Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis

AbstractInvasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.

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Fibroblasts from pBOO promote tumorigenesis by secreting TGFbeta1 to induce EMT in bladder urothelial carcinoma cells

Bioscience Reports ◽

10.1042/bsr20170944 ◽

2018 ◽

Cited By ~ 1

Author(s):

Xiongbing Lu ◽

Lingxing Duan ◽

Jian Zhang ◽

Zhihua Zeng ◽

Renrui Kuang

Keyword(s):

Bladder Cancer ◽

Cell Invasion ◽

Outlet Obstruction ◽

Neutralizing Antibody ◽

Urinary Bladder Cancer ◽

High Propensity ◽

Muscle Invasive ◽

Activated Fibroblasts ◽

Carcinoma Associated Fibroblasts ◽

Tgf Β1

Abstract Urinary bladder cancer (UBC) is one of the most common malignancies worldwide. UBC patients at muscle invasive stage have poor clinical outcome, due to high propensity for metastasis. Non-tumor activated fibroblasts, named α-SMA+Fs, is similar to carcinoma-associated fibroblasts (CAFs) which could express α-SMA. However, whether α-SMA+Fs patients could induce UBC cell invasion is unclear. Herein, we found that characterization of primary α-SMA+Fs separated from PBOO (partial bladder outlet obstruction) rats was fell in between normal fibroblasts (α-SMA-Fs) and CAFs. Additionally, the conditional medium from α-SMA+Fs enhanced the NBT-II cell invasion through inducing EMT, and the oncogenic function of mixed supernatant of α-SMA+Fs/CAFs was stronger than that of CAFs. Inhibition of TGF-β1 by TGF-β1 neutralizing antibody decreased the EMT-associated gene expression and NBT-II cell invasion, suggesting that α-SMA+Fs can induce tumor EMT through TGF-β1. Xenograft experiments showed that the tumorigenic effect of α-SMA+Fs in mice was also between CAFs and α-SMA-Fs, and α-SMA+Fs/CAFs also had a strong tumorigenic effect. We preformed rats with PBOO and found that the incidence of invasive bladder cancer in PBOO+BBN group was higher than in BBN group, suggesting the PBOO treatment contributed to tumorigenesis. Thus, α-SMA+Fs promoted tumorigenesis by secreting TGF-β1 to induce EMT.

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Lysophosphatidic Acid Upregulates Recepteur D’origine Nantais Expression and Cell Invasion via Egr-1, AP-1, and NF-κB Signaling in Bladder Carcinoma Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21010304 ◽

2020 ◽

Vol 21 (1) ◽

pp. 304

Author(s):

Pham Ngoc Khoi ◽

Shinan Li ◽

Ung Trong Thuan ◽

Dhiraj Kumar Sah ◽

Taek Won Kang ◽

...

Keyword(s):

Bladder Cancer ◽

Lysophosphatidic Acid ◽

Cell Invasion ◽

Bladder Carcinoma ◽

Carcinoma Cells ◽

Lpa Receptor ◽

Carcinoma Metastasis ◽

Muscle Invasive ◽

G Protein Coupled ◽

Bladder Carcinoma Cells

Muscle invasive bladder carcinoma is a highly malignant cancer with a high mortality rate, due to its tendency to metastasize. The tyrosine kinase recepteur d’origine nantais (RON) promotes bladder carcinoma metastasis. Lysophosphatidic acid (LPA) is a phospholipid derivative, which acts as a signaling molecule to activate three high affinity G-protein coupled receptors, LPA1, LPA2, and LPA3. This in turn leads to cell proliferation and contributes to oncogenesis. However, little is known about the effects of LPA on invasive bladder cancer (IBC). In this study, we discovered that LPA upregulated RON expression, which in turn promoted cell invasion in bladder cancer T24 cells. As expected, we found that the LPA receptor was essential for the LPA induced increase in RON expression. More interestingly, we discovered that LPA induced RON expression via the MAPK (ERK1/2, JNK1/2), Egr-1, AP-1, and NF-κB signaling axes. These results provide experimental evidence and novel insights regarding bladder malignancy metastasis, which could be helpful for developing new therapeutic strategies for IBC treatment.

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Biological significance of GATA3, cytokeratin 20, cytokeratin 5/6 and p53 expression in muscle-invasive bladder cancer

PLoS ONE ◽

10.1371/journal.pone.0221785 ◽

2019 ◽

Vol 14 (8) ◽

pp. e0221785 ◽

Cited By ~ 6

Author(s):

Chung-Chieh Wang ◽

Yu-Chieh Tsai ◽

Yung-Ming Jeng

Keyword(s):

Bladder Cancer ◽

Biological Significance ◽

Invasive Bladder Cancer ◽

Cytokeratin 20 ◽

Muscle Invasive Bladder Cancer ◽

P53 Expression ◽

Cytokeratin 5 ◽

Muscle Invasive

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New Strategies in Muscle-Invasive Bladder Cancer: On the Road to Personalized Medicine: Figure 1.

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-10-2770 ◽

2011 ◽

Vol 17 (9) ◽

pp. 2608-2612 ◽

Cited By ~ 67

Author(s):

Jay B. Shah ◽

David J. McConkey ◽

Colin P.N. Dinney

Keyword(s):

Bladder Cancer ◽

Personalized Medicine ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

The Road ◽

On The Road ◽

Muscle Invasive ◽

New Strategies

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XIAP Interaction with E2F1 and Sp1 via its BIR2 and BIR3 domains specific activated MMP2 to promote bladder cancer invasion

Oncogenesis ◽

10.1038/s41389-019-0181-8 ◽

2019 ◽

Vol 8 (12) ◽

Cited By ~ 4

Author(s):

Jiheng Xu ◽

Xiaohui Hua ◽

Rui Yang ◽

Honglei Jin ◽

Jingxia Li ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Invasion ◽

Feedback Loop ◽

Ectopic Expression ◽

Direct Interaction ◽

Protein Translation ◽

Negative Regulator ◽

Cancer Cell Invasion ◽

Design Synthesis ◽

First Time

AbstractXIAP has generally been thought to function in bladder cancer. However, the potential function of structure-based function of XIAP in human BC invasion has not been well explored before. We show here that ectopic expression of the BIR domains of XIAP specifically resulted in MMP2 activation and cell invasion in XIAP-deleted BC cells, while Src was further defined as an XIAP downstream negative regulator for MMP2 activation and BC cell invasion. The inhibition of Src expression by the BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation; which was resulted from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, respectively. The interaction of BIR2/BIR3 with E2F1/Sp1 unexpectedly occurred, which could be blocked by serum-induced XIAP translocation. Taken together, our studies, for the first time revealed that: (1) BIR2 and BIR3 domains of XIAP play their role in cancer cell invasion without affecting cell migration by specific activation of MMP2 in human BC cells; (2) by BIR2 interacting with E2F1 and BIR3 interacting with Sp1, XIAP initiates E2F1/Sp1 positive feedback loop-dependent transcription of miR-203, which in turn inhibits Src protein translation, further leading to MMP2-cleaved activation; (3) XIAP interaction with E2F1 and Sp1 is observed in the nucleus. Our findings provide novel insights into understanding the specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.

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