PREDICTIVE VALUE OF CLAUDIN-4 EXPRESSION IN NON-MUSCLE INVASIVE UROTHELIAL BLADDER CANCER
Claudin-4 in urothelial bladder cancer
Abstract
Claudin-4 is an integral membrane protein of tight junctions, and its expression is frequently altered in epithelial cancers. Non-muscle-invasive urothelial bladder cancer (NMIBC) is a common neoplasm with an unpredictable clinical course that requires more precise stratification and risk assessment. The aim of this study was to investigate the association between Claudin-4 expression and clinicopathologic features of NMIBC, and to assess the predictive impact of Claudin-4 regarding to disease prognosis. The study comprised tumor tissue samples obtained from 441 patients with urothelial bladder cancer who had undergone transurethral resection. Samples were embedded in tissue microarrays and analyzed immunohistochemically for Claudin-4 expression. High expression was found in 41.6% of pTa and 47.8% of pT1 tumors. High Claudin-4 expression significantly correlated to high histologic grade (p = 0.002), and hematuria (p = 0.038). High Claudin-4 expression was more frequently observed in tumors with divergent differentiation, early invasive cancers associated with carcinoma in situ, and recurrent disease, however, these associations were not statistically significant. Kaplan—Meier survival analysis failed to indicate a significant difference in overall survival between the patients with high and low Claudin-4 expression. Conversely, recurrence-free survival was significantly associated with Claudin-4 expression (p = 0.023). In conclusion, overexpression of Claudin-4 is associated with high tumor grade and shorter recurrence-free survival. As an indicator of aggressive tumor behavior, Claudin-4 may serve as a potentially useful and accessible addition to the pathohistological panel for the prediction of clinical behavior of urothelial bladder cancer, as well as a promising therapeutic target.
References
Abd-Elazeem MA, Abd-Elazeem MA. Claudin 4 expression in triple-negative breast cancer: correlation with androgen receptors and Ki-67 expression. Ann Diagn Pathol 2015; 19(1): 37-42. [CrossRef] [PubMed]
Arabi TZ, Fawzy NA, Sabbah BN, Ouban A. Claudins in genitourinary tract neoplasms: mechanisms, prognosis, and therapeutic prospects. Front Cell Dev Biol 2023; 11:1308082. [CrossRef] [PubMed]
Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ). Eur Urol 2022; 81(1):75-94. [CrossRef] [PubMed]
Bernardi L, Bizzarro T, Pironi F, Szymczuk S, Buda R, Fabbri E, et al. The "Brescia panel" (Claudin-4 and BRCA-associated protein 1) in the differential diagnosis of mesotheliomas with epithelioid features versus metastatic carcinomas. Cancer Cytopathol 2021; 129(4): 275-82. [CrossRef] [PubMed]
Chen B, Bu R, Xu X. Expression of Tight Junction Proteins Is Altered in Bladder Cancer. Anal Cell Pathol (Amst) 2020; 2020: 6341256. [CrossRef] [PubMed]
Cooley LF, McLaughlin KA, Meeks JJ. Genomic and Therapeutic Landscape of Non-muscle-invasive Bladder Cancer. Urol Clin North Am 2020; 47(1): 35-46. [CrossRef] [PubMed]
Crețu OI, Stepan MD, Florescu MM, Stepan AE. Immunoexpression of Claudin 4 in Gastric Adenocarcinomas. Curr Health Sci J 2022; 48(4):373-8. [CrossRef] [PubMed]
El-Fattah, Ghada A. Abd, Said, Eman M, Roshdy, Rania G. Evaluation of the role of tight junction molecules: claudin-1 and claudin-4 in urothelial neoplasms. Egyptian Journal of Pathology 2021; 41(1):p 34-40. [CrossRef]
Elsayed AM, Mahmoud EI, Salem MM, Khairy RA. Immunohistochemical Expression of Claudin-1 and Claudin-4 in Urothelial Carcinoma of the Urinary Bladder. Asian Pac J Cancer Prev 2024; 25(2): 637-46. [CrossRef] [PubMed]
Fujita H, Hamazaki Y, Noda Y, Oshima M, Minato N. Claudin-4 deficiency results in urothelial hyperplasia and lethal hydronephrosis. PLoS One 2012; 7(12): e52272–e52272. [CrossRef] [PubMed]
Fujiwara-Tani R, Fujii K, Mori S, Kishi S, Sasaki T, Ohmori H, et al. Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/ Polyps with Dysplasia. Int J Mol Sci 2020; 21(11): 3840. [CrossRef] [PubMed]
Fujiwara-Tani R, Mori S, Ogata R, Sasaki R, Ikemoto A, Kishi S, et al. Claudin-4: A New Molecular Target for Epithelial Cancer Therapy. Int J Mol Sci 2023; 24(6): 5494. [CrossRef] [PubMed]
Hicks DA, Galimanis CE, Webb PG, Spillman MA, Behbakht K, Neville MC, Baumgartner HK. Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration. BMC Cancer 2016; 16(1): 788. [CrossRef] [PubMed]
Kuwada M, Chihara Y, Luo Y, Li X, Nishiguchi Y, Fujiwara R, et al. Pro-chemotherapeutic effects of antibody against extracellular domain of claudin-4 in bladder cancer. Cancer Lett 2015; 369(1): 212-21. [CrossRef] [PubMed]
Li HT, Duymich CE, Weisenberger DJ, Liang G. Genetic and Epigenetic Alterations in Bladder Cancer. Int Neurourol J 2016; 20(Suppl 2): S84-94. [CrossRef] [PubMed]
Liu H, Zhang Z, Zhou S, Liu X, Li G, Song B, Xu W. Claudin-1/4 as directly target gene of HIF-1α can feedback regulating HIF-1α by PI3K-AKT-mTOR and impact the proliferation of esophageal squamous cell though Rho GTPase and p-JNK pathway. Cancer Gene Ther 2022; 29(6): 665-82. [CrossRef] [PubMed]
Ma X, Miao H, Jing B, Pan Q, Zhang H, Chen Y, et al. Claudin-4 controls the proliferation, apoptosis, migration and in vivo growth of MCF-7 breast cancer cells. Oncol Rep 2015; 34(2): 681-90. [CrossRef] [PubMed]
SĂndulescu AŞ, Stepan AE, MĂrgĂritescu C, Badiu AM, Matei M, Simionescu CE. Claudin-4 Immunoexpression in Urothelial Carcinomas. Curr Health Sci J 2020; 46(4): 379-82. [CrossRef] [PubMed]
Sasaki T, Fujiwara-Tani R, Kishi S, Mori S, Luo Y, Ohmori H, et al. Targeting claudin-4 enhances chemosensitivity of pancreatic ductal carcinomas. Cancer Med 2019; 8(15): 6700-8. [CrossRef] [PubMed]
Stojnev S, Krstic M, Ristic A, Todorovic J, Mladenovic M, Ristic-Petrovic A, et al. Correlation between expression of epigenetic silencer EZH2 and Claudin-4 and their prognostic value in urothelial bladder cancer - immunohistochemical study. Virchows Arch 2017; 471 (Suppl 1):S29. OFP-09-012. ISSN: 0945-6317 (Print) 1432-2307 (Online). The 29th European Congress of Pathology, 2 – 6 September 2017, RAI Amsterdam, The Netherlands.
Süren D, Yildirim M, Sayiner A, Alikanoğlu AS, Atalay I, Gündüz UR, et al. Expression of claudin 1, 4 and 7 in thyroid neoplasms. Oncol Lett 2017; 13(5): 3722-6. [CrossRef] [PubMed]
Székely E, Törzsök P, Riesz P, Korompay A, Fintha A, Székely T, et al. Expression of claudins and their prognostic significance in noninvasive urothelial neoplasms of the human urinary bladder. J Histochem Cytochem 2011; 59(10): 932-41. [CrossRef] [PubMed]
Teoh JY, Kamat AM, Black PC, Grivas P, Shariat SF, Babjuk M. Recurrence mechanisms of non-muscle-invasive bladder cancer - a clinical perspective. Nat Rev Urol 2022; 19(5): 280-94. [CrossRef] [PubMed]
Villagomez FR, Lang J, Webb P, Neville M, Woodruff ER, Bitler BG. Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer. bioRxiv [Preprint]. 2024: . [CrossRef] [PubMed]
Wang DW, Zhang WH, Danil G, Yang K, Hu JK. The role and mechanism of claudins in cancer. Front Oncol 2022; 12: 1051497. [CrossRef] [PubMed]
Yamada G, Murata M, Takasawa A, Nojima M, Mori Y, Sawada N, Takahashi H. Increased expressions of claudin 4 and 7 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Med Mol Morphol 2016; 49(3): 163-9. [CrossRef] [PubMed]
Zejc T, Piontek J, Schulzke JD, Fromm M, Ervens J, Rosenthal R. Clinical Significance of Claudin Expression in Oral Squamous Cell Carcinoma. Int J Mol Sci 2022; 23(19):11234. [CrossRef] [PubMed]
