Loss of the wild-type allele promotes carcinogenesis of bladder urothelial cells with p53 missense mutation

Loss of the wild-type allele promotes carcinogenesis of bladder urothelial cells with p53 missense mutation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Loss of the wild-type allele promotes carcinogenesis of bladder urothelial cells with p53 missense mutation Takashi Kobayashi, Akihiro Hamada, Yuki Kita, Toru Sakatani, Kenji Nakamura, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4843625/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Feb, 2025 Read the published version in Oncogene → Version 1 posted 9 You are reading this latest preprint version Abstract In advanced bladder cancer cases, p53 is the most frequently altered gene. Despite missense mutation accounts for over 60% of p53 alterations while homozygous deletion (HOM) for only 5% or less, most of the previously reported mouse models are deficient of p53. Accordingly, there have been few studies addressing whether missense mutations have an advantage over HOM in bladder cancer development. Pten-deficient, Trp53-mutant (Trp53R172H/+) organoids derived from Krt5-expressing mouse urothelium (K5-mUrorganoid) were tumorigenic in athymic mice, but every formed tumors showed loss of wild-type allele of Trp53 (Trp53R172H/LOH). Both Trp53R172H/Δ and Trp53Δ/Δ K5-mUrorganoids formed tumor in athymic mice, whereas only Trp53R172H/Δ K5-mUrorganoid formed tumor even when directly inoculated in immunocompetent syngeneic mice. The absence of wild-type Trp53 was associated with upregulation of proliferative signaling, and the presence of a mutant Trp53 allele was associated with reduced intratumoral CD8+ T cells, increased CD206+ M2 macrophages, and increased Foxp3+ regulatory T cells. This study highlights the functional significance of p53 mutant LOH in bladder carcinogenesis conferring several hallmarks of cancer such as sustaining proliferative signaling and avoiding immune destruction, and provides a novel immunocompetent mouse model of urothelial carcinoma harboring p53 mutations as a novel tool for cancer immunology research. Biological sciences/Cancer/Urological cancer/Bladder cancer Biological sciences/Developmental biology/Disease model Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations There is NO conflict of interest to disclose. Supplementary Files OncogeneSupplementaryFigureMXM.pdf OncogeneSupplementaryTableS2cytokinearrayAH01.xlsx Cite Share Download PDF Status: Published Journal Publication published 22 Feb, 2025 Read the published version in Oncogene → Version 1 posted Editorial decision: revise 04 Nov, 2024 Review # 2 received at journal 03 Nov, 2024 Reviewer # 2 agreed at journal 22 Oct, 2024 Review # 1 received at journal 15 Sep, 2024 Reviewer # 1 agreed at journal 28 Aug, 2024 Reviewers invited by journal 21 Aug, 2024 Submission checks completed at journal 02 Aug, 2024 Editor assigned by journal 01 Aug, 2024 First submitted to journal 01 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4843625","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":343238081,"identity":"0579d263-d0f1-4a81-8470-4cb7883c25e0","order_by":0,"name":"Takashi 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University","correspondingAuthor":false,"prefix":"","firstName":"Mayumi","middleName":"","lastName":"Kamada","suffix":""},{"id":343238098,"identity":"cf355697-7374-4e05-afd1-e8476d1c63d5","order_by":17,"name":"Osamu Ogawa","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Osamu","middleName":"","lastName":"Ogawa","suffix":""}],"badges":[],"createdAt":"2024-08-01 17:15:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4843625/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4843625/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41388-025-03311-5","type":"published","date":"2025-02-22T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66671366,"identity":"6147a5d1-5901-4ddc-8c29-9e71034a9ad9","added_by":"auto","created_at":"2024-10-15 10:31:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3715797,"visible":true,"origin":"","legend":"\u003cp\u003eEstablishment of Trp53-mutant K5-mUrorganoids as a model of human bladder cancer that undergoes autonomous enrichment toward Trp53-mutant LOH during tumorigenesis. A. Schematics of establishing K5-mUrorganoids. Genetically engineered mice with the indicated genotype were treated with tamoxifen orally for 3 consecutive days, and then the bladder urothelial cells were collected and subjected to 3D organoid culture (K5-mUrorganoid). CRISPR/Cas9-based gene editing was performed using an adeno-associated virus (AAV) expressing single-guide (sg)RNA. K5-mUrorganoids were then subjected to ex vivo evaluation or to subcutaneous, orthotopic, and renal subcapsular inoculation for in vivo tumorigenicity assays. B. Representative images of Sanger sequencing showing successful gene editing at the targeted positions (red arrows) by guide RNAs (gRNAs) for Kmt2c (left) and Pten (right). PAM, proto-spacer adjacent motif. C. Representative macroscopic (left) and microscopic (right, hematoxylin and eosin (H\u0026amp;E) staining) images of tumors derived from Trp53R172H/+; Kmt2c-KO; Pten KO K5-mUrorganoids inoculated in athymic mice at the indicated sites. Note that the tumors exhibit histological characteristics of human muscle-invasive bladder cancer (MIBC) with squamous differentiation. Scale bars indicate 100 µm. D. Representative bright-field (left) and H\u0026amp;E (right) microscopic images of tumor-derived organoids (TuOrs). The TuOrs retained the histological phenotype, including keratin pearl structures. Scale bars indicate 100 µm. E. Representative gel image of genomic PCR for Trp53 status in parent Trp53R172H/+; Kmt2c-KO; Pten KO K5-mUrorganoids (PaOr, left) and TuOrs (right). Note that the band for wild-type (WT) Trp53 was undetectable in TuOrs, whereas the band for mutant Trp53 was thickened. F. Digital PCR results of WT organoids, organoids with Trp53R172H/+, organoids with Trp53R172H/+; Kmt2c KO; Pten KO, tumors, and TuOrs. See also Supplementary Figs. S1–S5.\u003c/p\u003e","description":"","filename":"OncogeneFigure1v.1502.png","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/c63a0789f4d0eca73fa33bf6.png"},{"id":66671367,"identity":"67fe5dd9-0997-4c9c-81a3-cda1fbeb9729","added_by":"auto","created_at":"2024-10-15 10:31:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":245259,"visible":true,"origin":"","legend":"\u003cp\u003ep53 loss of heterozygosity (LOH) is common in human muscle-invasive bladder cancer (MIBC) and is required for mouse tumorigenesis in the context of p53-altered bladder cancer. A. The proportion of patients according to the p53 gene status in The Cancer Genome Atlas (TCGA) data. B. Ex vivo cell proliferation rate in organoids with distinct genotypes (n=10). *P\u0026lt;0.05 C. In vivo tumor-forming rates in athymic mice for organoids with distinct genotypes (n=12). See also Supplementary Figs. S6–S11.\u003c/p\u003e","description":"","filename":"OncogeneFigure2v.15.png","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/227c9dd44d978272cd785af3.png"},{"id":66670796,"identity":"2a59681f-9066-41f7-96d7-c598d925bdee","added_by":"auto","created_at":"2024-10-15 10:23:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":810013,"visible":true,"origin":"","legend":"\u003cp\u003eRNA-seq demonstrated distinct enrichment patterns of gene sets by loss of Pten and wild-type (WT) Trp53. A. The enrichment patterns found using Gene Set Enrichment Analysis (GSEA) are depicted for the K5-mUrorganoid genotypes. The normalized enrichment score (NES) for each comparison between the indicated genotypes was expanded and exhibited in the scatter plots. The size of each dot indicates the sum of the P-value score based on the P-value (1, not significant; 2, P\u0026lt;0.05; 3, P\u0026lt;0.01) of the horizontal axis and the vertical axis. The categories were determined according to the original report (60) and differentially colored as indicated. a) Gene sets differentially enriched for the WT Trp53 allele status. b) Gene sets differentially enriched for the Pten status. B. Oxidative phosphorylation (OXPHOS) was significantly upregulated in K5-mUrorganoids with Pten loss. C. Column charts showing the results of Seahorse adenosine triphosphate (ATP) assays for (a) OXPHOS, (b) glycolysis, and (c) total ATP production rates for K5-mUrorganoids with the indicated genotypes. The ATP production rate from OXPHOS and total ATP production rate were significantly higher in the organoids with Pten loss than in the Pten WT organoids (P = 0.002 and 0.001, respectively). See also Supplementary Figs. S12 and S13.\u003c/p\u003e","description":"","filename":"OncogeneFigure3v.15.png","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/cd9d3f1a3cbdf5227b186750.png"},{"id":66670799,"identity":"bedb9240-18b3-4978-83e5-9fabdebec593","added_by":"auto","created_at":"2024-10-15 10:23:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":272265,"visible":true,"origin":"","legend":"\u003cp\u003eTrp53R172H/Δ; PtenΔ/Δ K5-mUrorganoids showed higher tumor formation rates in immunocompetent mice. A. Schematic design of the experiment (left) showing that 1×106 cells of K5-mUrorganoids (Parent organoid; PaOr) with the indicated genotypes were inoculated subcutaneously into athymic (n=12) or B6 (n=8) mice. Kaplan–Meier curves (right) showing the time to tumor formation in athymic (top) and B6 (bottom) mice. B. Schematic design of the experiment (left) showing that tumor-derived organoids (TuOrs) were generated from PaOr tumors grown in athymic mice. Here, 1×106 cells of TuOrs with the indicated genotype were inoculated subcutaneously into athymic (n=8) or B6 (n=8) mice. Kaplan–Meier curves (right) showing the time to tumor formation in athymic (top) and B6 (bottom) mice. C. Representative bright-field microscopic images of PaOrs and TuOrs with the indicated genotypes. Scale bars indicate 100 µm. D. Schematic design of the experiment (left) showing that AAV-sgTrp53R172H or sgControl was used to infect two independently generated Trp53R172H/Δ; PtenΔ/Δ TuOrs. These organoids were inoculated subcutaneously into athymic (n=6) or B6 (n=6) mice. Kaplan–Meier curves (right) showing the time to tumor formation for each TuOr. See also Supplementary Figs. S14 and S15.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/8bbe3337a3377186faed59b0.png"},{"id":66670792,"identity":"267e45c9-6b26-4431-a7da-90fdea783532","added_by":"auto","created_at":"2024-10-15 10:23:47","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":3050121,"visible":true,"origin":"","legend":"\u003cp\u003eImmune microenvironment of tumors from tumor-derived organoids (TuOrs). The number of infiltrated cells (left) and representative images (right) of immunohistochemistry assays using (A) anti-CD8, (B) anti-CD206, and (C) anti-Foxp3 antibodies. Scale bars indicate 100 µm.\u003c/p\u003e","description":"","filename":"OncogeneFigure5v.15.png","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/847b836445bfdf5e7751be72.png"},{"id":66670798,"identity":"2bcc66f0-6b93-41c4-a166-b4f05a4d2621","added_by":"auto","created_at":"2024-10-15 10:23:48","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":496394,"visible":true,"origin":"","legend":"\u003cp\u003eDifferential cytokine profiles between PtenΔ/Δ tumor-derived organoids (TuOrs) expressing mutant or no Trp53. A. a) Log2 fold-change (Log2FC) in cytokine expression levels of Trp53Δ/Δ; PtenΔ/Δ TuOrs relative to Trp53R172H/Δ; PtenΔ/Δ TuOrs (comparison A) from female (horizontal axis, TuOr#1) and male (vertical axis, TuOr#2) mice. b) Log2FC in cytokine expression levels of Trp53R172H/Δ; PtenΔ/Δ TuOrs treated with sgTrp53R172H relative to those treated with sgControl (comparison B). The blue dots represent the cytokines increased in TuOrs expressing Trp53R172H/Δ, while the red dots represent the cytokines increased in TuOrs expressing no Trp53. B. Venn diagrams for (a) upregulated and (b) downregulated cytokines in K5-mUrorganoids expressing mutant Trp53 compared with those expressing no Trp53 commonly between comparisons A and B. C. List of 12 cytokines that were downregulated in K5-mUrorganoids expressing mutant Trp53 compared with those expressing no Trp53 commonly between comparisons A and B. The bars represent Log2FC.\u003c/p\u003e","description":"","filename":"OncogeneFigure6v.15.png","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/3f94d990c3fbb824a194a4e8.png"},{"id":66670794,"identity":"ba8dc2ea-6a93-4343-9577-3d67af6d96a3","added_by":"auto","created_at":"2024-10-15 10:23:47","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":156379,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic of the tumorigenic process of the K5-mUrorganoid model. Pten loss in normal urothelial cells causes a metabolic shift, while a Trp53 missense mutation followed by loss of heterozygosity (LOH) promotes cell proliferation and a tumor-forming ability. The K5-mUrorganoids with mutant Trp53 with LOH release relatively lower levels of cytokines compared with the Trp53-null organoids, creating an immune-cold tumor microenvironment that favors tumorigenesis.\u003c/p\u003e","description":"","filename":"OncogeneFigure7v.15.png","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/4c28ce2f18e318d657c73997.png"},{"id":76951720,"identity":"257f4e68-c125-4ffa-b827-69ac5474eb59","added_by":"auto","created_at":"2025-02-23 08:06:37","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3134492,"visible":true,"origin":"","legend":"","description":"","filename":"OncogeneMSAH03.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1_covered_c8d52ba8-ee03-4892-9bb1-7e79077cf6c4.pdf"},{"id":66670789,"identity":"165d21c6-5ac9-4540-9f3d-3da0ef863baf","added_by":"auto","created_at":"2024-10-15 10:23:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":3446995,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"OncogeneSupplementaryFigureMXM.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/89473d45f0f29abac3520321.pdf"},{"id":66670795,"identity":"4f1e6512-6fd1-47c5-8270-d6ed22c5db90","added_by":"auto","created_at":"2024-10-15 10:23:47","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":27522,"visible":true,"origin":"","legend":"","description":"","filename":"OncogeneSupplementaryTableS2cytokinearrayAH01.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4843625/v1/1930df769a0b16fc5efe5204.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Loss of the wild-type allele promotes carcinogenesis of bladder urothelial cells with p53 missense mutation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"oncogene","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"onc","sideBox":"Learn more about [Oncogene](http://www.nature.com/onc/)","snPcode":"41388","submissionUrl":"https://mts-onc.nature.com/cgi-bin/main.plex","title":"Oncogene","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4843625/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4843625/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"In advanced bladder cancer cases, p53 is the most frequently altered gene. Despite missense mutation accounts for over 60% of p53 alterations while homozygous deletion (HOM) for only 5% or less, most of the previously reported mouse models are deficient of p53. Accordingly, there have been few studies addressing whether missense mutations have an advantage over HOM in bladder cancer development. Pten-deficient, Trp53-mutant (Trp53R172H/+) organoids derived from Krt5-expressing mouse urothelium (K5-mUrorganoid) were tumorigenic in athymic mice, but every formed tumors showed loss of wild-type allele of Trp53 (Trp53R172H/LOH). Both Trp53R172H/Δ and Trp53Δ/Δ K5-mUrorganoids formed tumor in athymic mice, whereas only Trp53R172H/Δ K5-mUrorganoid formed tumor even when directly inoculated in immunocompetent syngeneic mice. The absence of wild-type Trp53 was associated with upregulation of proliferative signaling, and the presence of a mutant Trp53 allele was associated with reduced intratumoral CD8+ T cells, increased CD206+ M2 macrophages, and increased Foxp3+ regulatory T cells. This study highlights the functional significance of p53 mutant LOH in bladder carcinogenesis conferring several hallmarks of cancer such as sustaining proliferative signaling and avoiding immune destruction, and provides a novel immunocompetent mouse model of urothelial carcinoma harboring p53 mutations as a novel tool for cancer immunology research.","manuscriptTitle":"Loss of the wild-type allele promotes carcinogenesis of bladder urothelial cells with p53 missense mutation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-15 10:23:38","doi":"10.21203/rs.3.rs-4843625/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-11-04T13:41:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-04T04:31:29+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-10-22T11:38:48+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-09-15T15:05:46+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-08-29T02:33:28+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-08-21T13:42:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-02T08:34:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-01T16:10:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Oncogene","date":"2024-08-01T16:10:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"oncogene","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"onc","sideBox":"Learn more about [Oncogene](http://www.nature.com/onc/)","snPcode":"41388","submissionUrl":"https://mts-onc.nature.com/cgi-bin/main.plex","title":"Oncogene","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"be6abae3-5121-452b-a5ba-6a63f2e73fa7","owner":[],"postedDate":"October 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":36367754,"name":"Biological sciences/Cancer/Urological cancer/Bladder cancer"},{"id":36367755,"name":"Biological sciences/Developmental biology/Disease model"}],"tags":[],"updatedAt":"2025-02-23T08:06:16+00:00","versionOfRecord":{"articleIdentity":"rs-4843625","link":"https://doi.org/10.1038/s41388-025-03311-5","journal":{"identity":"oncogene","isVorOnly":false,"title":"Oncogene"},"publishedOn":"2025-02-22 05:00:00","publishedOnDateReadable":"February 22nd, 2025"},"versionCreatedAt":"2024-10-15 10:23:38","video":"","vorDoi":"10.1038/s41388-025-03311-5","vorDoiUrl":"https://doi.org/10.1038/s41388-025-03311-5","workflowStages":[]},"version":"v1","identity":"rs-4843625","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4843625","identity":"rs-4843625","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}