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Occludin facilitates tumour angiogenesis in bladder cancer by regulating IL8/STAT3 through STAT4.

ABSTRACT: Bladder cancer (BLCA) is a common genitourinary cancer in patients, and tumour angiogenesis is indispensable for its occurrence and development. However, the indepth mechanism of tumour angiogenesis in BLCA remains elusive. According to recent studies, the tight junction protein family member occludin (OCLN) is expressed at high levels in BLCA tissues and correlates with a poor prognosis. Downregulation of OCLN inhibits tumour angiogenesis in BLCA cells and murine xenografts, whereas OCLN overexpression exerts the opposite effect. Mechanistically, the RT-qPCR analysis and Western blotting results showed that OCLN increased interleukin-8 (IL8) and p-signal transducer and activator of transcription 3 (STAT3) levels to promote BLCA angiogenesis. RNA sequencing analysis and dual-luciferase reporter assays indicated that OCLN regulated IL8 transcriptional activity via the transcription factor STAT4. In summary, our results provide new perspectives on OCLN, as this protein participates in the development of BLCA angiogenesis by activating the IL8/STAT3 pathway via STAT4 and may serve as a novel and unique therapeutic target.

SUBMITTER: Yang F

PROVIDER: S-EPMC8995457 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Occludin facilitates tumour angiogenesis in bladder cancer by regulating IL8/STAT3 through STAT4.

Yang Fan F Liu Xue-Qi XQ He Jian-Zhong JZ Xian Shi-Ping SP Yang Peng-Fei PF Mai Zhi-Ying ZY Li Miao M Liu Ye Y Zhang Xing-Ding XD

Journal of cellular and molecular medicine 20220227 8

Bladder cancer (BLCA) is a common genitourinary cancer in patients, and tumour angiogenesis is indispensable for its occurrence and development. However, the indepth mechanism of tumour angiogenesis in BLCA remains elusive. According to recent studies, the tight junction protein family member occludin (OCLN) is expressed at high levels in BLCA tissues and correlates with a poor prognosis. Downregulation of OCLN inhibits tumour angiogenesis in BLCA cells and murine xenografts, whereas OCLN overex ...[more]

PMID: 35224833

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Project description:Angiogenesis is involved in many pathological and physiological processes and is mainly driven by hypoxia. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, was recently shown to be induced by hypoxia in various types of tumours, so we aimed to investigate the role and mechanism of KPNA2 in angiogenesis under hypoxia. After overexpression or knockdown of KPNA2 in human umbilical vein endothelial cells (HUVEC) by adenovirus vector infection, the tube formation, proliferation and migration of HUVEC under hypoxia were detected by tubule formation assay, 5-ethynyl-2'-deoxyuridine (EdU) staining and Transwell assay, respectively. After overexpression or knockdown of KPNA2 in a murine hindlimb ischemia model by local injection of purified adenovirus vector into the gastrocnemius muscle, blood flow changes were examined with a laser Doppler system. Changes in KPNA2-binding proteins under hypoxia were detected by immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP). The effect of KPNA2 on signal transducer and activator of transcription 3 (STAT3) was detected by Western blotting and quantitative RT‒PCR. KPNA2 was upregulated in the HUVEC hypoxia model and murine hindlimb ischemia model. Overexpression of KPNA2 increased the proliferation, migration and tube formation of HUVEC under hypoxia, while knockdown of KPNA2 reduced the proliferation, migration and tube formation of HUVEC. Overexpression of KPNA2 promoted the restoration of blood flow in the murine hindlimb ischemia model, while knockout of KPNA2 inhibited the restoration of blood flow in the murine hindlimb ischemia model. Mechanistically, hypoxia promoted the binding of STAT3 to KPNA2. Overexpression of KPNA2 promoted STAT3 phosphorylation and then upregulated vascular endothelial growth factor (VEGF) and angiopoietin 2(ANGPT2), whereas knockdown of KPNA2 inhibited STAT3 phosphorylation and then downregulated VEGF and ANGPT2. Our study demonstrates that hypoxia promotes the binding of STAT3 to KPNA2 and KPNA2 promotes angiogenesis under hypoxia by promoting the binding of STAT3 and JAK1 and regulating STAT3 phosphorylation.

Project description:BackgroundSWI/SNF, a well-known ATP-dependent chromatin-remodeling complex, plays an essential role in several biological processes. SNF5, the core subunit of the SWI/SNF remodeling complex, inactivated in 95% of malignant rhabdoid tumors (MRT), highlighting its significance in tumorigenesis. However, the role of SNF5 in bladder cancer (BC) remains unknown. In this study, we aimed to investigate the function and potential clinical applicability of SNF5 in BC.MethodsData from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were used to evaluate the clinical significance of SNF5 in BC. We performed Gene Set Enrichment Analysis (GSEA) and functional assays to investigate the role of SNF5 in BC. Genomics of Drug Sensitivity in Cancer (GDSC) and drug-susceptibility tests were performed to identify the potential value of SNF5 in the treatment of BC.ResultsLow SNF5 expression conferred a poor prognosis and was significantly associated with the N-stage in BC. ROC curves indicated that SNF5 could distinguish BC from the normal tissues. In vitro and in vivo functional assays demonstrated that attenuated SNF5 expression could promote cell proliferation and enhance migration by STAT3 activation. We imputed that low SNF5 expression could confer greater resistance against conventional first-line drugs, including cisplatin and gemcitabine in BC. GDSC and drug-resistance assays suggested that low SNF5 expression renders T24 and 5637 cells high sensitivity to EGFR inhibitor gefitinib, and combination of EZH2 inhibitor GSK126 and cisplatin.ConclusionsTo the best of our knowledge, the present study, for the first time, showed that low SNF5 expression could promote cell proliferation and migration by activating STAT3 and confer poor prognosis in BC. Importantly, SNF5 expression may be a promising candidate for identifying BC patients who could benefit from EGFR-targeted chemotherapy or cisplatin in combination with EZH2 inhibitor treatment regimens.

Dataset Information

Occludin facilitates tumour angiogenesis in bladder cancer by regulating IL8/STAT3 through STAT4.

Publications

Occludin facilitates tumour angiogenesis in bladder cancer by regulating IL8/STAT3 through STAT4.

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