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Epithelial-mesenchymal transition induced by GRO-?-CXCR2 promotes bladder cancer recurrence after intravesical chemotherapy.

ABSTRACT: Non-muscle invasive bladder cancers (NMIBC) are typically treated by transurethral resection with intravesical chemotherapy. However, the post-therapeutic incidence of tumor recurrence and progression to muscle invasive disease is high, and the underlying mechanism(s) remains unknown. In this study, we observed that recurrent bladder cancer cells exhibit a mesenchymal phenotype, which is initiated by the autocrine GRO-? signaling. Mechanically, the chemotherapeutic drug epidoxorubicin induces GRO-? expression in primary bladder cancer cells at G1/S phase via p38-dependent activation of NF-?B. GRO-? phosphorylation of Snail on Ser246 supports Snail's accumulation in the nucleus, and thereby promotes transcription repression activity of Snail from E-cadherin promoters. In accordance, disrupting the GRO-?-Snail axis in NMIBC represents a promising alternative to prevent post-therapeutic tumor progression and recurrence.

SUBMITTER: Chen L

PROVIDER: S-EPMC5542185 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Epithelial-mesenchymal transition induced by GRO-α-CXCR2 promotes bladder cancer recurrence after intravesical chemotherapy.

Chen Lu L Pan Xiu-Wu XW Huang Hai H Gao Yi Y Yang Qi-Wei QW Wang Lin-Hui LH Cui Xin-Gang XG Xu Dan-Feng DF

Oncotarget 20170701 28

Non-muscle invasive bladder cancers (NMIBC) are typically treated by transurethral resection with intravesical chemotherapy. However, the post-therapeutic incidence of tumor recurrence and progression to muscle invasive disease is high, and the underlying mechanism(s) remains unknown. In this study, we observed that recurrent bladder cancer cells exhibit a mesenchymal phenotype, which is initiated by the autocrine GRO-α signaling. Mechanically, the chemotherapeutic drug epidoxorubicin induces GR ...[more]

PMID: 28423359

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Project description:BackgroundMetastatic bladder cancer (BLCA) is a lethal disease with an unmet need for study. Transgelin (TAGLN) is an actin-binding protein that affects the dynamics of the actin cytoskeleton indicating its robust potential as a metastasis initiator. Here, we sought to explore the expression pattern of TAGLN and elucidate its specific functioning and mechanisms in BLCA.MethodsA comprehensive assessment of TAGLN expression in BLCA was performed in three cohorts with a total of 847 patients. The potential effects of TAGLN on BLCA were further determined using clinical genomic analyses that guided the subsequent functional and mechanistic studies. In vitro migration, invasion assays and in vivo metastatic mouse model were performed to explore the biological functions of TAGLN in BLCA cells. Immunofluorescence, western blot and correlation analysis were used to investigate the molecular mechanisms of TAGLN.FindingsTAGLN was highly expressed in BLCA and correlated with advanced prognostic features. TAGLN promoted cell colony formation and cell migration and invasion both in vitro and in vivo by inducing invadopodia formation and epithelial-mesenchymal transition, during which a significant correlation between TAGLN and Slug was observed. The progression-dependent correlation between TGF-β and TAGLN was analysed at both the cellular and tissue levels, while TGF-β-mediated migration was abolished by the suppression of TAGLN.InterpretationOverall, TAGLN is a promising novel prognosis biomarker of BLCA, and its metastatic mechanisms indicate that TAGLN may represent a novel target agent that can be utilized for the clinical management of invasive and metastatic BLCA. FUND: This work was supported by the National Natural Science Foundation of China [81772703, 81672546, 81602253]; the Natural Science Foundation of Beijing [71772219, 7152146]. and Innovative Fund for Doctoral Students of Peking University Health Science Center (BUM2018BSS002). Funders had no role in the design of the study, data collection, data analysis, interpretation, or the writing of this report.

Dataset Information

Epithelial-mesenchymal transition induced by GRO-?-CXCR2 promotes bladder cancer recurrence after intravesical chemotherapy.

Publications

Epithelial-mesenchymal transition induced by GRO-α-CXCR2 promotes bladder cancer recurrence after intravesical chemotherapy.

Similar Datasets

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