scholarly journals MED10 Drives the Oncogenicity and Refractory Phenotype of Bladder Urothelial Carcinoma Through the Upregulation of hsa-miR-590

2022 ◽  
Vol 11 ◽  
Author(s):  
Chia-Chang Wu ◽  
Yuan-Hung Wang ◽  
Su-Wei Hu ◽  
Wen-Ling Wu ◽  
Chi-Tai Yeh ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Disease Progression ◽  
Expression Profiling ◽  
Critical Role ◽  
Therapy Response ◽  
Mediator Complex ◽  
Immunocytochemical Staining ◽  
Bax Protein ◽  
Bladder Urothelial Carcinoma

BackgroundDysfunctional transcription machinery with associated dysregulated transcription characterizes many malignancies. Components of the mediator complex, a principal modulator of transcription, are increasingly implicated in cancer. The mediator complex subunit 10 (MED10), a vital kinase module of the mediator, plays a critical role in bladder physiology and pathology. However, its role in the oncogenicity, metastasis, and disease recurrence in bladder cancer (BLCA) remains unclear.ObjectiveThus, we investigated the role of dysregulated or aberrantly expressed MED10 in the enhanced onco-aggression, disease progression, and recurrence of bladder urothelial carcinoma (UC), as well as the underlying molecular mechanism.MethodsUsing an array of multi-omics big data analyses of clinicopathological data, in vitro expression profiling and functional assays, and immunocytochemical staining, we assessed the probable roles of MED10 in the progression and prognosis of BLCA/UC.ResultsOur bioinformatics-aided gene expression profiling showed that MED10 is aberrantly expressed in patients with BLCA, is associated with high-grade disease, is positively correlated with tumor stage, and confers significant survival disadvantage. Reanalyzing the TCGA BLCA cohort (n = 454), we showed that aberrantly expressed MED10 expression is associated with metastatic and recurrent disease, disease progression, immune suppression, and therapy failure. Interestingly, we demonstrated that MED10 interacts with and is co-expressed with the microRNA, hsa-miR-590, and that CRISPR-mediated knockout of MED10 elicits the downregulation of miR-590 preferentially in metastatic UC cells, compared to their primary tumor peers. More so, silencing MED10 in SW1738 and JMSU1 UC cell lines significantly attenuates their cell proliferation, migration, invasion, clonogenicity, and tumorsphere formation (primary and secondary), with the associated downregulation of BCL-xL, MKI67, VIM, SNAI1, OCT4, and LIN28A but upregulated BAX protein expression. In addition, we showed that high MED10 expression is a non-inferior biomarker of urothelial recurrence compared with markers of cancer stemness; however, MED10 is a better biomarker of local recurrence than any of the stemness markers.ConclusionThese data provide preclinical evidence that dysregulated MED10/MIR590 signaling drives onco-aggression, disease progression, and recurrence of bladder UC and that this oncogenic signal is therapeutically actionable for repressing the metastatic/recurrent phenotypes, enhancing therapy response, and shutting down stemness-driven disease progression and relapse in patients with BLCA/UC.

scholarly journals The inhibitory effect of silencing CDCA3 on migration and proliferation in bladder urothelial carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dexin Shen ◽  
Yayun Fang ◽  
Fenfang Zhou ◽  
Zhao Deng ◽  
Kaiyu Qian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Urothelial Carcinoma ◽  
Carcinoma Cells ◽  
Expression Level ◽  
Tumor Cell Growth ◽  
Migration Ability ◽  
Bladder Urothelial Carcinoma ◽  
Related Proteins

Abstract Background CDCA3 is an important component of the E3 ligase complex with SKP1 and CUL1, which could regulate the progress of cell mitosis. CDCA3 has been widely identified as a proto-oncogene in multiple human cancers, however, its role in promoting human bladder urothelial carcinoma has not been fully elucidated. Methods Bioinformatic methods were used to analyze the expression level of CDCA3 in human bladder urothelial carcinoma tissues and the relationship between its expression level and key clinical characteristics. In vitro studies were performed to validate the specific functions of CDCA3 in regulating cell proliferation, cell migration and cell cycle process. Alterations of related proteins was investigated by western blot assays. In vivo studies were constructed to validate whether silencing CDCA3 could inhibit the proliferation rate in mice model. Results Bioinformatic analysis revealed that CDCA3 was significantly up-regulated in bladder urothelial carcinoma samples and was related to key clinical characteristics, such as tumor grade and metastasis. Moreover, patients who had higher expression level of CDCA3 tend to show a shorter life span. In vitro studies revealed that silencing CDCA3 could impair the migration ability of tumor cells via down-regulating EMT-related proteins such as MMP9 and Vimentin and inhibit tumor cell growth via arresting cells in the G1 cell cycle phase through regulating cell cycle related proteins like p21. In vivo study confirmed that silencing CDCA3 could inhibit the proliferation of bladder urothelial carcinoma cells. Conclusions CDCA3 is an important oncogene that could strengthen the migration ability of bladder urothelial carcinoma cells and accelerate tumor cell growth via regulating cell cycle progress and is a potential biomarker of bladder urothelial carcinoma.

Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic hypoxia

2002 ◽  
Vol 282 (6) ◽  
pp. L1314-L1323 ◽  
Author(s):  
J. Chen ◽  
L. He ◽  
B. Dinger ◽  
L. Stensaas ◽  
S. Fidone
Keyword(s):  
Carotid Body ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Critical Role ◽  
Immunocytochemical Staining ◽  
Type I ◽  
Type I Cells ◽  
I Cells

Chronic exposure in a low-Po 2 environment (i.e., chronic hypoxia, CH) elicits an elevated hypoxic ventilatory response and increased hypoxic chemosensitivity in arterial chemoreceptors in the carotid body. In the present study, we examine the hypothesis that changes in chemosensitivity are mediated by endothelin (ET), a 21-amino-acid peptide, and ETA receptors, both of which are normally expressed by O2-sensitive type I cells. Immunocytochemical staining showed incremental increases in ET and ETAexpression in type I cells after 3, 7, and 14 days of CH (380 Torr). Peptide and receptor upregulation was confirmed in quantitative RT-PCR assays conducted after 14 days of CH. In vitro recordings of carotid sinus nerve activity after in vivo exposure to CH for 1–16 days demonstrated a time-dependent increase in chemoreceptor activity evoked by acute hypoxia. In normal carotid body, the specific ETAantagonist BQ-123 (5 μM) inhibited 11% of the nerve discharge elicited by hypoxia, and after 3 days of CH the drug diminished the hypoxia-evoked discharge by 20% ( P < 0.01). This inhibitory effect progressed to 45% at day 9 of CH and to nearly 50% after 12, 14, and 16 days of CH. Furthermore, in the presence of BQ-123, the magnitude of the activity evoked by hypoxia did not differ in normal vs. CH preparations, indicating that the increased activity was the result of endogenous ET acting on an increasing number of ETA. Collectively, our data suggest that ET and ETA autoreceptors on O2-sensitive type I cells play a critical role in CH-induced increased chemosensitivity in the rat carotid body.

scholarly journals HNRNPH1 Is a Novel Regulator Of Cellular Proliferation and Disease Progression in Chronic Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Menghan Liu ◽  
Lin Yang ◽  
Xiaojun Liu ◽  
Ziyuan Nie ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Cellular Proliferation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Multiple Cancer

RNA binding proteins act as essential modulators in cancers by regulating biological cellular processes. Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), as a key member of the heterogeneous nuclear ribonucleoproteins family, is frequently upregulated in multiple cancer cells and involved in tumorigenesis. However, the function of HNRNPH1 in chronic myeloid leukemia (CML) remains unclear. In the present study, we revealed that HNRNPH1 expression level was upregulated in CML patients and cell lines. Moreover, the higher level of HNRNPH1 was correlated with disease progression of CML. In vivo and in vitro experiments showed that knockdown of HNRNPH1 inhibited cell proliferation and promoted cell apoptosis in CML cells. Importantly, knockdown of HNRNPH1 in CML cells enhanced sensitivity to imatinib. Mechanically, HNRNPH1 could bind to the mRNA of PTPN6 and negatively regulated its expression. PTPN6 mediated the regulation between HNRNPH1 and PI3K/AKT activation. Furthermore, the HNRNPH1–PTPN6–PI3K/AKT axis played a critical role in CML tumorigenesis and development. The present study first investigated the deregulated HNRNPH1–PTPN6–PI3K/AKT axis moderated cell growth and apoptosis in CML cells, whereby targeting this pathway may be a therapeutic CML treatment.

scholarly journals The Deubiquitinating Enzyme Inhibitor PR-619 Enhances the Cytotoxicity of Cisplatin via the Suppression of Anti-Apoptotic Bcl-2 Protein: In Vitro and In Vivo Study

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1268 ◽  
Author(s):  
Kuan-Lin Kuo ◽  
Shing-Hwa Liu ◽  
Wei-Chou Lin ◽  
Po-Ming Chow ◽  
Yu-Wei Chang ◽  
...  
Keyword(s):  
Antitumor Effect ◽  
Enzyme Inhibitor ◽  
Critical Role ◽  
Deubiquitinating Enzymes ◽  
Mice Model ◽  
Bladder Urothelial Carcinoma ◽  
Xenograft Mice Model ◽  
Xenograft Mice

After chemotherapy for the treatment of metastatic bladder urothelial carcinoma (UC), most patients inevitably encounter drug resistance and resultant treatment failure. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins and play a critical role in maintaining protein homeostasis. This study investigated the antitumor effect of PR-619, a DUBs inhibitor, in combination with cisplatin, for bladder UC treatment. Our results showed that PR-619 effectively induced dose- and time-dependent cytotoxicity, apoptosis, and ER-stress related apoptosis in human UC (T24 and BFTC-905) cells. Additionally, co-treatment of PR-619 with cisplatin potentiated cisplatin-induced cytotoxicity in UC cells and was accompanied by the concurrent suppression of Bcl-2. We also proved that Bcl-2 overexpression is related to the chemo-resistant status in patients with metastatic UC by immunohistochemistry (IHC) staining. In a xenograft mice model, we confirmed that PR-619 enhanced the antitumor effect of cisplatin on cisplatin-naïve and cisplatin-resistant UCs. Our results demonstrated that PR-619 effectively enhanced the cisplatin-induced antitumor effect via concurrent suppression of the Bcl-2 level. These findings provide promising insight for developing a therapeutic strategy for UC treatment.

scholarly journals Trifluoperazine, an Antipsychotic Drug, Effectively Reduces Drug Resistance in Cisplatin-Resistant Urothelial Carcinoma Cells via Suppressing Bcl-xL: An In Vitro and In Vivo Study

2019 ◽  
Vol 20 (13) ◽  
pp. 3218 ◽  
Author(s):  
Kuan-Lin Kuo ◽  
Shing-Hwa Liu ◽  
Wei-Chou Lin ◽  
Fu-Shun Hsu ◽  
Po-Ming Chow ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Urothelial Carcinoma ◽  
Cisplatin Resistance ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
G1 Arrest ◽  
Antitumor Effects ◽  
In Vivo Models

Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma (UC). Most patients inevitably encounter drug resistance and resultant disease relapse. Reduced apoptosis plays a critical role in chemoresistance. Trifluoperazine (TFP), an antipsychotic agent, has demonstrated antitumor effects on various cancers. This study investigated the efficacy of TFP in inhibiting cisplatin-resistant bladder UC and explored the underlying mechanism. Our results revealed that cisplatin-resistant UC cells (T24/R) upregulated the antiapoptotic factor, B-cell lymphoma-extra large (Bcl-xL). Knockdown of Bcl-xL by siRNA resensitized cisplatin-resistant cells to the cisplatin cytotoxic effect. TFP (10–45 μM) alone elicited dose-dependent cytotoxicity, apoptosis, and G0/G1 arrest on T24/R cells. Co-treatment of TFP potentiated cisplatin-induced cytotoxicity in T24/R cells. The phenomenon that TFP alleviated cisplatin resistance to T24/R was accompanied with concurrent suppression of Bcl-xL. In vivo models confirmed that TFP alone effectively suppressed the T24/R xenograft in nude mice. TFP co-treatment enhanced the antitumor effect of cisplatin on the T24/R xenograft. Our results demonstrated that TFP effectively inhibited cisplatin-resistant UCs and circumvented cisplatin resistance with concurrent Bcl-xL downregulation. These findings provide a promising insight to develop a therapeutic strategy for chemoresistant UCs.

scholarly journals Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3478
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Kai-Yi Tzou ◽  
Chia-Da Lin ◽  
Su-Wei Hu ◽  
Yuan-Hung Wang ◽  
...  
Keyword(s):  
Critical Role ◽  
Therapy Response ◽  
Migration And Invasion ◽  
Disease Relapse ◽  
Testosterone Metabolism ◽  
Aberrant Expression ◽  
Network Analyses ◽  
The Impact

Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein–protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through “SRD5A1 withdrawal” or “SHBG induction” is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Acute cigarette smoke exposure induces apoptosis of alveolar macrophages

2001 ◽  
Vol 281 (6) ◽  
pp. L1392-L1401 ◽  
Author(s):  
Kazutetsu Aoshiba ◽  
Jun Tamaoki ◽  
Atsushi Nagai
Keyword(s):  
Cigarette Smoke ◽  
Alveolar Macrophages ◽  
Critical Role ◽  
Light And Electron Microscopy ◽  
In Vivo Studies ◽  
Cigarette Smoke Exposure ◽  
Protein Accumulation ◽  
Cytochrome C Release ◽  
Bax Protein

Alveolar macrophages (AMs) may play a critical role in cigarette smoke (CS)-related pulmonary diseases. This study was designed to determine whether CS induces apoptosis of AMs. In in vitro studies, mouse, rat, and human AMs and human blood monocyte-derived macrophages cultured with aqueous whole CS extracts underwent apoptosis that was detected by light and electron microscopy and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. The gas phase of CSE did not cause apoptosis. The CS-induced apoptosis was associated with increased oxidative stress, Bax protein accumulation, mitochondrial dysfunction, and mitochondrial cytochrome c release but was independent of p53, Fas, and caspase activation. This apoptosis was inhibited by antioxidants such as glutathione, ascorbic acid, and α-tocopherol. In in vivo studies where rats were exposed to the smoke from 10 cigarettes over 5 h in an exposure chamber, ∼3% of AMs obtained by bronchoalveolar lavage after 24 h showed apoptosis. These results suggest that acute CS exposure is capable of inducing apoptosis of AMs.

scholarly journals A novel signature constructed by ferroptosis-associated genes (FAGs) for the prediction of prognosis in bladder urothelial carcinoma (BLCA) and associated with immune infiltration

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiao-chen Luan ◽  
Teng-yue Zeng ◽  
Qi-jie Zhang ◽  
De-run Xia ◽  
Rong Cong ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Immune Cell ◽  
Risk Groups ◽  
The Cancer Genome Atlas ◽  
Prognostic Analysis ◽  
Regulated Cell Death ◽  
Bladder Urothelial Carcinoma ◽  
Prediction Of Prognosis ◽  
Pathway Analyses

Abstract Background Ferroptosis, a novel form of regulated cell death, has been implicated in the pathogenesis of cancers. Nevertheless, the potential function and prognostic values of ferroptosis in bladder urothelial carcinoma (BLCA) are complex and remain to be clarified. Therefore, we proposed to systematically examine the roles of ferroptosis-associated genes (FAGs) in BLCA. Methods According to The Cancer Genome Atlas (TCGA) database, differently expressed FAGs (DEFAGs) and differently expressed transcription factors (DETFs) were identified in BLCA. Next, the network between DEFAGs and DETFs, GO annotations and KEGG pathway analyses were performed. Then, through univariate, LASSO and multivariate regression analyses, a novel signature based on FAGs was constructed. Moreover, survival analysis, PCA analysis, t-SNE analysis, ROC analysis, independent prognostic analysis, clinicopathological and immune correlation analysis, and experimental validation were utilized to evaluate the signature. Results Twenty-eight DEFAGs were identified, and four FAGs (CRYAB, TFRC, SQLE and G6PD) were finally utilized to establish the FAGs based signature in the TCGA cohort, which was subsequently validated in the GEO database. Moreover, we found that immune cell infiltration, immunotherapy-related biomarkers and immune-related pathways were significantly different between two risk groups. Besides, nine molecule drugs with the potential to treat bladder cancer were identified by the connectivity map database analysis. Finally, the expression levels of crucial FAGs were verified by the experiment, which were consistent with our bioinformatics analysis, and knockdown of TFRC could inhibit cell proliferation and colony formation in BLCA cell lines in vitro. Conclusions Our study identified prognostic ferroptosis-associated genes and established a novel FAGs signature, which could accurately predict prognosis in BLCA patients.

scholarly journals Moesin (MSN) as a Novel Proteome-Based Diagnostic Marker for Early Detection of Invasive Bladder Urothelial Carcinoma in Liquid-Based Cytology

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1018
Author(s):  
Jeong Hwan Park ◽  
Cheol Lee ◽  
Dohyun Han ◽  
Jae Seok Lee ◽  
Kyung Min Lee ◽  
...  
Keyword(s):  
Early Detection ◽  
Urothelial Carcinoma ◽  
Diagnostic Marker ◽  
Three Dimensional ◽  
Biological Significance ◽  
Predictive Biomarker ◽  
Bladder Urothelial Carcinoma ◽  
Potential Biomarker ◽  
Liquid Based Cytology

Bladder urothelial carcinoma (BUC) is the most lethal malignancy of the urinary tract. Treatment for the disease highly depends on the invasiveness of cancer cells. Therefore, a predictive biomarker needs to be identified for invasive BUC. In this study, we employed proteomics methods on urine liquid-based cytology (LBC) samples and a BUC cell line library to determine a novel predictive biomarker for invasive BUC. Furthermore, an in vitro three-dimensional (3D) invasion study for biological significance and diagnostic validation through immunocytochemistry (ICC) were also performed. The proteomic analysis suggested moesin (MSN) as a potential biomarker to predict the invasiveness of BUC. The in vitro 3D invasion study showed that inhibition of MSN significantly decreased invasiveness in BUC cell lines. Further validation using ICC ultimately confirmed moesin (MSN) as a potential biomarker to predict the invasiveness of BUC (p = 0.023). In conclusion, we suggest moesin as a potential diagnostic marker for early detection of BUC with invasion in LBC and as a potential therapeutic target.

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