Abstract
BackgroundLong noncoding RNAs (lncRNAs), a type of pervasive genes that regulates various biological processes, are differentially expressed in different types of malignant tumors. The role of lncRNAs in the carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we investigated the role of the lncRNA DKFZp434J0226 in PDAC.MethodsAberrantly expressed mRNAs and lncRNAs among six PDAC and paired non-tumorous tissues were profiled using microarray analysis. Quantitative real-time polymerase chain reaction was used to evaluate DKFZp434J0226 expression in PDAC tissues. CCK-8 assay, wound-healing assay, soft agar colony formation assay, and transwell assay were performed to assess the invasiveness and proliferation of PDAC cells. Furthermore, RNA pull-down, immunofluorescence, RNA immunoprecipitation, and western blotting assays were performed to investigate the association between DKFZp434J0226 and SF3B6. Tumor xenografts in mice were used to test for tumor formation in vivo.ResultsIn our study, 222 mRNAs and 128 lncRNAs were aberrantly expressed (≥ twofold change). Of these, 66 mRNAs and 53 lncRNAs were upregulated, while 75 lncRNAs and 156 mRNAs were downregulated. KEGG pathway analysis and the Gene ontology category indicated that these genes were associated with the regulation of mRNA alternative splicing and metabolic balance. Clinical analyses revealed that overexpression of DKFZp434J0226 was associated with worse tumor grading, frequent perineural invasion, advanced tumor-node-metastasis stage, and decreased overall survival and time to progression. Functional assays demonstrated that DKFZp434J0226 promoted PDAC cell migration, invasion, and growth in vitro and accelerated tumor proliferation in vivo. Mechanistically, DKFZp434J0226 interacted with the splicing factor SF3B6 and promoted its phosphorylation, which further regulated the alternative splicing of pre-mRNA.ConclusionsThis study indicates that DKFZp434J0226 regulates alternative splicing through phosphorylation of SF3B6 in PDAC and leads to an oncogenic phenotype in PDAC.
Highlights
Pancreatic cancer is considered a rare type of cancer, with an estimated 57,600 newly diagnosed patients in 2020 in the United States according to the American Cancer Society, accounting for 3.2% (57,600 of 18,06,590) of all cancer cases (Siegel et al 2020)
LncRNA expression profile in pancreatic ductal adenocarcinoma (PDAC) Systematic variations in the expression of Long noncoding RNA (lncRNA) between six PDAC samples and paired non-tumor samples were demonstrated by hierarchical clustering (Fig. 1A)
Human Homeobox transcription factor (HOX) clusters have been found to contribute to the formation of numerous lncRNAs (Rinn et al 2007)
Summary
Pancreatic cancer is considered a rare type of cancer, with an estimated 57,600 newly diagnosed patients in 2020 in the United States according to the American Cancer Society, accounting for 3.2% (57,600 of 18,06,590) of all cancer cases (Siegel et al 2020). As the most common pancreatic malignant tumor, pancreatic ductal adenocarcinoma (PDAC) accounts for more than 85% of pancreatic cancer cases (Li et al 2004). Only less than 20% of tumors can be surgically removed at diagnosis. These patients usually respond poorly to chemotherapy. The role of lncRNAs in the carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. We investigated the role of the lncRNA DKFZp434J0226 in PDAC
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