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      LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes

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          Abstract

          Background

          Pancreatic cancer is one of the most lethal malignancies and has an extremely poor diagnosis and prognosis. The development of resistance to gemcitabine is still a major challenge. The long noncoding RNA PVT1 was reported to be involved in carcinogenesis and chemoresistance; however, the mechanism by which PVT1 regulates the sensitivity of pancreatic cancer to gemcitabine remains poorly understood.

          Methods

          The viability of pancreatic cancer cells was assessed by MTT assay in vitro and xenograft tumor formation assay in vivo. The expression levels of PVT1 and miR-619-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting analysis and qRT-PCR were performed to assess the protein and mRNA levels of Pygo2 and ATG14, respectively. Autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of PVT1 were further investigated by gain- and loss-of-function assays in vitro.

          Results

          In the present study, we demonstrated that PVT1 was up-regulated in gemcitabine-resistant pancreatic cancer cell lines. Gain- and loss-of-function assays revealed that PVT1 impaired sensitivity to gemcitabine in vitro and in vivo. We further found that PVT1 up-regulated the expression of both Pygo2 and ATG14 and thus regulated Wnt/β-catenin signaling and autophagic activity to overcome gemcitabine resistance through sponging miR-619-5p. Moreover, we discovered three TCF/LEF binding elements (TBEs) in the promoter region of PVT1, and activation of Wnt/β-catenin signaling mediated by the up-regulation of Pygo2 increased PVT1 expression by direct binding to the TBE region. Furthermore, PVT1 was discovered to interact with ATG14, thus promoting assembly of the autophagy specific complex I (PtdIns3K-C1) and ATG14-dependent class III PtdIns3K activity.

          Conclusions

          These data indicate that PVT1 plays a critical role in the sensitivity of pancreatic cancer to gemcitabine and highlight its potential as a valuable target for pancreatic cancer therapy.

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          Most cited references32

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          Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy.

          Joungmok Kim, Young Chul Kim, Chong Fang … (2013)
          Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the nonautophagy Vps34 complex by phosphorylating T163/S165 in Vps34 and therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the proautophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy-essential gene present only in the proautophagy Vps34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy. Copyright © 2013 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 287 times – based on 0 reviews     Review now
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            Predicting RNA-Protein Interactions Using Only Sequence Information

            Usha K. Muppirala, Vasant G. Honavar, Drena Dobbs (2011)
            Background RNA-protein interactions (RPIs) play important roles in a wide variety of cellular processes, ranging from transcriptional and post-transcriptional regulation of gene expression to host defense against pathogens. High throughput experiments to identify RNA-protein interactions are beginning to provide valuable information about the complexity of RNA-protein interaction networks, but are expensive and time consuming. Hence, there is a need for reliable computational methods for predicting RNA-protein interactions. Results We propose RPISeq , a family of classifiers for predicting R NA- p rotein i nteractions using only seq uence information. Given the sequences of an RNA and a protein as input, RPIseq predicts whether or not the RNA-protein pair interact. The RNA sequence is encoded as a normalized vector of its ribonucleotide 4-mer composition, and the protein sequence is encoded as a normalized vector of its 3-mer composition, based on a 7-letter reduced alphabet representation. Two variants of RPISeq are presented: RPISeq-SVM, which uses a Support Vector Machine (SVM) classifier and RPISeq-RF, which uses a Random Forest classifier. On two non-redundant benchmark datasets extracted from the Protein-RNA Interface Database (PRIDB), RPISeq achieved an AUC (Area Under the Receiver Operating Characteristic (ROC) curve) of 0.96 and 0.92. On a third dataset containing only mRNA-protein interactions, the performance of RPISeq was competitive with that of a published method that requires information regarding many different features (e.g., mRNA half-life, GO annotations) of the putative RNA and protein partners. In addition, RPISeq classifiers trained using the PRIDB data correctly predicted the majority (57-99%) of non-coding RNA-protein interactions in NPInter-derived networks from E. coli, S. cerevisiae, D. melanogaster, M. musculus, and H. sapiens. Conclusions Our experiments with RPISeq demonstrate that RNA-protein interactions can be reliably predicted using only sequence-derived information. RPISeq offers an inexpensive method for computational construction of RNA-protein interaction networks, and should provide useful insights into the function of non-coding RNAs. RPISeq is freely available as a web-based server at http://pridb.gdcb.iastate.edu/RPISeq/.
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              Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis.

              Jennifer L Larson-Casey, Jessy Deshane, Alan J. Ryan … (2016)
              Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder with increasing incidence. Mitochondrial oxidative stress in alveolar macrophages is directly linked to pulmonary fibrosis. Mitophagy, the selective engulfment of dysfunctional mitochondria by autophagasomes, is important for cellular homeostasis and can be induced by mitochondrial oxidative stress. Here, we show Akt1 induced macrophage mitochondrial reactive oxygen species (ROS) and mitophagy. Mice harboring a conditional deletion of Akt1 in macrophages (Akt1(-/-)Lyz2-cre) and Park2(-/-) mice had impaired mitophagy and reduced active transforming growth factor-β1 (TGF-β1). Although Akt1 increased TGF-β1 expression, mitophagy inhibition in Akt1-overexpressing macrophages abrogated TGF-β1 expression and fibroblast differentiation. Importantly, conditional Akt1(-/-)Lyz2-cre mice and Park2(-/-) mice had increased macrophage apoptosis and were protected from pulmonary fibrosis. Moreover, IPF alveolar macrophages had evidence of increased mitophagy and displayed apoptosis resistance. These observations suggest that Akt1-mediated mitophagy contributes to alveolar macrophage apoptosis resistance and is required for pulmonary fibrosis development.
              Article 0 comments Cited 148 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jingfeng Tang:
                ORCID: http://orcid.org/0000-0002-5524-4518
                Jingfeng_hut@163.com
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 29 July 2020
                Publication date PMC-release: 29 July 2020
                Publication date Collection: 2020
                Volume: 19
                Electronic Location Identifier: 118
                Affiliations
                [1 ]GRID grid.411410.1, ISNI 0000 0000 8822 034X, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), , Hubei University of Technology, ; 28 NanLi Road, Wuhan, 430068 Hubei China
                [2 ]GRID grid.452675.7, Nanjing Clinical Medical Center for Infectious Diseases, , the Second Affiliated Hospital of Southeast University (the Second Hospital of Nanjing), ; Nanjing, China
                [3 ]GRID grid.17089.37, Department of Biological Sciences, , University of Alberta, ; Edmonton, Alberta Canada
                [4 ]GRID grid.17089.37, Department of Biochemistry, , University of Alberta, ; Edmonton, Alberta Canada
                [5 ]GRID grid.17089.37, Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, , University of Alberta, ; Edmonton, AB Canada
                Author information
                http://orcid.org/0000-0002-5524-4518
                Article
                Publisher ID: 1237
                DOI: 10.1186/s12943-020-01237-y
                PMC ID: 7389684
                PubMed ID: 32727463
                SO-VID: e4c00ed5-2fce-4694-af22-9c6c5819c7fd
                Copyright © © The Author(s) 2020
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 28 April 2020
                Date accepted : 21 July 2020
                Funding
                Funded by: National Natural Science Foundation of China (CN)
                Award ID: 31701228
                Award ID: 31871420
                Award ID: 31871176
                Award Recipient :
                Funded by: Wuhan Science and Technology Project
                Award ID: 2019020701011475
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pvt1,gemcitabine resistance,autophagy,mir-619-5p,wnt/β-catenin
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pvt1, gemcitabine resistance, autophagy, mir-619-5p, wnt/β-catenin

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