miR34a/GOLPH3 Axis abrogates Urothelial Bladder Cancer Chemoresistance via Reduced Cancer Stemness

Zhang, Qing; Zhuang, Junlong; Deng, Yongming; Yang, Lin; Cao, Wenmin; Chen, Wei; Lin, Tong; Lv, Xiaoyu; H, Yu; Xue, Yanshi; Guo, Hongqian

doi:10.7150/thno.21713

Cited by 55 publications

(58 citation statements)

References 26 publications

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“…In bladder cancer cells, the over-expression or knockdown of GOLPH3 increases or decreases the expression of CSC factors (CD44, KLF4, ALDH1, and SOX2), respectively. The levels of miR-34-5p are down-regulated in gemcitabine-and cisplatin-resistant bladder cancer cells, contributing to enriched CSC populations [147] (Figure 2 and Table 4). Furthermore, the ability of miR-34-5p to target multiple genes (see Tables 3 and 4) can explain why this miRNA functions effectively with several chemotherapeutics.…”

Section: Golph3mentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

Cells

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The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

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Section: Golph3mentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

Cells

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“…MicroRNAs (miRNAs) play a critical role in tumor progression by regulating gene expression at the posttranscriptional level. Several miRNAs, including miR-22 (20), miR-21 (21), miR-429 (22), miR-34a (23), and miR-139-5p (24), have been implicated in bladder cancer. miR-432-5p has been reported to play an important role in tumor progression.…”

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confidence: 99%

Down‐regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR‐432‐5p/β‐catenin feedback loop

et al. 2019

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RNA‐binding motif protein 5 (RBM5) acts as a tumor suppressor in various human cancers and presents with several important characteristics, such as the potentiation of apoptosis, inhibition of the cell cycle, and alternative splicing of Fas and caspase‐2 precursor mRNA. However, its role in bladder urothelial carcinoma (BUC) remains unknown. In this study, we found that RBM5 expression was significantly down‐regulated in BUC tissues when compared with the adjacent nontumor tissues. The down‐regulation of RBM5 activates ²‐catenin, which binds to the T‐cell factor/lymphocyte enhancer factor element of the miR‐432‐5p promoter and elevates the expression of miR‐432‐5p in bladder cancer cells. The up‐regulated miR‐432‐5p directly targets 3′‐UTR and depresses RBM5 expression. Thus, RBM5–miR‐432‐5p–²‐catenin forms a feedback loop in regulating bladder cancer cell apoptosis. Our findings provide evidence that the regulatory feedback loop among RBM5, miR‐432‐5p, and Wnt–²‐catenin is responsible for the progress of bladder cancer cells.—Zhang, Y.‐P., Liu, K.‐L., Wang, Y.‐X., Yang, Z., Han, Z.‐W., Lu, B.‐S., Qi, J.‐C, Yin, Y.‐W., Teng, Z.‐H., Chang, X.‐L., Li, J.‐D., Xin, H., Li, W. Down‐regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR‐432‐5p/²‐catenin feedback loop. FASEB J. 33, 10973–10985 (2019). http://www.fasebj.org

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“…42 Nevertheless, the other study showed that overexpression of miR-320 could promote the invasion and metastasis of ovarian cancer. 45 Zhang et al 14 found that miR-590-3p was downregulated in GEM-resistant T24 cells, unexpectedly, upregulated in our qRT-PCR. For miR-590-3p, it could inhibit cell proliferation, cell migration, and clonogenic activity of head and neck cancer cells.…”

Section: Discussionmentioning

confidence: 50%

“…14 Interaction between differentially expressed miR-NAs and identified DEGs was retrieved using the R package multiMiR. 14 Interaction between differentially expressed miR-NAs and identified DEGs was retrieved using the R package multiMiR.…”

Section: Target Genes Prediction Of Differentially Expressed Mirnasmentioning

confidence: 99%

Comprehensive analysis of microRNA‐messenger RNA regulatory network in gemcitabine‐resistant bladder cancer cells

Zhang

Chang

Gong

et al. 2018

J of Cellular Biochemistry

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Chemotherapy is still a standard treatment of unresectable bladder cancer or distant metastases. The chemotherapy resistance always occurs after a period of treatment indicating poor prognosis. The current study aimed to explore the molecular mechanism of chemoresistance in bladder cancer cells. The gene expression profiles of GSE77883, including three untreated T24 cells samples and three gemcitabine‐resistant T24 cells samples, was downloaded from Gene Expression Omnibus database. The screening of differentially expressed genes (DEGs), gene function analysis, and interaction prediction between microRNAs (miRNAs) and DEGs were performed by R software. The protein‐protein interaction (PPI) and miRNA‐DEGs networks were constructed and visualized by Cytoscape software. Then, the small molecules, with potential synergistic or antagonistic effects to gemcitabine resistance, were identified using the Connectivity Map database. Finally, gemcitabine‐resistant T24 cell line was established and key genes were validated by quantitative real‐time polymerase chain reaction (qRT‐PCR). In total, 536 upregulated and 513 downregulated genes were screened and mainly enriched in oxidative stress response and signaling pathways related to extracellular matrix–receptor interaction and focal adhesion. PPI network showed interleukin 6, tumor necrosis factor, kinesin family member 11, and BUB1 mitotic checkpoint serine/threonine kinase B were key genes. The miRNA‐DEGs regulatory networks included 18 miRNAs and 185 DEGs, including miR‐182‐5p, miR‐590‐3p, miR‐320a and serum‐ and glucocorticoid‐regulated kinase 1 (SGK1). Then, the related key genes and miRNAs were confirmed by qRT‐PCR. Furthermore, 81 small molecules with antagonistic or synergistic effect to GEM were screened. We have investigated the molecular mechanisms driving GEM‐resistance in bladder cancer cells that would contribute to the development of chemotherapy for advanced bladder cancer.

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miR34a/GOLPH3 Axis abrogates Urothelial Bladder Cancer Chemoresistance via Reduced Cancer Stemness

Cited by 55 publications

References 26 publications

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Down‐regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR‐432‐5p/β‐catenin feedback loop

Comprehensive analysis of microRNA‐messenger RNA regulatory network in gemcitabine‐resistant bladder cancer cells

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