在肿瘤生物学中，Rho GDP-解离抑制蛋白β（RhoGDIβ）的功能角色似乎在不同研究中存在矛盾。因此，在泌尿膀胱癌发生的分子机制方面对该蛋白的差异功能进行探索在该领域具有重要意义。本研究评估了人类尿路上皮细胞（UROtsa细胞）暴露于膀胱致癌物N-丁基-N-（4-羟基丁基）亚硝胺（BBN）的不同时间长度后，RhoGDIβ的表达模式、生物学功能以及转化和进展的分子机制。结果显示，与车辆处理的对照细胞相比，经过2个月BBN暴露后，RhoGDIβ蛋白表达下调，而经过6个月的暴露后则上调。细胞功能评估显示，RhoGDIβ抑制了经过2个月BBN处理的UROtsa细胞生长，但促进了经过6个月BBN处理的细胞侵袭。机制研究揭示，2个月BBN暴露明显减少了DNMT3a的丰度，导致miR-219a启动子甲基化减少，miR-219a与RhoGDIβ mRNA 3'UTR结合增加，而RhoGDIβ蛋白翻译降低。而经过6个月BBN处理后，细胞显示PP2A/JNK/C-Jun轴磷酸化增强，从而调控了整体RhoGDIβ mRNA转录和蛋白表达以及细胞侵袭。这些发现表明，RhoGDIβ很可能在BBN暴露的早期阶段抑制人类尿路上皮细胞的转化，而在后期阶段促进已转化/进展的尿路上皮细胞的侵袭。这些研究还表明，RhoGDIβ可能是评估人类膀胱癌进展的有用生物标志物。© 2023. BioMed Central Ltd., part of Springer Nature.

Functional role of Rho GDP-dissociation inhibitor beta (RhoGDIβ) in tumor biology appears to be contradictory across various studies. Thus, the exploration of the molecular mechanisms underlying the differential functions of this protein in urinary bladder carcinogenesis is highly significant in the field. Here, RhoGDIβ expression patterns, biological functions, and mechanisms leading to transformation and progression of human urothelial cells (UROtsa cells) were evaluated following varying lengths of exposure to the bladder carcinogen N-butyl-N-(4-hydmoxybutyl) nitrosamine (BBN).It was seen that compared to expression in vehicle-treated control cells, RhoGDIβ protein expression was downregulated after 2-month of BBN exposure, but upregulated after 6-month of exposure. Assessments of cell function showed that RhoGDIβ inhibited UROtsa cell growth in cells with BBN for 2-month exposure, whereas it promoted the invasion of cells treated with BBN for 6 months. Mechanistic studies revealed that 2-month of BBN exposure markedly attenuated DNMT3a abundance, and this led to reduced miR-219a promoter methylation, increased miR-219a binding to the RhoGDIβ mRNA 3'UTR, and reduced RhoGDIβ protein translation. While after 6-mo of BBN treatment, the cells showed increased PP2A/JNK/C-Jun axis phosphorylation and this in turn mediated overall RhoGDIβ mRNA transcription and protein expression as well as invasion.These findings indicate that RhoGDIβ is likely to inhibit the transformation of human urothelial cells during the early phase of BBN exposure, whereas it promotes invasion of the transformed/progressed urothelial cells in the late stage of BBN exposure. The studies also suggest that RhoGDIβ may be a useful biomarker for evaluating the progression of human bladder cancers.© 2023. BioMed Central Ltd., part of Springer Nature.