scholarly journals MicroRNA-138 Regulates Metastatic Potential of Bladder Cancer Through ZEB2

2015 ◽  
Vol 37 (6) ◽  
pp. 2366-2374 ◽  
Author(s):  
De-Kang Sun ◽  
Jian-Ming Wang ◽  
Peng Zhang ◽  
Yong-Qiang Wang
Keyword(s):  
Bladder Cancer ◽  
Cell Invasion ◽  
Biological Effects ◽  
Metastatic Potential ◽  
Luciferase Reporter ◽  
Bladder Tissue ◽  
Bioinformatics Analyses ◽  
Normal Bladder ◽  
Key Factor ◽  
Normal Bladder Tissue

Background/Aims: The cases of bladder cancer (BC) with poor prognosis largely result from the distal metastases of the primary tumor. Since microRNAs (miRNAs) play critical roles during cancer metastases, determination of the involved miRNAs in the regulation of the metastases of BC may provide novel therapeutic targets for BC treatment. Here, we aimed to study the role of miR-138 in regulation of BC cell invasion and metastases. Methods: We analyzed the levels of miR-138 and ZEB2, a key factor that regulates cancer cell invasion, in the BC specimens from the patients. We also studied the correlation between miR-138 and ZEB2. We performed bioinformatics analyses on the binding of miR-138 to the 3'-UTR of ZEB2 mRNA, and verified the biological effects of this binding through promoter luciferase reporter assay. The effects of miR-138-modification on BC cell invasion were evaluated in a transwell cell invasion assay and a scratch would healing assay. Results: We found that the levels of miR-138 were significantly decreased and the levels of ZEB2 were significantly increased in BC specimens, compared to the paired normal bladder tissue. Metastatic BC appeared to contained lower levels of miR-138. Moreover, miR-138 and ZEB2 inversely correlated in BC specimens. Bioinformatics analyses showed that miR-138 targeted the 3'-UTR of ZEB2 mRNA to inhibit its translation. Furthermore, miR-138 overexpression inhibited ZEB2-mediated cell invasion and metastases, while miR-138 depletion increased ZEB2-mediated cell invasion and metastases in BC cells. Conclusion: Suppression of miR-138 in BC cells may promote ZEB2-mediated cancer invasion and metastases. Thus, miR-138 appears to be an intriguing therapeutic target to prevent metastases of BC.

Expression of MET and HGF in bladder cancer tumorigenesis and invasion.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4573-4573
Author(s):  
Randy F. Sweis ◽  
Petros Grivas ◽  
Alexander T. Pearson ◽  
Kathleen C. Day ◽  
Mark L. Day ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Logistic Regression ◽  
Normal Tissue ◽  
Tyrosine Kinase Receptor ◽  
Human Bladder ◽  
Microarray Probe ◽  
Bladder Tissue ◽  
Normal Bladder ◽  
Cancer Transcriptome ◽  
Normal Bladder Tissue

4573 Background: The human MET gene encodes the hepatocyte growth factor (HGF) tyrosine kinase receptor. Limited studies in human bladder cancer have demonstrated that expression of MET protein is linked with disease progression and survival. We hypothesized that the expression of both MET and its ligand HGF are altered in bladder cancer. Methods: Expression of MET and HGF in human bladder tissues was explored using Oncomine, an online compendium of cancer transcriptome profiles. The largest relevant dataset was identified and contained 157 samples (Sanchez-Carbayo, et al. 2006). Normalized and log2 transformed mRNA expression values for Affymetrix U133 microarray probe sets corresponding to the genes of interest were compiled and averaged for each gene. Mann-Whitney U testing was used to compare means. Nominal and standard least squares logistic regression was used to evaluate the predictive significance of, and relevance of clinicopathologic variables on, gene expression. Statistical analyses were carried out using JMP 9.0.2. Results: Expression of MET and HGF was compared across subsets of normal bladder tissue (n=48), superficial tumors (n=28), and invasive tumors (n = 81). Relative to normal tissue, MET expression was greater in superficial (p = 0.0008) and invasive tumors (p<0.0001). HGF expression was reduced in both invasive and superficial tumors vs. normal tissue (both p< 0.0001), but was higher in invasive vs. superficial tumors (p= 0.0007). In a logistic regression model of tumor samples, both MET and HGF correlated with tumor invasion (model p=0.0003). Interaction between MET and HGF was not significant (p=0.55). Neither MET nor HGF expression was predicted by regression using age, gender, grade, or nodal stage (p=0.16 and 0.27, respectively). Conclusions: Decreased HGF expression and MET over-expression are strongly associated with tumorigenesis and invasion in bladder cancer. The reduction in HGF expression is blunted in invasive vs. superficial tumors, suggesting a potential loss of negative feedback in more aggressive tumors. Expression of both genes could not be predicted by modeling clinicopathologic variables. MET signaling represents a potential therapeutic target in bladder cancer.

scholarly journals Expression of Semaphorin 3A in Malignant and Normal Bladder Tissue: Immunohistochemistry Staining and Morphometric Evaluation

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 109
Author(s):  
Ilan Bejar ◽  
Jacob Rubinstein ◽  
Jacob Bejar ◽  
Edmond Sabo ◽  
Hilla K Sheffer ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Carcinoma In Situ ◽  
Urothelial Cancer ◽  
Basal Layer ◽  
Low Grade ◽  
High Grade ◽  
Bladder Tissue ◽  
Normal Bladder ◽  
Normal Bladder Tissue

Introduction: Our previous studies showed elevated levels of Semaphorin3a (Sema3A) in the urine of patients with urothelial cancer compared to healthy patients. The aim of this study was to analyze the extent of Sema3A expression in normal and malignant urothelial tissue using immune-staining microscopic and morphometric analysis. Materials and Methods: Fifty-seven paraffin-embedded bladder samples were retrieved from our pathology archive and analyzed: 14 samples of normal urothelium, 21 samples containing low-grade urothelial carcinoma, 13 samples of patients with high-grade urothelial carcinoma, 7 samples containing muscle invasive urothelial carcinoma, and 2 samples with pure urothelial carcinoma in situ. All samples were immunostained with anti Sema3A antibodies. The area of tissue stained with Sema3A and its intensity were analyzed using computerized morphometry and compared between the samples’ groups. Results: In normal bladder tissue, very light Sema3A staining was demonstrated on the mucosal basal layer and completely disappeared on the apical layer. In low-grade tumor samples, cells in the basal layer of the mucosa were also lightly stained with Sema3A, but Seama3A expression intensified upon moving apically, reaching its highest level on apical cells exfoliating to the urine. In high grade urothelial tumors, Seama3A staining was intense in the entire thickness of the mucosa. In samples containing carcinoma in situ, staining intensity was high and homogenous in all the neoplastic cells. Conclusions: Sema3A may be serve as a potential non-invasive marker of urothelial cancer.

SATB1 and Her2 as predictive molecular and immunohistochemical markers for urothelial cell carcinoma of the bladder

2020 ◽  
pp. 1-11
Author(s):  
Samia Hussein ◽  
Anan Fathi ◽  
Nehal S. Abouhashem ◽  
Samar Amer ◽  
Mohamed Hemida ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Prognostic Significance ◽  
Immunohistochemical Analysis ◽  
Lymph Node Involvement ◽  
Genetic Alterations ◽  
Response To Therapy ◽  
Clinicopathological Parameters ◽  
Bladder Tissue ◽  
Normal Bladder ◽  
Erbb2 Mrna

Studying bladder cancer molecular biology revealed the presence of genetic alterations. So, detection of molecular biomarkers that help in monitoring the disease, evaluating the prognosis of the patients, and their response to therapy is needed. In this study, we investigated the expression and the prognostic significance of SATB-1 and ERBB2 mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in urothelial bladder cancer cases and the surrounding normal bladder tissue. The correlations between the expression of both markers and the clinicopathological parameters were performed with further analysis of the correlation between the expression of SATB-1 and ERBB2. Compared to control, the expression of SATB-1 and ERBB2 mRNA and protein in cancer tissues were significantly up-regulated (p< 0.05). Also, a positive correlation between both markers was found (r= 0.53, p< 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement at both mRNA and protein levels (p< 0.001). In conclusion, there is a clinical significance of SATB-1 and ERBB2 as potential biomarkers for predicting bladder cancer patients of aggressive behavior and poor prognosis.

A phase 3 randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± BMS-986205 in cisplatin-eligible muscle invasive bladder cancer (MIBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4587-TPS4587
Author(s):  
Guru Sonpavde ◽  
Andrea Necchi ◽  
Shilpa Gupta ◽  
Gary D. Steinberg ◽  
Juergen E. Gschwend ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Clinical Stage ◽  
Randomized Study ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Positive Lymph Node ◽  
Clinical Activity ◽  
Phase 3 ◽  
Bladder Tissue ◽  
Normal Bladder

TPS4587 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible MIBC, the recommended tx regimen is cisplatin-based NAC prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, suggesting that the PD-1/PD-L1 axis is a valid therapeutic target. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. BMS-986205, a selective, potent, once-daily oral IDO1 inhibitor that works early in the IDO1 pathway to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + BMS-986205 in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± BMS-986205 followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + BMS-986205 (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320.

A phase III randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± linrodostat mesylate, followed by adjuvant postsurgical NIVO ± linrodostat, in cisplatin-eligible muscle invasive bladder cancer (MIBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5091-TPS5091
Author(s):  
Guru Sonpavde ◽  
Andrea Necchi ◽  
Shilpa Gupta ◽  
Gary D. Steinberg ◽  
Juergen Gschwend ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Clinical Stage ◽  
Randomized Study ◽  
Pathologic Complete Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Bladder Tissue ◽  
Normal Bladder ◽  
Muscle Invasive

TPS5091 Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible, muscle invasive BC (MIBC), the recommended tx is cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, supporting the therapeutic pursuit of the PD-1/PD-L1 axis. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. Linrodostat mesylate, a selective, potent, once-daily oral IDO1 inhibitor that works to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + linrodostat in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± linrodostat followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + linrodostat (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320 .

The LncRNA MIR155HG is Upregulated by SP1 in Melanoma Cells and Drives Melanoma Progression via Modulating the MiR-485-3p/PSIP1 Axis

2021 ◽  
Vol 21 ◽  
Author(s):  
Jia Huo ◽  
Yuan Wang ◽  
Yanfei Zhang ◽  
Wei Wang ◽  
Peiwen Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Melanoma Cell ◽  
Biological Effects ◽  
Melanoma Cells ◽  
Luciferase Reporter ◽  
Bioinformatics Analyses ◽  
Melanoma Progression ◽  
Non Coding Rna ◽  
Patient Prognosis ◽  
Tumor Types

Background: MIR155HG is a long non-coding RNA (lncRNA) that has been shown to be dysregulated in a range of tumor types, but the functions of this lncRNA in melanoma remain to be explored. Objectives: We explored the functions of lncRNA MIR155HG in melanoma progression. Methods: The expression of miR155HG was analyzed in clinical melanoma. Bioinformatics analysis was performed to assess the potential tumor-related functions of miR155HG. The interaction of miR155HG and SP1 and the inhibition of PSIP1 by miR-485-3p were analyzed by ChIP, luciferase reporter experiments, and biological effects in melanoma were explored by colony formation assays, EdU cell proliferation assays, Transwell analysis and intracranial melanoma mouse model. Results: Herein, we found that MIR155HG was markedly upregulated in melanoma cell lines and tissues. We further determined that the SP1 transcription factor was responsible for driving MIR155HG upregulation in melanoma. Elevated MIR155HG levels were linked to decreased overall survival (OS) in melanoma patients, and we further determined that MIR155HG expression was an independent predictor of melanoma patient prognosis. When MIR155HG was knocked down in melanoma cells, this impaired their proliferative, migratory, and invasive activity. Using predictive bioinformatics analyses, we identified miR-485-3p as a microRNA (miRNA) capable of binding to both MIR155HG and the 3’ UTR of PSIP1. Conclusion: Together, these results suggest that MIR155HG is capable of promoting melanoma cell proliferation via the miR-485-3p/PSIP1 axis. These novel findings provide new insights into the development of melanoma, potentially highlighting future avenues for therapeutic intervention.

scholarly journals Silenced lncRNA SNHG14 restrains the biological behaviors of bladder cancer cells via regulating microRNA-211-3p/ESM1 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rui Feng ◽  
Zhongxing Li ◽  
Xing Wang ◽  
Guangcheng Ge ◽  
Yuejun Jia ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Colony Formation ◽  
Biological Characteristics ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Normal Tissues ◽  
Normal Bladder ◽  
Signaling Axis

Abstract Background Bladder cancer (BCa) is a malignant tumor that occurs on the mucosa of the bladder, in which dysregulated long non-coding RNAs (lncRNAs) are involved. This study investigated the effect of lncRNA small nucleolar RNA host gene 1 (SNHG14) on the biological characteristics of BCa cells from microRNA (miR)-211-3p/ESM1 signaling axis. Methods BCa tissues and the matched normal tissues were collected to test SNHG14, miR-211-3p and ESM1 levels. SNHG14, miR-211-3p and ESM1 levels in BCa cell lines (T24, 5637, UMUC-3 and EJ) and normal bladder epithelial cells SV-HVC-1 were detected for screening the cell lines for follow-up experiments. T24 and UMUC-3 cells were transfected with different plasmids of SNHG14, miR-211-3p or ESM1 to observe the biological characteristics of BCa cells by MTT, colony formation, Transwell assays and flow cytometry. Tumor xenograft was implemented to inspect tumor growth in vivo. The targeting relationships of SNHG14, miR-211-3p and ESM1 were verified by bioinformatics software, RNA pull down assay and luciferase reporter assay. Results Enhanced SNHG14, ESM1 and suppressed miR-211-3p were found in BCa tissues and cells. SNHG14 up-regulated ESM1 via competitive binding with miR-211-3p. Decreased SNHG14 or up-regulated miR-211-3p depressed cell cycle entry, colony formation, invasion, migration and proliferation abilities, and facilitated apoptosis of BCa cells. Decreased SNHG14 or up-regulated miR-211-3p reduced the tumor volume and weight of nude mice with BCa, as well as promoted apoptosis and restrained proliferation of tumor cells. miR-211-3p inhibition or ESM1 overexpression reversed the effects of down-regulation of SNHG14 on BCa, and miR-211-3p up-regulation or ESM1 downregulation reversed the effect of SNHG14 overexpression on BCa. SNHG14 targeted miR-211-3p to regulate ESM1 expression. Conclusion Our study highlights that silenced SNHG14 or elevated miR-211-3p represses the tumorigenic ability of BCa cells, which may be linked to ESM1 knockdown.

scholarly journals KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Lei Liu ◽  
Jianfeng Cui ◽  
Yajing Zhao ◽  
Xiaochen Liu ◽  
Lipeng Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Critical Role ◽  
Metastatic Potential ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tissue Specimens ◽  
Invasion Assays

Abstract Background KDM6A, a histone demethylase, is frequently mutated in bladder cancer (BCa). However, the role and detailed molecular mechanism of KDM6A involved in bladder cancer progression remains unknown. Methods Tissue specimens were used to determine the expression levels and prognostic values of KDM6A and ARHGDIB. The MTT, colony formation, wound healing and Transwell migration and invasion assays were employed to detect the BCa cell proliferation, migration and invasion, respectively. Chemotaxis of macrophages was used to evaluate the ability of KDM6A to recruit macrophages. A subcutaneous tumour model and tail vein tumour injection in nude mice were used to assess the role of KDM6A in vivo. RNA sequencing, qPCR, Western blot, ChIP and phalloidin staining assay were performed to investigate the molecular functions of KDM6A. Dual-luciferase reporter assay was used to determine the effects of KDM6A and FOXA1 on the promoters of the ARHGDIB and KDM6A. Results We showed that the KDM6A inhibited the motility and invasiveness of the BCa cells. Mechanistically, KDM6A promotes the transcription of ARHGDIB by demethylating histone H3 lysine di/trimethylation (H3K27me2/3) and consequently leads to inhibition of Rac1. EZH2, which catalyses the methylation of H3K27, functions to silence ARHGDIB expression, and an EZH2 inhibitor can neutralize the metastatic effect caused by KDM6A deficiency. Furthermore, we demonstrated that FOXA1 directly binds to the KDM6A promoter and thus transactivates KDM6A, leading to diminished metastatic potential. Conclusion Our findings establish the critical role of the FOXA1-KDM6A-ARHGDIB axis in restraining the malignancy of BCa and identify KDM6A and EZH2 as potential therapeutic targets in the management of BCa.

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