Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma

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da Paixao, Vinicius Ferreira ; Sosa, Omar Julio ; da Silva Pellegrina, Diogo Vieira ; Dazzani, Bianca ; Correa, Thalita Bueno ; Bertoldi, Ester Riserio ; da Cruz e Alves-de-Moraes, Luis Bruno ; Pessoa, Diogo de Oliveira ; Oliveira, Victoria de Paiva ; Chiong Zevallos, Ricardo Alberto ; Russo, Lilian Cristina ; Forti, Fabio Luis ; Ferreira, Joao Eduardo ; Freitas, Helano Carioca ; Jukemura, Jose ; Cesar Machado, Marcel Cerqueira ; Begnami, Maria Dirlei ; Setubal, Joao Carlos ; Basseres, Daniela Sanchez ; Reis, Eduardo Moraes

• Document type: Journal article
• Source: CELLULAR ONCOLOGY; v. 45, n. 3, p. 26-pg., 2022-05-14.

Abstract

Purpose Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored. Methods We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways. Results We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation. Conclusions Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development. (AU)

• FAPESP's process: 13/13844-2 - Identification of biomarkers for molecular diagnosis of pancreatic ductal adenocarcinoma by high-resolution analysis of the transcriptome and exome
• Grantee: Eduardo Moraes Rego Reis
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/19757-2 - EXPLORING IKKbeta KINASE AS AN ANTI-METASTATIC THERAPEUTIC TARGET IN KRAS-INDUCED LUNG CANCER
• Grantee: Daniela Sanchez Basseres
• Support Opportunities: Regular Research Grants