Alterations of p53 and Rb Pathways Are Associated with High Proliferation in Bladder Urothelial Carcinomas

Goussia, Anna; Papoudou‐Bai, Alexandra; Charchanti, Antonia; Kitsoulis, Panagiotis; Kanavaros, Panagiotis; Kalef-Ezra, J.; Stefanou, Dimitrios; Agnantis, Niki J.

doi:10.21873/anticanres.12685

Cited by 13 publications

(17 citation statements)

References 20 publications

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“…A more recent study of 413 high grade muscle invasive bladder malignancies found that the RB gene, RNA or protein expression was altered in 17% of the malignancies [ 20 ]. Bladder malignancies with alterations in the RB and p53 pathways have been noted to have high proliferation rates [ 21 ]. In addition to a mutation, deletion or epigenetic silencing of the RB gene, the RB tumor suppressive pathway can be circumvented by overexpression of cyclin D, Cyclin D which along with its binding partners CDK4/6 hyperphosphorylates RB, thus disabling its tumor suppressive activity.…”

Section: Introductionmentioning

confidence: 99%

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

et al. 2018

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Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner. The decrease in cell viability was due to an induction of apoptosis and cell cycle arrest. These results were recapitulated in in vivo studies where selinexor decreased tumor growth. Tumors treated with selinexor expressed lower levels of XPO1, cyclin A, cyclin B, and CDK2 and increased levels of RB and CDK inhibitor p27, a result that is consistent with growth arrest. Cells expressing wildtype RB, a potent tumor suppressor that promotes growth arrest and apoptosis, were most susceptible to selinexor. Cell fractionation and immunofluorescence studies showed that selinexor treatment increased nuclear RB levels and mechanistic studies revealed that RB ablation curtailed the response to the drug. Conversely, limiting CDK4/6 dependent RB phosphorylation by palbociclib was additive with selinexor in reducing bladder tumor cell viability, confirming that RB activity has a role in the response to XPO1 inhibition. These results provide a rationale for XPO1 inhibition as a novel strategy for the treatment of bladder malignancies.

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Section: Introductionmentioning

confidence: 99%

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

et al. 2018

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“…RUNX3, SRFP1, and E‐cadherin are related to WNT/beta‐catenin pathway, and the methylation is related to proliferation and lymph node metastasis, poor prognosis, and tumor stage 28–30 . p16INK4a inhibits cyclin‐dependent kinases (CDK) CDK4 and CDK6, and thereby preventing G1‐to‐S cell‐cycle phase progression; thus, the methylation of p16INK4a is reported cell‐cycle progression 31 . As well as, the inhibition of DNMT1 leads to the activation of p16, RUNX3, SFRP1, and E‐cadherin 29,32–34 .…”

Section: Discussionmentioning

confidence: 99%

DNA methyltransferase expression is associated with cell proliferation in salivary mucoepidermoid carcinoma

Guimarães

Almeida

Castilho

et al. 2020

J Oral Pathology Medicine

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Objectives The present study investigated the correlation between the expression of DNA methyltransferase (DNMT)1, DNMT3A, and DNMT3B and the proliferation of mucoepidermoid carcinomas (MECs) using the molecular markers Ki‐67 and cyclin D1. This study also demonstrates the effects of 5‐aza‐2‐deoxycytidine (5AC) on the MEC tumor cell lines in relation to DNMT1 and DNMT3A expression, and cell‐cycle arrest. Materials and Methods The immunohistochemistry of DNMT1, DNMT3A, DNMT3B, Ki‐67, and cyclin D1 was analyzed in 40 samples of MEC and 15 samples of healthy minor salivary glands. The effects of 5AC on DNMT1 and DNMT3B expression in MEC cell lines were analyzed by Western blot, and the effects of 5AC on the cell cycle were analyzed using flow cytometry. Results The expression of DNMT1 and DNMT3B was more intense in MECs than in healthy salivary glands. A strong correlation was found between the expression of the DNMTs and the proliferation markers. This correlation was validated In Vitro, where treatment with 5AC reduced the expression of the DNMTs and the percentage of cells at the G2/M phase of the cell cycle. Conclusion The expression of DNMT1, DNMT3A, DNMT3B is correlated significantly with the expression of Ki‐67 and cyclin D1. The treatment with 5AC reduces DNMT expression and decreases the percentage of cells at the G2/M phase of the cell cycle, while increasing the cells at the G0/G1 phase.

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“…25 A more recent study reported that the X chromosome protects against BCa via upregulation of the canonical P53 pathway. 26 We and others found that p53 mutation has a significant impact on BCa outcome, [27][28][29] suggesting that both STAG2 and P53 mutations are associated with BCa recurrence and progression. Previous studies on the relationship between STAG2…”

Section: Introductionmentioning

confidence: 93%

STAG2 Coupled With p53 Alteration Has a Significant Impact on Bladder Cancer Recurrence and Progression

Chen

Xu²,

Meng

et al. 2019

Preprint

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Background:There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. Stromal antigen 2 (STAG2) and p53 are the most common mutations in bladder cancer and their association with the prognosis of bladder cancer remains unclear.Methods:Patients were divided into two cohorts according to stage and surgical procedure. The value of combined STAG2 expression (+/-) and P53 mutation (+/-) was evaluated for prediction of recurrence in 334 patients diagnosed by transurethral resection of bladder tumor (TURBT) and for prediction of survival in 144 patients who underwent radical cystectomy and pelvic lymphadenectomy( RCPLT).Results:We found that,in the 334 TURBT-treated patients, recurrence rate was significantly greater for STAG2(+) tumors than STAG2(-) tumors (73.5% vs. 55.0%, P=0.001). Of 144 RCPLT-treated patients, 127 (88.2%) were STAG2(+), of which 71 (55.9%) survived 5 years, compared to none of the 17 STAG2(-) patients. Patients with combined STAG2(+)/P53 mutation(+) tumors had the highest recurrence rate (83.5%) while patients with STAG2(-)/P53(-) tumors had the lowest recurrence rate (50%). Patients with STAG2(+)/P53(-) tumors achieved the highest 5-year survival rate (69.7%). Systemic chemotherapy did not improve prognosis of RCPLT-treated patients, but appeared to benefit STAG2(-) patients.Conclusions: Our results suggest that combined STAG2 expression and P53 status is a valuable biomarker for BCa prognosis, accurately predicting recurrence in TURBT-treated patients. STAG2(+)/P53(-) predicted a higher five-year survival and STAG2(-) predicted low five-year survival in RCPLT-treated patients. Chemotherapy may interfere with this predictive efficacy, especially in STAG2(-) patients.

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Alterations of p53 and Rb Pathways Are Associated with High Proliferation in Bladder Urothelial Carcinomas

Abstract: The results showed that a) alterations of the p53 and Rb pathways are associated with high proliferation of tumor cells in BUC and b) high expression of cell-cycle proteins is associated with adverse histopathological parameters of these tumors.

Cited by 13 publications

References 20 publications

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

DNA methyltransferase expression is associated with cell proliferation in salivary mucoepidermoid carcinoma

STAG2 Coupled With p53 Alteration Has a Significant Impact on Bladder Cancer Recurrence and Progression

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