Hypoxia inducible factor‐1 activator munc‐18‐interacting protein 3 promotes tumour progression in urothelial carcinoma. Issue 1 (20th January 2023)

• Record Type: Journal Article
• Authors: Ikeda, Junichi; Ohe, Chisato; Tanaka, Noritaka; Yoshida, Takashi; Saito, Ryoichi; Atsumi, Naho; Kobayashi, Takashi; Kinoshita, Hidefumi; Tsuta, Koji; Sakamoto, Takeharu
• Is Part Of: Clinical and translational discovery. Volume 3:Issue 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-20
• Subjects: Bladder cancer -- HIF‐1 -- Mint3 -- tissue microarray -- urothelial carcinoma; Medicine -- Periodicals; Medicine; Periodicals; 616
• DOI: 10.1002/ctd2.158
• Languages: English
• ISSNs: 2768-0622

Abstract

Abstract: Background: Although the introduction of multiple agents targeting immune and oncogenic signaling pathways has substantially changed the treatment strategies for urothelial carcinoma (UC), these drugs still have some limitations, such as adverse effects and limited responses depending on the molecular subtype of UC. Therefore, the development of novel molecular‐targeted therapies is required. Munc18‐1‐interacting protein 3 (Mint3), which specifically activates hypoxia inducible factor‐1 (HIF‐1) during normoxia in cancer and some stromal cells, might be a good target for UC treatment without severe adverse effects. However, the expression and function of Mint3 in UC remain unclear. Methods: We prepared bladder cancer ( n = 117) and upper tract UC ( n = 207) cohorts and analyzed the correlation between Mint3 expression in the tissue microarray and the clinicopathological factors/prognosis. To clarify the function of Mint3 in UC cells, control and Mint3‐depleted UC cells were analyzed for HIF‐1 activity, HIF‐1 target gene expression, cell proliferation, glycolysis, motility and invasion in vitro. Tumorigenicity and angiogenesis in control and Mint3‐depleted UC cells were analyzed in mouse xenograft models. A Mint3 inhibitor, naphthofluorescein and gemcitabine were administrated into UC xenograft‐bearing mice. Results: Mint3 was expressed at various levels in UC cells; high expression was correlated with a poor prognosis but not with the molecular subtype of UC in two independent UC cohorts. Mint3 depletion did not affect cell proliferation but attenuated HIF‐1 activity, HIF‐1 target gene expression, glycolysis and motility/invasion in both luminal‐ and basal‐molecular‐subtype UC cells in vitro. Mint3 depletion in UC cells also attenuated tumour growth and angiogenesis in xenograft models. In addition, pharmacological inhibition of Mint3 sensitized chemo‐resistant UC xenografts to gemcitabine. Conclusions: Our findings indicate that Mint3 is a potential target for UC therapy with or without chemotherapy, independent of the molecular subtype of UC. Abstract : Graphical Headlights Munc18‐1‐interacting protein 3 (Mint3) showed higher expression in urothelial carcinoma (UC) than normal urothelium. The expression level of Mint3 correlated with the malignancy of UC. Depletion of Mint3 suppressed a progression of UC in vivo. Mint3 inhibitor, Naphthofluorescein enhanced anti‐tumour activity of gemcitabine.