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      Is Open Access

      Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer

      research-article
      1 , , 1 , 1 , 1 , 2 , 1 , 2 , 1 , 1 , 1 , 1 , 1 , 1 , 3 , 4 , 5 , 6 , 1 , 6 , 7 , 6 , 7 , 8 , 9 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 14 , 14 , 15 , 16 , 1 , 1 , 1 , 1 , 2 , 13 , 1 ,
      The EMBO Journal
      Nature Publishing Group UK
      Prostate, Inflammation, TRP, PSA, Immunity, Cancer, Immunology, Membranes & Trafficking

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          Abstract

          Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.

          Synopsis

          The molecular origins of chronic tissue inflammation and its impact on cancer growth remain elusive. This study identifies TRPM8 transcripts as androgen-independent driver of sterile inflammation in the prostate gland, promoting anticancer innate immunity in the tumor microenvironment.

          • TRPM8 RNA is secreted via extracellular vesicles (EVs) by normal and prostate cancer cells in the absence of cell damage.

          • Upon EV endocytosis, TRPM8 mRNA binds TLR3 in endosomes, thereby promoting NF-kB/IRF3 activation and release of pro-inflammatory signals.

          • NF-kB induces the androgen-independent expression of PSA encoded by the KLK3 gene.

          • TRPM8/TLR3 signaling induces inflammation in prostate cancer xenografts, promoting infiltration and anticancer activity of NK cells.

          Abstract

          TLR3-activation by extracellular vesicle-delivered TRPM8 mRNA triggers aseptic inflammation in the prostate epithelium, promoting tumor suppression by NK cells.

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          STAR: ultrafast universal RNA-seq aligner.

          Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
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            Cutadapt removes adapter sequences from high-throughput sequencing reads

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              Is Open Access

              NCBI GEO: archive for functional genomics data sets—update

              The Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) is an international public repository for high-throughput microarray and next-generation sequence functional genomic data sets submitted by the research community. The resource supports archiving of raw data, processed data and metadata which are indexed, cross-linked and searchable. All data are freely available for download in a variety of formats. GEO also provides several web-based tools and strategies to assist users to query, analyse and visualize data. This article reports current status and recent database developments, including the release of GEO2R, an R-based web application that helps users analyse GEO data.
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                Author and article information

                Contributors
                alessandro.alaimo@unitn.it
                andrea.lunardi@unitn.it
                Journal
                EMBO J
                EMBO J
                The EMBO Journal
                Nature Publishing Group UK (London )
                0261-4189
                1460-2075
                5 February 2024
                5 February 2024
                March 2024
                : 43
                : 5
                : 780-805
                Affiliations
                [1 ]Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, ( https://ror.org/05trd4x28) Trento, Italy
                [2 ]Department for BioMedical Research, Urology Research Laboratory, University of Bern, ( https://ror.org/02k7v4d05) Bern, Switzerland
                [3 ]Department of Oncology, University of Torino, ( https://ror.org/048tbm396) Torino, Italy
                [4 ]Center for Experimental Research and Medical Studies (CeRMS), AOU Città della Salute e della Scienza di Torino, Torino, Italy
                [5 ]Department of Veterinary Sciences, University of Torino, ( https://ror.org/048tbm396) Torino, Italy
                [6 ]Department of Molecular Biotechnology and Health Sciences, University of Torino, ( https://ror.org/048tbm396) Torino, Italy
                [7 ]Molecular Biotechnology Center (MBC) “Guido Tarone”, University of Torino, ( https://ror.org/048tbm396) Torino, Italy
                [8 ]Department of Biotechnology and Life Sciences, University of Insubria, ( https://ror.org/00s409261) Busto Arsizio, VA Italy
                [9 ]Department of Pathology, University of Torino and AOU Città della Salute e della Scienza di Torino, ( https://ror.org/048tbm396) Torino, Italy
                [10 ]Division of Pathology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS Vita Salute, San Raffaele University, ( https://ror.org/01gmqr298) Milano, Italy
                [11 ]Medical Oncology Department, Santa Chiara Hospital-APSS, ( https://ror.org/007x5wz81) Trento, Italy
                [12 ]Operative Unit of Clinical Pathology, Santa Chiara Hospital-APSS, Trento, Italy
                [13 ]GRID grid.5734.5, ISNI 0000 0001 0726 5157, Department of Urology, Inselspital, , Bern University Hospital, University of Bern, ; Bern, Switzerland
                [14 ]Operative Unit of Anatomy Pathology, Santa Chiara Hospital-APSS, Trento, Italy
                [15 ]Centre for Medical Sciences-CISMed, University of Trento, ( https://ror.org/05trd4x28) Trento, Italy
                [16 ]GRID grid.419546.b, ISNI 0000 0004 1808 1697, Oncology 1 Unit, Department of Oncology, , Istituto Oncologico Veneto IOV IRCCS, ; Padova, Italy
                Author information
                http://orcid.org/0000-0002-5888-6268
                http://orcid.org/0000-0002-3568-0048
                http://orcid.org/0000-0001-8121-8260
                http://orcid.org/0000-0001-5080-9287
                http://orcid.org/0000-0003-3400-4440
                http://orcid.org/0000-0003-4329-3221
                http://orcid.org/0000-0002-1804-025X
                http://orcid.org/0000-0001-5408-6397
                http://orcid.org/0009-0002-8149-4614
                http://orcid.org/0000-0002-9460-1856
                http://orcid.org/0000-0002-3739-3966
                http://orcid.org/0000-0002-4862-7705
                http://orcid.org/0000-0003-0217-3223
                http://orcid.org/0000-0003-4855-8620
                http://orcid.org/0000-0001-6218-2565
                Article
                40
                10.1038/s44318-024-00040-5
                10907604
                38316991
                46eec5f1-5f3d-49b6-a046-ca39b4de4709
                © The Author(s) 2024

                Open Access This 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/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.

                History
                : 11 May 2023
                : 6 January 2024
                : 10 January 2024
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100006781, Giovanni Armenise-Harvard Foundation (GAHF);
                Award ID: Career Development Award
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003407, Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR);
                Award ID: 2017PLLYN
                Award ID: 2017PLLYN
                Award ID: 2017PLLYN
                Award ID: 2017PLLYN
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100020581, Fondazione AIRC per la ricerca sul cancro ETS (AIRC);
                Award ID: AIRC-IG 27893
                Award ID: AIRC-IG 24851
                Award ID: AIRC-MFAG 2017 ID20621
                Award ID: AIRC-IG 25978
                Award ID: ID 22792
                Award Recipient :
                Funded by: Lega Italiana Lotta ai Tumori
                Award ID: LILT-Bolzano
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000289, Cancer Research UK (CRUK);
                Award ID: ID A26822
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004361, Krebsliga Schweiz (Swiss Cancer League);
                Award ID: KFS-4960-02-2020
                Award Recipient :
                Funded by: Swiss National Science Foundation
                Award ID: SNSF 31003A_169352
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004710, Fondazione Umberto Veronesi (Umberto Veronesi Foundation);
                Award ID: IF-FUV 2016
                Award Recipient :
                Funded by: University of Trento
                Award ID: Starting Grant Young Researcher 2019
                Award Recipient :
                Categories
                Article
                Custom metadata
                © European Molecular Biology Organization 2024

                Molecular biology
                prostate,inflammation,trp,psa,immunity,cancer,immunology,membranes & trafficking
                Molecular biology
                prostate, inflammation, trp, psa, immunity, cancer, immunology, membranes & trafficking

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