{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T11:25:41Z","timestamp":1765538741047,"version":"3.48.0"},"reference-count":25,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"a Grant-in-Aid for Young Investigators from the Japan Society for the Promotion of Science","award":["19K18590"],"award-info":[{"award-number":["19K18590"]}]},{"name":"a Grant-in-Aid for Young Investigators from the Japan Society for the Promotion of Science","award":["24K19673"],"award-info":[{"award-number":["24K19673"]}]},{"name":"the Office for Diversity Promotion, Fukushima Medical University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Although immunosuppressive factors contribute to the recurrence of non-muscle invasive bladder cancer (NMIBC) during Bacillus Calmette\u2013Gu\u00e9rin (BCG) therapy, the mechanism remains unclear. Methods: In this study, key players in the immunosuppression associated with recurrence after BCG therapy were identified through comprehensive genetic and functional analyses of untreated NMIBC. Results: Microarray analysis of bladder cancer tissue from 13 eligible NMIBC patients revealed an association between high expression of integrin \u03b28 (ITGB8) and recurrence after BCG treatment (p &lt; 0.001). In UMUC cells exhibiting high ITGB8 expression, ITGB8 knockdown significantly decreased cell growth, invasion, adhesion, and secretion of the immunosuppressive cytokine transforming growth factor-\u03b21 (TGF-\u03b21, p &lt; 0.01 for each). In addition, ITGB8 and TGF-\u03b21 expression were correlated in immunohistochemistry of surgical specimens from 13 patients (p &lt; 0.05). These results indicate that ITGB8 regulates TGF-\u03b21 secretion. Conclusions: ITGB8 may contribute to post-BCG therapy recurrence of NMIBC by suppressing tumor immunity through the activation of TGF-\u03b21. Evaluation of ITGB8 expression in preoperative NMIBC could potentially predict recurrence following intravesical BCG therapy.<\/jats:p>","DOI":"10.3390\/cancers17243964","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T11:13:33Z","timestamp":1765538013000},"page":"3964","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunosuppressive Role of Integrin \u03b28 in Recurrence After Bacillus Calmette\u2013Gu\u00e9rin (BCG) Therapy for Non-Muscle Invasive Bladder Cancer"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1545-1827","authenticated-orcid":false,"given":"Seiji","family":"Hoshi","sequence":"first","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2179-5028","authenticated-orcid":false,"given":"Satoru","family":"Meguro","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syunta","family":"Makabe","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akifumi","family":"Onagi","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emina","family":"Kayama","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Yaginuma","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitomi","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Tanji","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-9478","authenticated-orcid":false,"given":"Ruriko","family":"Honda-Takinami","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0731-4577","authenticated-orcid":false,"given":"Kanako","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7912-5468","authenticated-orcid":false,"given":"Junya","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidenori","family":"Akaihata","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soichiro","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motohide","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Kojima","sequence":"additional","affiliation":[{"name":"Department of Urology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.eururo.2016.06.010","article-title":"Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends","volume":"71","author":"Antoni","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.eururo.2021.08.010","article-title":"European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ)","volume":"81","author":"Babjuk","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"329","DOI":"10.6004\/jnccn.2020.0011","article-title":"Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology","volume":"18","author":"Flaig","year":"2020","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"466\u2013465; discussion 467\u2013475","DOI":"10.1016\/j.eururo.2005.12.031","article-title":"Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials","volume":"49","author":"Sylvester","year":"2006","journal-title":"Eur. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1016\/S0022-5347(05)64273-5","article-title":"Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: A meta-analysis of the published results of randomized clinical trials","volume":"168","author":"Sylvester","year":"2002","journal-title":"J. Urol."},{"key":"ref_6","first-page":"Cd011935","article-title":"Intravesical Bacillus Calmette-Gu\u00e9rin versus mitomycin C for Ta and T1 bladder cancer","volume":"1","author":"Schmidt","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/sj.bjc.6602026","article-title":"Role of urothelial cells in BCG immunotherapy for superficial bladder cancer","volume":"91","author":"Bevers","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.biopha.2007.05.004","article-title":"Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: A success story with room for improvement","volume":"61","author":"Brandau","year":"2007","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/s41580-018-0007-0","article-title":"Contextual determinants of TGF\u03b2 action in development, immunity and cancer","volume":"19","author":"David","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Izquierdo, M., Del Ca\u00f1izo, C.G., Rubio, C., Reina, I.A., Hern\u00e1ndez Arroyo, M., Rodr\u00edguez Antol\u00edn, A., Due\u00f1as Porto, M., and Guerrero-Ramos, F. (2023). Immune Predictors of Response after Bacillus Calmette-Gu\u00e9rin Treatment in Non-Muscle-Invasive Bladder Cancer. Cancers, 15.","DOI":"10.3390\/cancers15235554"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a022103","DOI":"10.1101\/cshperspect.a022103","article-title":"Structural Biology and Evolution of the TGF-\u03b2 Family","volume":"8","author":"Hinck","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wells, C.A., Ravasi, T., Faulkner, G.J., Carninci, P., Okazaki, Y., Hayashizaki, Y., Sweet, M., Wainwright, B.J., and Hume, D.A. (2003). Genetic control of the innate immune response. BMC Immunol., 4.","DOI":"10.1186\/1471-2172-4-5"},{"key":"ref_13","first-page":"485","article-title":"Immune escape mechanisms and immunotherapy of urothelial bladder cancer","volume":"7","author":"Yang","year":"2021","journal-title":"J. Clin. Transl. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Harjunp\u00e4\u00e4, H., Llort Asens, M., Guenther, C., and Fagerholm, S.C. (2019). Cell Adhesion Molecules and Their Roles and Regulation in the Immune and Tumor Microenvironment. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01078"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1200\/JCO.1988.6.6.947","article-title":"Adjuvant therapy in large bowel adenocarcinoma: Long-term results of a Southwest Oncology Group Study","volume":"6","author":"Panettiere","year":"1988","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110393","DOI":"10.1016\/j.biopha.2020.110393","article-title":"Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect","volume":"129","author":"Han","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1111\/j.1464-410X.2008.08274.x","article-title":"Bacille-Calmette Gu\u00e8rin induces caspase-independent cell death in urothelial carcinoma cells together with release of the necrosis-associated chemokine high molecular group box protein 1","volume":"103","author":"See","year":"2009","journal-title":"BJU Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Rubio, C., Avenda\u00f1o-Ortiz, J., Ruiz-Palomares, R., Karaivanova, V., Alberquilla, O., S\u00e1nchez-Dom\u00ednguez, R., Casalvilla-Due\u00f1as, J.C., Montalb\u00e1n-Hern\u00e1ndez, K., Lodewijk, I., and Rodr\u00edguez-Izquierdo, M. (2022). Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells\u2019 Pluripotency in Bladder Cancer. Cancers, 14.","DOI":"10.3390\/cancers14020287"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Leblond, M.M., Zdimerova, H., Desponds, E., and Verdeil, G. (2021). Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy. Cancers, 13.","DOI":"10.3390\/cancers13184712"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0302-2838(03)00371-3","article-title":"Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: Results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial","volume":"44","author":"Sylvester","year":"2003","journal-title":"Eur. Urol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1080\/01635581.2020.1856895","article-title":"Targeting Major Signaling Pathways of Bladder Cancer with Phytochemicals: A Review","volume":"73","author":"Chestnut","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sanguedolce, F., Falagario, U.G., Zanelli, M., Palicelli, A., Zizzo, M., Busetto, G.M., Cormio, A., Carrieri, G., and Cormio, L. (2024). Integrating the PD-L1 Prognostic Biomarker in Non-Muscle Invasive Bladder Cancer in Clinical Practice-A Comprehensive Review on State-of-the-Art Advances and Critical Issues. J. Clin. Med., 13.","DOI":"10.3390\/jcm13082182"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"a004994","DOI":"10.1101\/cshperspect.a004994","article-title":"Integrin structure, activation, and interactions","volume":"3","author":"Campbell","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_24","first-page":"E4168","article-title":"Atypical interactions of integrin \u03b1(V)\u03b2(8) with pro-TGF-\u03b21","volume":"114","author":"Wang","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.immuni.2015.04.012","article-title":"Integrin \u03b1v\u03b28-Mediated TGF-\u03b2 Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation","volume":"42","author":"Worthington","year":"2015","journal-title":"Immunity"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/24\/3964\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T11:21:31Z","timestamp":1765538491000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/24\/3964"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":25,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cancers17243964"],"URL":"https:\/\/doi.org\/10.3390\/cancers17243964","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]}}}