scholarly journals The Interplay between Oxidative Phosphorylation and Glycolysis as a Potential Marker of Bladder Cancer Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8107 ◽  
Author(s):  
Greta Petrella ◽  
Giorgia Ciufolini ◽  
Riccardo Vago ◽  
Daniel Oscar Cicero
Keyword(s):  
Bladder Cancer ◽  
Oxidative Phosphorylation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Genomics ◽  
Low Grade ◽  
Metabolic State ◽  
Extracellular Medium ◽  
Potential Marker ◽  
Risk Of Progression

Urothelial bladder cancer (UBC) is the most common tumor of the urinary system. One of the biggest problems related to this disease is the lack of markers that can anticipate the progression of the cancer. Genomics and transcriptomics have greatly improved the prediction of risk of recurrence and progression. Further progress can be expected including information from other omics sciences such as metabolomics. In this study, we used 1H-NMR to characterize the intake of nutrients and the excretion of products in the extracellular medium of three UBC cell lines, which are representatives of low-grade tumors, RT4, high-grade, 5637, and a cell line that shares genotypic features with both, RT112. We have observed that RT4 cells show an activated oxidative phosphorylation, 5637 cells depend mostly on glycolysis to grow, while RT112 cells show a mixed metabolic state. Our results reveal the relative importance of glycolysis and oxidative phosphorylation in the growth and maintenance of different UBC cell lines, and the relationship with their genomic signatures. They suggest that cell lines associated with a low risk of progression present an activated oxidative metabolic state, while those associated with a high risk present a non-oxidative state and high glycolytic activity.

scholarly journals The Interplay Between Oxidative Phosphorylation and Glycolysis as a Potential Marker of Bladder Cancer Progression in Vitro and in Vivo

2020 ◽  
Author(s):  
Greta Petrella ◽  
Giorgia Ciufolini ◽  
Giusy Burgio ◽  
Andrea Salonia ◽  
Francesco Montorsi ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Oxidative Phosphorylation ◽  
Cell Lines ◽  
Low Grade ◽  
High Grade ◽  
Risk Of Progression ◽  
Muscle Invasive

Abstract BackgroundUrothelial bladder cancer (UBC) is the most common tumor of the urinary system, the ninth most common cancer worldwide and the one with the most expensive treatment from diagnosis to death. One of the biggest problems related to this disease is the lack of sufficiently accurate markers that can anticipate the progression of the cancer from a low-grade non-muscle invasive to a high-grade muscle invasive UBC. Genomics and transcriptomics have recently added a number of molecular markers to traditional observations based on pathological parameters, which have greatly improved the prediction of risk of recurrence and progression. The inclusion of information from other omics sciences, such as metabolomics, could significantly improve this scenario.MethodsIn this study, we present the metabolic characterization using 1H-NMR of three UBC cell lines representing tumors with low-risk of progression, RT4, high-risk, 5637, and a cell line that shares characteristics with both, RT112. The metabolic profiles were classified by multivariate analysis. To validate the in vitro results, concentrations of two metabolites were measured in vivo in the urine of 91 patients with non-invasive and invasive tumors.ResultsRT4 cells mainly use oxidative phosphorylation to produce ATP and biomass, 5637 cells depend mainly on glycolysis, while RT112 cells show a mixed state with both metabolisms partially activated. The lactate/alanine ratio proved to be the most sensitive marker to the different type of metabolism active in the cells in vitro. By measuring its value in vivo in urine, we have found a two-fold increase among patients with high-grade tumors compared to low-grade ones.ConclusionsOur results reveal for the first time the relative importance of glycolysis and oxidative phosphorylation in the growth and maintenance of different UBC cell lines, and the relationship with their genomic signatures. They suggest that oxidative and non-oxidative metabolic states are primarily related to cell lines with low and high risk of progression, respectively. From this observation and our preliminary in vivo results, it appears that the lactate/alanine ratio in patients' urine is a good candidate to become a new marker to predict the conversion of low-grade tumors into more malignant forms.

scholarly journals Exosome-Derived LINC00960 and LINC02470 Promote the Epithelial-Mesenchymal Transition and Aggressiveness of Bladder Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1419
Author(s):  
Cheng-Shuo Huang ◽  
Jar-Yi Ho ◽  
Jung-Hwa Chiang ◽  
Cheng-Ping Yu ◽  
Dah-Shyong Yu
Keyword(s):  
Bladder Cancer ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition ◽  
Bladder Cancer Cells

Exosomes are essential for several tumor progression-related processes, including the epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer have rarely been addressed. In this study, we identified two potential aggressiveness-promoting exosomal lncRNAs, LINC00960 and LINC02470. Exosomes derived from high-grade bladder cancer cells enhanced the viability, migration, invasion and clonogenicity of recipient low-grade bladder cancer cells and activated major EMT-upstream signaling pathways, including β-catenin signaling, Notch signaling, and Smad2/3 signaling pathways. Nevertheless, LINC00960 and LINC02470 were expressed at significantly higher levels in T24 and J82 cells and their secreted exosomes than in TSGH-8301 cells. Moreover, exosomes derived from LINC00960 knockdown or LINC02470 knockdown T24 cells significantly attenuated the ability of exosomes to promote cell aggressiveness and activate EMT-related signaling pathways in recipient TSGH-8301 cells. Our findings indicate that exosome-derived LINC00960 and LINC02470 from high-grade bladder cancer cells promote the malignant behaviors of recipient low-grade bladder cancer cells and induce EMT by upregulating β-catenin signaling, Notch signaling, and Smad2/3 signaling. Both lncRNAs may serve as potential liquid biomarkers for the prognostic surveillance of bladder cancer progression.

scholarly journals TSPAN7 Exerts Anti-Tumor Effects in Bladder Cancer Through the PTEN/PI3K/AKT Pathway

2021 ◽  
Vol 10 ◽  
Author(s):  
Xi Yu ◽  
Shenglan Li ◽  
Mingrui Pang ◽  
Yang Du ◽  
Tao Xu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Tumor Grade ◽  
Biological Properties ◽  
Akt Pathway ◽  
Dynamic Regulation ◽  
Potential Marker

The tetraspanin protein superfamily participate in the dynamic regulation of cellular membrane compartments expressed in a variety of tumor types, which may alter the biological properties of cancer cells such as cell development, activation, growth and motility. The role of tetraspanin 7 (TSPAN7) has never been investigated in bladder cancer (BCa). In this study, we aimed to investigate the biological function of TSPAN7 and its therapeutic potential in human BCa. First, via reverse transcription and quantitative real-time PCR (qRT-PCR), we observed downregulation of TSPAN7 in BCa tissues samples and cell lines and found that this downregulation was associated with a relatively high tumor stage and tumor grade. Low expression of TSPAN7 was significantly correlated with a much poorer prognosis for BCa patients than was high expression. Immunohistochemistry (IHC) showed that low TSPAN7 expression was a high-risk predictor of BCa patient overall survival. Furthermore, the inhibitory effects of TSPAN7 on the proliferation and migration of BCa cell lines were detected by CCK-8, wound-healing, colony formation and transwell assays in vitro. Flow cytometry analysis revealed that TSPAN7 induced BCa cell lines apoptosis and cell cycle arrest. In vivo, tumor growth in nude mice bearing tumor xenografts could be obviously affected by overexpression of TSPAN7. Western blotting showed that overexpression of TSPAN7 activated Bax, cleaved caspase-3 and PTEN but inactivated Bcl-2, p-PI3K, and p-AKT to inhibit BCa cell growth via the PTEN/PI3K/AKT pathway. Taken together, our study will help identify a potential marker for BCa diagnosis and supply a target molecule for BCa treatment.

scholarly journals Targeting Long Non-Coding RNA TTN-AS1 Suppresses Bladder Cancer Progression

2021 ◽  
Vol 12 ◽  
Author(s):  
Huiyuan Xiao ◽  
Wen Huang ◽  
Yanlei Li ◽  
Rongxin Zhang ◽  
Long Yang
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Disease Free Survival ◽  
Tumor Formation ◽  
Clinical Effects ◽  
Data Set ◽  
Downstream Target ◽  
Kaplan Meier ◽  
Activating Transcription Factor

Background: To explore the biological and clinical effects of titin-antisense RNA1 (TTN-AS1) in bladder cancer (BC) and the association between TTN-AS1 and activating transcription factor 2 (ATF2) in BC.Methods: The Kaplan–Meier method was performed to analyze the association between the expression of TTN-AS1 and prognosis of BC patients from TCGA data set and our institution. Quantitative real-time PCR (RT-PCR) was conducted to explore the expression of TTN-AS1 between the patients who underwent TURBT and Re-TURBT. MTT, colony formation, and tumor formation assays were conducted to evaluate the effect of TTN-AS1 on the ability of proliferation in BC cell lines. Transwell assay was performed to evaluate the effect of TTN-AS1 on the ability of invasion in BC cell lines. Bioinfomatics and immunohistochemical staining was used to identify the relationship between TTN-AS1 and ATF2.Results: The higher expression of TTN-AS1 was related to poorer disease-free survival (DFS) in patients with BC. The expression of TTN-AS1 was higher in BC patients who underwent Re-TURBT compared with BC patients who underwent TURBT. Knocking down TTN-AS1 resulted in inhibiting the ability of proliferation and invasion of BC cells. ATF2 may serve as a downstream target of TTN-AS1 in BC, and the high expression of ATF2 is also related to adverse DFS.Conclusion: Our study reveals that TTN-AS1 serves as an oncogene by activating ATF2 in BC. The findings suggest that TTN-AS1 may act as a novel therapeutic target for patients with BC.

scholarly journals miR-616-5p Promotes Invasion and Migration of Bladder Cancer via Downregulating NR2C2 Expression

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenbiao Ren ◽  
Jiao Hu ◽  
Huihuang Li ◽  
Jinbo Chen ◽  
Jian Ding ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Rna Molecules ◽  
Invasion And Migration ◽  
Downstream Target ◽  
Normal Bladder ◽  
Uroepithelial Cell ◽  
And Migration

BackgroundMicroRNAs, small non-coding RNA molecules with about 22 nucleotides in length, play a significant role in the development of bladder cancer. Previous studies found that miR-616-5p could promote the progress of cancers. However, its role in bladder cancer remains unclear. In the study, we aimed to demonstrate how miR-616-5p impacts the invasion and migration of bladder cancer and its potential downstream targets.MethodsFirstly, qRT-PCR was used to detect the expression of miR-616-5p in normal bladder uroepithelial cell lines and bladder cancer cell lines. Then, chamber–transwell invasion and wound healing migration assays were used to detect the roles of miR-616-5p and NR2C2 in invasion and migration. Subsequently, Western blot was used to evaluate the regulation effects of miR-616-5p and NR2C2. Finally, luciferase assays were performed to manifest the mechanism of miR-616-5p and NR2C2 regulation.ResultsWe found that miR-616-5p was upregulated in bladder cancer, and it could promote the invasion and migration of bladder cancer in vitro. Moreover, we demonstrated that NR2C2 was a downstream target of miR-616-5p. miR-616-5p could inhibit the expression of NR2C2 by binding to the 3′UTR of NR2C2 mRNA. Importantly, patients with a high expression of NR2C2 showed better prognoses in bladder cancer.ConclusionsThis study identifies that miR-616-5p can promote bladder cancer progression via altering the expression of NR2C2. Therefore, identifying miR-616-5p expression levels might be a useful strategy for developing potential therapeutic targets in bladder cancer.

scholarly journals mTORC1 deregulation and increased invasiveness cohere with dispersed endolysosomes in high-grade bladder cancer

2020 ◽  
Author(s):  
Pallavi Mathur ◽  
Camilla De Barros Santos ◽  
Hugo Lachuer ◽  
Bruno Latgé ◽  
François Radvanyi ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Culture Conditions ◽  
Low Grade ◽  
High Grade ◽  
Ph Homeostasis ◽  
Cancer Disease ◽  
Mtorc1 Signaling

AbstractLate endosomes/lysosomes (endolysosomes) emerge as a potential regulatory hub during cancer. Here, we investigate the intracellular landscape of this organelle in a collection of bladder cancer cell lines and normal human urothelium cells under standardized culture conditions. We find that high-grade bladder cancer cells are characterized by scattered endolysosomes that are accompanied by an altered cellular pH homeostasis and major changes of mTORC1 regulation. Mechanistically, we reveal that mTORC1 substrate specificity is altered, and mTORC1 responsiveness to endolysosome positioning is lost in high-grade cancer cells compared to low-grade cells, highlighting unexpected mechanisms of mTORC1 deregulation in the bladder cancer model. Because endolysosome positioning was critical for invasion from 3D spheroids, our results indicate that changes in their cellular positioning and ability to support signaling, strongly impact cancer cell behavior. Thus, monitoring detailed changes of endolysosomes at different steps of cancer disease reveals intricate spatial and temporal dimensions of tumorigenesis.Statement of significanceOur study reveals significant changes of endolysosomes in bladder cancer progression, highlighting endolysosome dysfunction as a fundamental driving progress in malignancies. The identified alterations in endolysosome positioning and associated mTORC1 signaling regulation could help to stratify emerging therapeutic strategies targeting the endolysosomal compartment.

scholarly journals RalGPS2 Interacts with Akt and PDK1 Promoting Tunneling Nanotubes Formation in Bladder Cancer and Kidney Cells Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6330
Author(s):  
Alessia D’Aloia ◽  
Edoardo Arrigoni ◽  
Barbara Costa ◽  
Giovanna Berruti ◽  
Enzo Martegani ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Cell Lines ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Time Lapse ◽  
Nucleotide Exchange ◽  
Class Iii ◽  
Tunneling Nanotubes

RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor for RalA GTPase that is involved in several cellular processes, including cytoskeletal organization. Previously, we demonstrated that RalGPS2 also plays a role in the formation of tunneling nanotubes (TNTs) in bladder cancer 5637 cells. In particular, TNTs are a novel mechanism of cell–cell communication in the tumor microenvironment, playing a central role in cancer progression and metastasis formation. However, the molecular mechanisms involved in TNTs formation still need to be fully elucidated. Here we demonstrate that mid and high-stage bladder cancer cell lines have functional TNTs, which can transfer mitochondria. Moreover, using confocal fluorescence time-lapse microscopy, we show in 5637 cells that TNTs mediate the trafficking of RalA protein and transmembrane MHC class III protein leukocyte-specific transcript 1 (LST1). Furthermore, we show that RalGPS2 is essential for nanotubes generation, and stress conditions boost its expression both in 5637 and HEK293 cell lines. Finally, we prove that RalGPS2 interacts with Akt and PDK1, in addition to LST1 and RalA, leading to the formation of a complex that promotes nanotubes formation. In conclusion, our findings suggest that in the tumor microenvironment, RalGPS2 orchestrates the assembly of multimolecular complexes that drive the formation of TNTs.

Using grade of tumor recurrence after BCG to guide further therapy.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 523-523
Author(s):  
Roger Li ◽  
Michael J. Metcalfe ◽  
William Tabayoyong ◽  
Charles Guo ◽  
Graciela M. Nogueras-Gonzalez ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Tumor Recurrence ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Low Grade ◽  
Initial Recurrence ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Bladder Sparing

523 Background: Tumors that recur after BCG therapy are considered to be high risk and patients are often recommended to undergo radical cystectomy (RC). However, the nuances associated with the grade of tumor recurrence after BCG treatment are not well understood. We aimed to characterize the pattern of bladder cancer progression and cancer specific survival (CSS) in patients with recurrences dichotomized by low grade versus high grade after intravesical BCG treatment. Furthermore, to assess the safety of continued bladder sparing therapy in these patients. Methods: We performed an IRB approved review of our bladder cancer database. Overall, 146 NMIBC patients were found to have tumor recurrence after induction BCG with/without maintenance therapy, 38 with LG and 108 with HG tumors. Baseline clinicopathologic characteristics including age, gender, primary tumor grade, stage, size, multiplicity and concurrent CIS were collected and compared between the two groups. The primary endpoint was PFS, with progression defined as the development of MIBC/distant metastasis. In addition, RFS, HG RFS, CFS, and CSS were also compared. Multivariable analysis was performed using the Cox regression model. All tests were two-sided and p < 0.05 was considered statistically significant. Results: As dichotomized by grade of recurrent tumor, estimated 5-year PFS was 85.6% (95% CI 60.8 - 95.2%) for those with LG recurrence and 67.9% (95% CI 54.1 – 78.4%) for those with HG recurrence. On KM analysis, patients whose initial LG recurrence on BCG therapy had improved subsequent RFS (5.2 vs. 2.8 yrs, p = 0.007), HG RFS (9.4 vs. 3.0 yrs, p < 0.001), CFS (p < 0.001), and compared to those who had a HG initial recurrence; CSS benefit approached significance (3.7 vs. 2 yrs, p = 0.12). Grade of tumor recurrence after BCG was an independent predictor of PFS (HR 3.7, 95% CI 1.3-10.9, p = 0.016). Conclusions: Grade of tumor recurrence after intravesical BCG is an important predictor of bladder cancer progression to MIBC/MUC. However, patients who have low grade recurrences on BCG still may progress and hence should be carefully counselled on bladder sparing therapy.

scholarly journals Urinary Biomarkers in Bladder Cancer: Where Do We Stand and Potential Role of Extracellular Vesicles

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1400 ◽  
Author(s):  
Manuel Castanheira de Oliveira ◽  
Hugo R. Caires ◽  
Maria J. Oliveira ◽  
Avelino Fraga ◽  
M. Helena Vasconcelos ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Escape ◽  
Membrane Vesicles ◽  
Diagnostic Procedures ◽  
Cell Types ◽  
Therapy Resistance ◽  
Great Promise ◽  
Low Grade

Extracellular vesicles (EVs) are small membrane vesicles released by all cells and involved in intercellular communication. Importantly, EVs cargo includes nucleic acids, lipids, and proteins constantly transferred between different cell types, contributing to autocrine and paracrine signaling. In recent years, they have been shown to play vital roles, not only in normal biological functions, but also in pathological conditions, such as cancer. In the multistep process of cancer progression, EVs act at different levels, from stimulation of neoplastic transformation, proliferation, promotion of angiogenesis, migration, invasion, and formation of metastatic niches in distant organs, to immune escape and therapy resistance. Moreover, as products of their parental cells, reflecting their genetic signatures and phenotypes, EVs hold great promise as diagnostic and prognostic biomarkers. Importantly, their potential to overcome the current limitations or the present diagnostic procedures has created interest in bladder cancer (BCa). Indeed, cystoscopy is an invasive and costly technique, whereas cytology has poor sensitivity for early staged and low-grade disease. Several urine-based biomarkers for BCa were found to overcome these limitations. Here, we review their potential advantages and downfalls. In addition, recent literature on the potential of EVs to improve BCa management was reviewed and discussed.

scholarly journals Photobiomodulation With Blue Laser Inhibits Bladder Cancer Progression

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuqi Xia ◽  
Weimin Yu ◽  
Fan Cheng ◽  
Ting Rao ◽  
Yuan Ruan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bladder Cancer ◽  
Cell Viability ◽  
Laser Irradiation ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Blue Laser ◽  
Migration And Invasion ◽  
Dependent Manner

Blue lasers are becoming more widely used in the diagnosis and treatment of bladder cancer; however, their photobiomodulation effects on bladder cancer cells remains unclear. The purpose of the current study was to explore the photobiomodulation effect of blue laser irradiation on bladder cancer progression and the associated mechanisms. The human uroepithelial cell line SV-HUC-1 and human bladder cancer cell lines T24 and EJ were exposed to blue laser irradiation (450 nm) at various energy densities, and cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and the levels of the proteins associated with the MAPK pathway proteins were determined. A significant decrease in cell viability was observed in a density-dependent manner after blue laser irradiation at &gt; 4 J/cm2 in both bladder cancer cell lines. However, the blue laser did not reduce cell viability in SV-HUC-1 cells until the energy density exceeded 16 J/cm2. Meanwhile, Ki67 levels, reflecting cell proliferation and senescence, were also significantly decreased after blue laser irradiation at 4 J/cm2 and 8 J/cm2 in the absence of cell cycle arrest. Moreover, blue laser irradiation at 4 J/cm2 and 8 J/cm2 caused a reduction in cell migration and invasion and also reduced the expression levels of MMP-2, MMP-9, Snail, N-cadherin, phospho-MEK and phospho-ERK, and elevated the expression levels of E-cadherin. Meanwhile ERK activator(tBHQ) significantly reversed the irradiation-induced suppression of proliferation, migration and invasion in T24 and EJ cell lines. The present study showed that blue laser irradiation inhibited bladder cancer proliferation in a density-dependent manner and inhibited bladder cancer progression by suppressing migration, invasion, and the EMT process in T24 and EJ cell lines. This inhibition was possibly mediated via suppression of the MAPK/MEK/ERK pathway. Thus, the use of a low-energy blue laser in the diagnosis and treatment of bladder cancer is possibly safe and may have an anti-tumor effect.

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