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.

Overexpression of Interleukin-8 and Interleukin-13 as potent immune markers associated with survival and dietary habits in esophageal squamous cell carcinoma

“…Higher level of IL8 was also reported in the sera of liver, gastric and non-small-cell lung cancer patients as compared to healthy controls [27]. Moreover, overexpression of IL8 was correlated with tumor progression, recurrence and the TNM stage in multiple cancers [28]. In our study, 83% patients showed overexpression of IL8 in their tissue (p=0.000).…”

Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer‐associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p‐ACLY axis

“…Substantial elevation of IL8 expression was detected in various types of cancer including OSCC, and IL8 has been reported to stimulate angiogenesis, recruit immunosuppressive cells, promote epithelial-to-mesenchymal transition, and enhance stemness and chemoresistance of tumor cells. [39][40][41][42] Notably, activation of AKT signaling is one of the major mechanisms by which IL8 regulates the phenotype and function of tumor and stromal cells. Du et al 34 reported that the IL8/CXCR1/AKT axis enhanced anoikic resistance and metastasis of osteosarcoma cells.…”

Tumor microenvironment and epithelial-mesenchymal transition in bladder cancer: Cytokines in the game?

“…Consequently, IL-8 promoted extracellular signal-regulated kinase (ERK), AKT, and signal transducer and activator of transcription (STAT) 3 signaling activation, resulting in an evident influence in EMT, since the E-cadherin decreased, while Vimentin, Snail, Slug and Twist increased ( Zhou et al, 2021 ). It was shown that a tight junction protein family member, occludin, regulated angiogenesis by controlling IL-8/STAT3 signaling pathway by STAT4 activation ( Yang et al, 2022 ). Retz MM et al showed that co-culture of B cells with the BlCa cell lines, TCCSUP, T24 and J82, increased bladder cell invasion and migration ( Ou et al, 2015 ).…”