Editorial

3 pages, 205 KiB

Open AccessEditorial

Molecular Diagnostic and Prognostication Assays for the Subtyping of Urinary Bladder Cancer Are on the Way to Illuminating Our Vision

by Thorsten H. Ecke, Florence Le Calvez-Kelm and Thomas Otto

Int. J. Mol. Sci. 2022, 23(10), 5620; https://doi.org/10.3390/ijms23105620 - 17 May 2022

Viewed by 1337

Abstract

After the successful publication of three Special Issues devoted to highlighting novel scientific research results in the field of bladder cancer and their clinical implications, we are now directing our efforts towards a fourth edition which will aim at compiling innovative research strategies [...] Read more.

After the successful publication of three Special Issues devoted to highlighting novel scientific research results in the field of bladder cancer and their clinical implications, we are now directing our efforts towards a fourth edition which will aim at compiling innovative research strategies that will ultimately guide and support clinicians in the decision-making process for targeted bladder cancer therapies [...] Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

Research

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16 pages, 3588 KiB

Open AccessArticle

Evodiamine Exhibits Anti-Bladder Cancer Activity by Suppression of Glutathione Peroxidase 4 and Induction of Ferroptosis

by Che-Yuan Hu, Hung-Tsung Wu, Yan-Shen Shan, Chung-Teng Wang, Gia-Shing Shieh, Chao-Liang Wu and Horng-Yih Ou

Int. J. Mol. Sci. 2023, 24(7), 6021; https://doi.org/10.3390/ijms24076021 - 23 Mar 2023

Cited by 6 | Viewed by 1877

Abstract

Evodiamine (EVO) exhibits anti-cancer activity through the inhibition of cell proliferation; however, little is known about its underlying mechanism. To determine whether ferroptosis is involved in the therapeutic effects of EVO, we investigated critical factors, such as lipid peroxidation levels and glutathione peroxidase [...] Read more.

Evodiamine (EVO) exhibits anti-cancer activity through the inhibition of cell proliferation; however, little is known about its underlying mechanism. To determine whether ferroptosis is involved in the therapeutic effects of EVO, we investigated critical factors, such as lipid peroxidation levels and glutathione peroxidase 4 (GPX4) expression, under EVO treatment. Our results showed that EVO inhibited the cell proliferation of poorly differentiated, high-grade bladder cancer TCCSUP cells in a dose- and time-dependent manner. Lipid peroxides were detected by fluorescence microscopy after cancer cell exposure to EVO. GPX4, which catalyzes the conversion of lipid peroxides to prevent cells from undergoing ferroptosis, was decreased dose-dependently by EVO treatment. Given the features of iron dependency and lipid-peroxidation-driven death in ferroptosis, the iron chelator deferoxamine (DFO) was used to suppress EVO-induced ferroptosis. The lipid peroxide level significantly decreased when cells were treated with DFO prior to EVO treatment. DFO also attenuated EVO-induced cell death. Co-treatment with a pan-caspase inhibitor or necroptosis inhibitor with EVO did not alleviate cancer cell death. These results indicate that EVO induces ferroptosis rather than apoptosis or necroptosis. Furthermore, EVO suppressed the migratory ability, decreased the expression of mesenchymal markers, and increased epithelial marker expression, determined by a transwell migration assay and Western blotting. The TCCSUP bladder tumor xenograft tumor model confirmed the effects of EVO on the inhibition of tumor growth and EMT. In conclusion, EVO is a novel inducer for activating the ferroptosis of bladder cancer cells and may be a potential therapeutic agent for bladder cancer. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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13 pages, 612 KiB

Open AccessArticle

TERT Promoter Mutations as Simple and Non-Invasive Urinary Biomarkers for the Detection of Urothelial Bladder Cancer in a High-Risk Region

by Hamid Pakmanesh, Omid Anvari, Nathalie Forey, Elisabete Weiderpass, Reza Malekpourafshar, Maryam Iranpour, Armita Shahesmaeili, Nahid Ahmadi, Azam Bazrafshan, Kazem Zendehdel, Caroline Kannengiesser, Ibrahima Ba, James McKay, Maria Zvereva, Md Ismail Hosen, Mahdi Sheikh and Florence Le Calvez-Kelm

Int. J. Mol. Sci. 2022, 23(22), 14319; https://doi.org/10.3390/ijms232214319 - 18 Nov 2022

Cited by 5 | Viewed by 2110

Abstract

Bladder cancer (BC) is the 10th most common cancer in the world. While there are FDA-approved urinary assays to detect BC, none have demonstrated sufficient sensitivity and specificity to be integrated into clinical practice. Telomerase Reverse Transcriptase (TERT) gene mutations have [...] Read more.

Bladder cancer (BC) is the 10th most common cancer in the world. While there are FDA-approved urinary assays to detect BC, none have demonstrated sufficient sensitivity and specificity to be integrated into clinical practice. Telomerase Reverse Transcriptase (TERT) gene mutations have been identified as the most common BC mutations that could potentially be used as non-invasive urinary biomarkers to detect BC. This study aims to evaluate the validity of these tests to detect BC in the Kerman province of Iran, where BC is the most common cancer in men. Urine samples of 31 patients with primary (n = 11) or recurrent (n = 20) bladder tumor and 50 controls were prospectively collected. Total urinary DNA was screened for the TERT promoter mutations (uTERTpm) by Droplet Digital PCR (ddPCR) assays. The performance characteristics of uTERTpm and the influence by disease stage and grade were compared to urine cytology results. The uTERTpm was 100% sensitive and 88% specific to detect primary BC, while it was 50% sensitive and 88% specific in detecting recurrent BC. The overall sensitivity and specificity of uTERTpm to detect bladder cancer were 67.7% and 88.0%, respectively, which were consistent across different tumor stages and grades. The most frequent uTERTpm mutations among BC cases were C228T (18/31), C250T (4/31), and C158A (1/31) with mutant allelic frequency (MAF) ranging from 0.2% to 63.3%. Urine cytology demonstrated a similar sensitivity (67.7%), but lower specificity (62.0%) than uTERTpm in detecting BC. Combined uTERTpm and urine cytology increased the sensitivity to 83.8%, but decreased the specificity to 52.0%. Our study demonstrated promising diagnostic accuracy for the uTERTpm as a non-invasive urinary biomarker to detect, in particular, primary BC in this population. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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15 pages, 3966 KiB

Open AccessArticle

Reduced IQGAP2 Promotes Bladder Cancer through Regulation of MAPK/ERK Pathway and Cytokines

by Fei Song, Roland Kotolloshi, Mieczyslaw Gajda, Martin Hölzer, Marc-Oliver Grimm and Daniel Steinbach

Int. J. Mol. Sci. 2022, 23(21), 13508; https://doi.org/10.3390/ijms232113508 - 04 Nov 2022

Cited by 5 | Viewed by 1409

Abstract

The progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is a major challenge in urologic oncology. However, understanding of the molecular processes remains limited. The dysregulation of IQGAP2 is becoming increasingly evident in most tumor entities, and it plays a [...] Read more.

The progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is a major challenge in urologic oncology. However, understanding of the molecular processes remains limited. The dysregulation of IQGAP2 is becoming increasingly evident in most tumor entities, and it plays a role in multiple oncogenic pathways, so we evaluated the role of IQGAP2 in bladder cancer. IQGAP2 was downregulated in tumors compared with normal urothelium tissues and cells. IQGAP2 effectively attenuated bladder cancer cell growth independently from apoptosis. Reduced IQGAP2 promoted EMT in bladder cancer cells via activation of the MAPK/ERK pathway. In addition, IQGAP2 might influence key cellular processes, such as proliferation and metastasis, through the regulation of cytokines. In conclusion, we suggest that IQGAP2 plays a tumor-suppressing role in bladder cancer, possibly via inhibiting the MAPK/ERK pathway and reducing cytokines. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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21 pages, 3938 KiB

Open AccessArticle

Response of the Urothelial Carcinoma Cell Lines to Cisplatin

by Andrea Holíčková, Jan Roška, Eveline Órásová, Vladimíra Bruderová, Patrik Palacka, Dana Jurkovičová and Miroslav Chovanec

Int. J. Mol. Sci. 2022, 23(20), 12488; https://doi.org/10.3390/ijms232012488 - 18 Oct 2022

Cited by 2 | Viewed by 1637

Abstract

Cisplatin (CDDP)-based chemotherapy is the standard of care in patients with muscle-invasive bladder cancer. However, in a large number of cases, the disease becomes resistant or does not respond to CDDP, and thus progresses and disseminates. In such cases, prognosis of patients is [...] Read more.

Cisplatin (CDDP)-based chemotherapy is the standard of care in patients with muscle-invasive bladder cancer. However, in a large number of cases, the disease becomes resistant or does not respond to CDDP, and thus progresses and disseminates. In such cases, prognosis of patients is very poor. CDDP manifests its cytotoxic effects mainly through DNA damage induction. Hence, response to CDDP is mainly dependent on DNA damage repair and tolerance mechanisms. Herein, we have examined CDDP response in a panel of the urothelial carcinoma cell (UCC) lines. We characterized these cell lines with regard to viability after CDDP treatment, as well as kinetics of induction and repair of CDDP-induced DNA damage. We demonstrate that repair of CDDP-induced DNA lesions correlates, at least to some extent, with CDDP sensitivity. Furthermore, we monitored expression of the key genes involved in selected DNA repair and tolerance mechanisms, nucleotide excision repair, homologous recombination and translesion DNA synthesis, and show that it differs in the UCC lines and positively correlates with CDDP resistance. Our data indicate that CDDP response in the UCC lines is dependent on DNA damage repair and tolerance factors, which may, therefore, represent valuable therapeutic targets in this malignancy. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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14 pages, 2427 KiB

Open AccessArticle

Prediction of Response to Cisplatin-Based Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer Patients by Molecular Subtyping including KRT and FGFR Target Gene Assessment

by Thorsten H. Ecke, Paula Carolin Voß, Thorsten Schlomm, Anja Rabien, Frank Friedersdorff, Dimitri Barski, Thomas Otto, Michael Waldner, Elke Veltrup, Friederike Linden, Roland Hake, Sebastian Eidt, Jenny Roggisch, Axel Heidenreich, Constantin Rieger, Lucas Kastner, Steffen Hallmann, Stefan Koch and Ralph M. Wirtz

Int. J. Mol. Sci. 2022, 23(14), 7898; https://doi.org/10.3390/ijms23147898 - 18 Jul 2022

Cited by 5 | Viewed by 1861

Abstract

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study [...] Read more.

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome—rate of ypT0 status—to justify subsequent prospective validation within the “BladderBRIDGister”. Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal–Wallis, Mann–Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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11 pages, 2068 KiB

Open AccessArticle

Effects of Supplemental Drugs on Hexaminolevulinate (HAL)-Induced PpIX Fluorescence in Bladder Cancer Cell Suspensions

by Kit Man Chan, Krasimir Vasilev and Melanie MacGregor

Int. J. Mol. Sci. 2022, 23(14), 7631; https://doi.org/10.3390/ijms23147631 - 10 Jul 2022

Cited by 2 | Viewed by 1551

Abstract

Seven different inhibitors of the heme metabolic pathway were applied in combination with HAL to study the formation of PpIX in bladder cancer HT1197 and normal fibroblast HFFF2 cells ex vivo, specifically with the aim to increase the fluorescence contrast between cancer and [...] Read more.

Seven different inhibitors of the heme metabolic pathway were applied in combination with HAL to study the formation of PpIX in bladder cancer HT1197 and normal fibroblast HFFF2 cells ex vivo, specifically with the aim to increase the fluorescence contrast between cancer and non-cancer cells. The mRNA expression of enzymes involved in the heme biosynthesis pathway were measured via PCR following incubation with the drugs in order to link the fluorescence levels and metabolic activity. The exogenous administration of HAL does lead to cancer-specific PpIX accumulation. However, the contrast between cancer and normal cells in suspension was not enhanced by the enzyme inhibitors and iron-chelating agents tested, nor did the mRNA expression necessarily correlate with the fluorescence intensity. The results indicate that a difference in the metabolic activity of cells in suspension may limit the applicability of exogenous enzyme inhibitor administration as a mean to improve the fluorescence-based detection of cancer cells shed in body fluids. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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18 pages, 1780 KiB

Open AccessArticle

Computational Analysis Identifies Novel Biomarkers for High-Risk Bladder Cancer Patients

by Radosław Piliszek, Anna A. Brożyna and Witold R. Rudnicki

Int. J. Mol. Sci. 2022, 23(13), 7057; https://doi.org/10.3390/ijms23137057 - 24 Jun 2022

Cited by 2 | Viewed by 1387

Abstract

In the case of bladder cancer, carcinoma in situ (CIS) is known to have poor diagnosis. However, there are not enough studies that examine the biomarkers relevant to CIS development. Omics experiments generate data with tens of thousands of descriptive variables, e.g., gene [...] Read more.

In the case of bladder cancer, carcinoma in situ (CIS) is known to have poor diagnosis. However, there are not enough studies that examine the biomarkers relevant to CIS development. Omics experiments generate data with tens of thousands of descriptive variables, e.g., gene expression levels. Often, many of these descriptive variables are identified as somehow relevant, resulting in hundreds or thousands of relevant variables for building models or for further data analysis. We analyze one such dataset describing patients with bladder cancer, mostly non-muscle-invasive (NMIBC), and propose a novel approach to feature selection. This approach returns high-quality features for prediction and yet allows interpretability as well as a certain level of insight into the analyzed data. As a result, we obtain a small set of seven of the most-useful biomarkers for diagnostics. They can also be used to build tests that avoid the costly and time-consuming existing methods. We summarize the current biological knowledge of the chosen biomarkers and contrast it with our findings. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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22 pages, 3344 KiB

Open AccessArticle

Wnt/β-Catenin Signalling and Its Cofactor BCL9L Have an Oncogenic Effect in Bladder Cancer Cells

by Roland Kotolloshi, Mieczyslaw Gajda, Marc-Oliver Grimm and Daniel Steinbach

Int. J. Mol. Sci. 2022, 23(10), 5319; https://doi.org/10.3390/ijms23105319 - 10 May 2022

Cited by 5 | Viewed by 2263

Abstract

Bladder cancer (BC) is characterised by a high recurrence and progression rate. However, the molecular mechanisms of BC progression remain poorly understood. BCL9L, a coactivator of β-catenin was mutated in the 5′ and 3′ untranslated regions (UTRs). We assessed the influence of UTRs [...] Read more.

Bladder cancer (BC) is characterised by a high recurrence and progression rate. However, the molecular mechanisms of BC progression remain poorly understood. BCL9L, a coactivator of β-catenin was mutated in the 5′ and 3′ untranslated regions (UTRs). We assessed the influence of UTRs mutations on BCL9L, and the role of BCL9L and Wnt/β-catenin signalling in BC cells. UTR mutations were analysed by a luciferase reporter. BCL9L protein was assessed by immunohistochemistry in BC tissues. Cell proliferation was examined by crystal violet staining and by the spheroid model. Moreover, migration and invasion were analysed in real-time using the xCelligence RTCA system. The A > T mutation at 3′ UTR of BCL9L reduces the luciferase reporter mRNA expression and activity. BCL9L is predominantly increased in dysplastic urothelial cells and muscle-invasive BC. Knockdown of BCL9L and inhibition of Wnt/β-catenin signalling significantly repress the proliferation, migration and invasion of Cal29 and T24. In addition, BCL9L knockdown reduces mRNA level of Wnt/β-catenin target genes in Cal29 but not in T24 cells. BCL9L and Wnt/β-catenin signalling play an oncogenic role in bladder cancer cells and seems to be associated with BC progression. Nevertheless, the involvement of BCL9L in Wnt/β-catenin signalling is cell-line specific. Full article

(This article belongs to the Special Issue Molecular Research on Bladder Cancer)

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