and regulate HMGB1 and affect the biological behaviors of cancer cells. The suppressive influence of ROR1-AS1 knockdown was rescued when miR-33a-5p was silenced, meanwhile, the promoting influence of ROR1-AS1 overexpression was mitigated by silencing HMGB1. Cells resistant to GEM became more sensitive to GEM when miR-33a-5p was overexpressed or ROR1-AS1 was silenced, whereas the improvement of GEM resistance was offset by inhibiting miR-33a-5p or upregulating HMGB1. ROR1-AS1 modulates the growth and EMT process of PC through the miR-33a-5p/HMGB1 axis. ROR1-AS1 knockdown or miR-33a-5p overexpression is effective to reduce GEM resistance in PC.