Differential functions of RhoGDIβ in malignant transformation and progression of urothelial cell following N-butyl-N-(4-hydmoxybutyl) nitrosamine exposure
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Published:2023-08-28
Issue:1
Volume:21
Page:
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ISSN:1741-7007
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Container-title:BMC Biology
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language:en
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Short-container-title:BMC Biol
Author:
Hua Xiaohui,Zou Ronghao,Bai Xiaoyue,Yang Yuyao,Lu Juan,Huang Chuanshu
Abstract
Abstract
Background
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).
Results
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.
Conclusions
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.
Funder
Natural Science Foundation of China
Oujiang Research Project
Scientific Research Foundation of Education Department of Anhui Province of China
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Developmental Biology,Plant Science,General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Physiology,Ecology, Evolution, Behavior and Systematics,Structural Biology,Biotechnology
Reference49 articles.
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.
3. Vishnu P, Mathew J, Tan WW. Current therapeutic strategies for invasive and metastatic bladder cancer. Onco Targets Ther. 2011;4:97–113.
4. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420(6916):629–35.
5. Zhen HY, Yang SM, Wu HN, Wang SL, Lv JQ, Ma LJ, et al. LyGDI is a promising biomarker for ovarian cancer. Int J Gynecol Cancer. 2010;20(3):316–22.