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Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion.

Franco R, Zappavigna S, Gigantino V, Luce A, Cantile M, Cerrone M, Facchini G, Perdonà S, Pignata S, Di Lorenzo G, Chieffi S, Vitale G, De Sio M, Sgambato A, Botti G, Yousif AM, Novellino E, Grieco P, Caraglia M - J. Exp. Clin. Cancer Res. (2014)

Bottom Line: UTR discriminated between NMIBC and MIBC and showed a significant correlation between low UTR expression and shorter disease free survival in NMIBC.Bladder cancer cell treatment with the antagonist urantide or the knock-down of UTR with a specific shRNA significantly blocked both the motility and invasion of bladder cancer cells.High UTR expression is an independent prognostic factor of good prognosis for NMIBC regulating motility and invasion of bladder cancer cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy. michele.caraglia@unina2.it.

ABSTRACT

Background: Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC)/invasive have different gene profile and clinical course. NMIBC prognosis is not completely predictable, since the relapse rate is higher than 20%, even in the form of MIBC. The aim of this study is to evaluate if UTR expression can discriminate between NMIBC and MIBC and predict the risk of relapses in NMIBCs.

Methods: We have investigated upon urotensin-II (UII) receptor (UTR) expression in vivo in 159 patients affected by NMIBC. The biological role of UTR was also investigated in vitro. UTR expression was evaluated in a tissue-micro-array, consisting of normal, NMIBC and invasive bTCC samples.

Results: UTR discriminated between NMIBC and MIBC and showed a significant correlation between low UTR expression and shorter disease free survival in NMIBC. The superagonist UPG84 induced growth suppression at nM concentrations on 3/4 cell lines. Bladder cancer cell treatment with the antagonist urantide or the knock-down of UTR with a specific shRNA significantly blocked both the motility and invasion of bladder cancer cells.

Conclusions: The evaluation of UTR expression can discriminate between NMIBC at high and low risk of relapse. Moreover, our data suggest that UTR is involved in the regulation of motility, invasion and proliferation of bladder cancer cells. High UTR expression is an independent prognostic factor of good prognosis for NMIBC regulating motility and invasion of bladder cancer cells.

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Expression of UTR by Western blotting. Cell lines of human bladder cancer are MCR, RT112, T24 and HT1376. The housekeeping protein α-tubulin was used as loading control. Bars, SDs. The experiments were performed at least three different times and the results were always similar.
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Figure 6: Expression of UTR by Western blotting. Cell lines of human bladder cancer are MCR, RT112, T24 and HT1376. The housekeeping protein α-tubulin was used as loading control. Bars, SDs. The experiments were performed at least three different times and the results were always similar.

Mentions: In order to evaluate the involvement of UTR-dependent signaling pathway on the growth of bladder cancer cells, biological effects of human agonists (UII and UPG84), and antagonists (urantide, UPG83 and UPG85), were evaluated on proliferation of human bladder cancer cell lines MCR, RT112, T24 and HT1376 (Figure 6) after 72 h of treatment. UII had no significant effects on the proliferation of all cell lines (Figure 7A-D). The 50% growth inhibitory concentration (IC:50) of urantide was 350 nM in T24 and 375 nM in RT112 while it was not achieved in HT1376 and MCR cells (Table 2). UPG84 induced 45-50% growth inhibition at a concentration close to the supposed Kd of UTR (about 10 nM) in all cell lines with the exception of RT112 cells that were almost insensitive (Figure 7E). Interestingly, UPG84 is a superagonist of UTR (Additional file1: Table S1) and the addition to cell culture for 72 h could affect UTR expression on cell surface for internalization process triggering. On this light, we have found that treatment of these cells with UPG84 induced a time-dependent down regulation of UTR expression that reached an about 50% and 60% decrease at 72 h from the beginning of the treatment on HT-1376 and T24 cells, respectively (Figure 7F). On the other hand, urantide induced 30 and 20% decrease of UTR expression in HT-1376 and T24 cells, respectively (Figure 7F).


Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion.

Franco R, Zappavigna S, Gigantino V, Luce A, Cantile M, Cerrone M, Facchini G, Perdonà S, Pignata S, Di Lorenzo G, Chieffi S, Vitale G, De Sio M, Sgambato A, Botti G, Yousif AM, Novellino E, Grieco P, Caraglia M - J. Exp. Clin. Cancer Res. (2014)

Expression of UTR by Western blotting. Cell lines of human bladder cancer are MCR, RT112, T24 and HT1376. The housekeeping protein α-tubulin was used as loading control. Bars, SDs. The experiments were performed at least three different times and the results were always similar.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061920&req=5

Figure 6: Expression of UTR by Western blotting. Cell lines of human bladder cancer are MCR, RT112, T24 and HT1376. The housekeeping protein α-tubulin was used as loading control. Bars, SDs. The experiments were performed at least three different times and the results were always similar.
Mentions: In order to evaluate the involvement of UTR-dependent signaling pathway on the growth of bladder cancer cells, biological effects of human agonists (UII and UPG84), and antagonists (urantide, UPG83 and UPG85), were evaluated on proliferation of human bladder cancer cell lines MCR, RT112, T24 and HT1376 (Figure 6) after 72 h of treatment. UII had no significant effects on the proliferation of all cell lines (Figure 7A-D). The 50% growth inhibitory concentration (IC:50) of urantide was 350 nM in T24 and 375 nM in RT112 while it was not achieved in HT1376 and MCR cells (Table 2). UPG84 induced 45-50% growth inhibition at a concentration close to the supposed Kd of UTR (about 10 nM) in all cell lines with the exception of RT112 cells that were almost insensitive (Figure 7E). Interestingly, UPG84 is a superagonist of UTR (Additional file1: Table S1) and the addition to cell culture for 72 h could affect UTR expression on cell surface for internalization process triggering. On this light, we have found that treatment of these cells with UPG84 induced a time-dependent down regulation of UTR expression that reached an about 50% and 60% decrease at 72 h from the beginning of the treatment on HT-1376 and T24 cells, respectively (Figure 7F). On the other hand, urantide induced 30 and 20% decrease of UTR expression in HT-1376 and T24 cells, respectively (Figure 7F).

Bottom Line: UTR discriminated between NMIBC and MIBC and showed a significant correlation between low UTR expression and shorter disease free survival in NMIBC.Bladder cancer cell treatment with the antagonist urantide or the knock-down of UTR with a specific shRNA significantly blocked both the motility and invasion of bladder cancer cells.High UTR expression is an independent prognostic factor of good prognosis for NMIBC regulating motility and invasion of bladder cancer cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy. michele.caraglia@unina2.it.

ABSTRACT

Background: Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC)/invasive have different gene profile and clinical course. NMIBC prognosis is not completely predictable, since the relapse rate is higher than 20%, even in the form of MIBC. The aim of this study is to evaluate if UTR expression can discriminate between NMIBC and MIBC and predict the risk of relapses in NMIBCs.

Methods: We have investigated upon urotensin-II (UII) receptor (UTR) expression in vivo in 159 patients affected by NMIBC. The biological role of UTR was also investigated in vitro. UTR expression was evaluated in a tissue-micro-array, consisting of normal, NMIBC and invasive bTCC samples.

Results: UTR discriminated between NMIBC and MIBC and showed a significant correlation between low UTR expression and shorter disease free survival in NMIBC. The superagonist UPG84 induced growth suppression at nM concentrations on 3/4 cell lines. Bladder cancer cell treatment with the antagonist urantide or the knock-down of UTR with a specific shRNA significantly blocked both the motility and invasion of bladder cancer cells.

Conclusions: The evaluation of UTR expression can discriminate between NMIBC at high and low risk of relapse. Moreover, our data suggest that UTR is involved in the regulation of motility, invasion and proliferation of bladder cancer cells. High UTR expression is an independent prognostic factor of good prognosis for NMIBC regulating motility and invasion of bladder cancer cells.

Show MeSH
Related in: MedlinePlus