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

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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.

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Data availability

All data analyzed during this study are included in this article and its supplementary information files. Raw and processed RNA-Seq data are available at the NCBI-GEO repository under accession GSE130688. The complete annotations of the lncRNAs detected in the PDAC transcriptome and discussed in the article are provided as supplementary material (Table S4).

Change history

  • 03 September 2022

    The original online version of this article was revised: The citation information for author name Fabio Luis Forti was corrected.

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Acknowledgements

The authors thank Júlio César Gomes de Sousa Filho (In Memorian) for technical support in the siRNA-mediated knockdown experiments.

Funding

The study was funded by a research grant from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) to EMR (grant nº 2013/13844–2) and DSB (grant nº 2016/19757–2). OJS, TB, LBCAM received fellowships from FAPESP. VFP, DVSP, ERB received fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). DOP received a fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). EMR and DSB are recipients of established researcher fellowships from CNPq.

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Author notes

  1. Vinicius Ferreira da Paixão and Omar Julio Sosa contributed equally.

Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil

    Vinicius Ferreira da Paixão, Bianca Dazzani, Thalita Bueno Corrêa, Luís Bruno da Cruz e Alves-de-Moraes, Diogo de Oliveira Pessoa, Victoria de Paiva Oliveira, Ricardo Alberto Chiong Zevallos, Lilian Cristina Russo, Fabio Luis Forti, João Carlos Setubal, Daniela Sanchez Bassères & Eduardo Moraes Reis

  2. Programa Interunidades de Pós-Graduação em Bioinformática, Universidade de São Paulo, São Paulo, SP, Brazil

    Omar Julio Sosa, Diogo Vieira da Silva Pellegrina & Ester Risério Bertoldi

  3. Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brazil

    João Eduardo Ferreira

  4. Departamento de Oncologia Médica, AC Camargo Cancer Center, São Paulo, SP, Brazil

    Helano Carioca Freitas

  5. Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

    José Jukemura

  6. Departamento de Emergências Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

    Marcel Cerqueira César Machado

  7. Departamento de Anatomia Patológica - AC Camargo Cancer Center, São Paulo, SP, Brazil

    Maria Dirlei Begnami

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  1. Vinicius Ferreira da Paixão
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Contributions

Conceived and designed the experiments: VFP, OJS, DVSP, DSB, EMR. Performed the experiments: VFP, OJS, DVSP. BD, TBC, ERB, DOP, VPO, RACZ, LCR. Analyzed the data: VFP, OJS, DVSP, BD, TBC, ERB, DOP, VPO, RACZ, LCRV, FLF, HCF, DSB, EMR. Contributed reagents/materials/analysis tools: LBCAM, JJ, MCCM, JEF, JCS, MDB. Wrote the manuscript: VFP, OJS, EMR. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Eduardo Moraes Reis.

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Ethics approval and consent to participate

Clinical samples used in this study were retrieved from the A.C. Camargo Cancer Center biorepository with informed consent. The study was approved by the Ethics Committee of the Institution (nº: 1839/13) and the study is registered at the research regulatory platform of the Brazilian Ministry of Health (CAAE: 15059213.0.0000.5432). The collection of human PDAC specimens for PDX generation was carried out with patient informed consent and approval of the Institutional Review Board of Ethics in Research from collaborating institutions (Hospital Sírio-Libanês, Hospital Alemão Oswaldo Cruz and Hospital 9 de Julho, Sao Paulo, Brazil) and the study is registered at the research regulatory platform of the Brazilian Ministry of Health (CAAE: 36005314.1.0000.5461).

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da Paixão, V.F., Sosa, O.J., da Silva Pellegrina, D.V. et al. Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma. Cell Oncol. 45, 479–504 (2022). https://doi.org/10.1007/s13402-022-00678-5

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