LncRNA CASC19 promotes pancreatic cancer progression by increasing PSPC1 protein stability and facilitating the oncogenic PSPC1/ β-Catenin pathway.

BACKGROUND

Pancreatic cancer, a highly lethal malignancy, is influenced by complex lncRNA-mediated gene expression. This study identified CASC19 as a significantly overexpressed lncRNA with high oncogenic potential in pancreatic cancer, aiming to uncover its molecular mechanism in tumor progression.

METHODS

CASC19 expression was evaluated by qRT-PCR. Proliferation abilities of CASC19 were evaluated by MTT assay, cell cycle and apoptosis assay, upon CASC19 overexpression and knockdown. Whereas its metastatic potential was evaluated by wound healing, migration and invasion assay. The effect of CASC19 on cellular transcriptome was also examined by RNA sequencing after CASC19 overexpression and silencing. Subcellular localization of the lncRNA was examined by subcellular fractionation followed by qRT-PCR. To find out the molecular mechanism of lncRNA function, RNA-pull down, mass-spectrometry, immunoprecipitation, protein stability and ubiquitination assays were done.

RESULTS

High CASC19 expression was found in pancreatic tumor tissues and multiple pancreatic cancer cell lines. In-vitro loss and gain-of-function experiments showed that CASC19 is an oncogenic lncRNA promoting proliferation and metastasis of pancreatic cancer, while inhibiting apoptosis. CASC19 was also found to regulate global transcriptome of pancreatic cancer cells, affecting pathways like TGF-β signaling pathway, β-Catenin-TCF complex assembly, etc. CASC19 was localized to nucleus of pancreatic cancer cells and was identified to interact with PSPC1, a metastatic reprogramming protein. The interaction results in prevention of ubiquitin-mediated degradation of PSPC1. Increased availability of PSPC1, in turn, potentiates nuclear retention of β-Catenin which ultimately triggers pancreatic cancer progression.

CONCLUSION

Our findings elaborate the mechanism of CASC19 mediated tumorigenesis in pancreatic cancer, highlighting the role of PSPC1 in the process. Targeting CASC19/PSPC1/β-Catenin axis could be a novel approach to impede the progression of the disease.