ABSTRACT
Drug resistance remains a significant challenge in cancer treatment. Recently, the interactions among various cell types within the tumor microenvironment (TME) have deepened our understanding of the mechanisms behind treatment resistance. Therefore, this review aims to synthesize current research focusing on infiltrating cells and drug resistance suggesting that targeting the TME could be a viable strategy to combat this issue. Numerous factors, including inflammation, metabolism, senescence, hypoxia, and angiogenesis, contribute to drug resistance could be a viable strategy to combat this issue. Overexpression of STAT3 is commonly associated with drug-resistant cancer cells or stromal cells. Current research often generalizes the impact of stromal cells on resistance, lacking specificity and statistical robustness. Thus, future research should take notice of this issue and aim to provide high-quality evidence. Despite the existing limitations, targeting the TME to overcome therapy resistance hold promising and valuable potential.
Subject(s)
Drug Resistance, Neoplasm , Neoplasms , Tumor Microenvironment , Humans , Neoplasms/pathology , Neoplasms/metabolism , Neoplasms/immunology , Neoplasms/drug therapy , AnimalsABSTRACT
Aging and circadian rhythms have been connected for decades, but their molecular interaction has remained unknown, especially for cancers. In this situation, we summarized the current research actuality and problems in this field using the bibliometric analysis. Publications in the PubMed and Web of Science databases were retrieved. Overall, there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer. Researchers from USA, Germany, Italy, China and England have greater studies than others. Top three publication institutions are University of California System, UDICE-French Research Universities and University of Texas System. Current research hotspots include oxidative stress, breast cancer, melatonin, cell cycle, calorie restriction, prostate cancer and NF-KB. In conclusion, results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer. These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.
ABSTRACT
Bladder cancer stands as a prevalent global malignancy, exhibiting notable sex-based variations in both incidence and prognosis. Despite substantial strides in therapeutic approaches, the formidable challenge of drug resistance persists. The genomic landscape of bladder cancer, characterized by intricate clonal heterogeneity, emerges as a pivotal determinant in fostering this resistance. Clonal evolution, encapsulating the dynamic transformations within subpopulations of tumor cells over time, is implicated in the emergence of drug-resistant traits. Within this review, we illuminate contemporary insights into the role of clonal evolution in bladder cancer, elucidating its influence as a driver in tumor initiation, disease progression, and the formidable obstacle of therapy resistance.
Subject(s)
Clonal Evolution , Drug Resistance, Neoplasm , Genomics , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/drug therapy , Humans , Drug Resistance, Neoplasm/genetics , Clonal Evolution/genetics , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacologyABSTRACT
BACKGROUND: Recently, numerous studies have reported the interaction between senescence and oxidative stress in cancer. However, there is a lack of a comprehensive understanding of the precise mechanisms involved. AIM: Therefore, our review aims to summarize the current findings and elucidate by presenting specific mechanisms that encompass functional pathways, target genes, and related aspects. METHODS: Pubmed and Web of Science databases were retrieved to search studies about the interaction between senescence and oxidative stress in cancer. Relevant publications in the reference list of enrolled studies were also checked. RESULTS: In carcinogenesis, oxidative stress-induced cellular senescence acts as a barrier against the transformation of stimulated cells into cancer cells. However, the senescence-associated secretory phenotype (SASP) is positively linked to tumorigenesis. In the cancer progression stage, targeting specific genes or pathways that promote oxidative stress-induced cellular senescence can suppress cancer progression. In terms of treatment, many current clinical therapies combine with novel drugs to overcome resistance and reduce side effects by attenuating oxidative stress-induced senescence. Notably, emerging drugs control cancer development by enhancing oxidative stress-induced senescence. These studies highlight the complacted effects of the interplay between oxidative stress and senescence at different cancer stages and among distinct cell populations. Future research should focus on characterizing the roles of distinct senescent cell types in various tumor stages and identifying the specific components of SASP. CONCLUDSION: We've summarized the mechanisms of senescence and oxidative stress in cancer and provided illustrative figures to guide future research in this area.
Subject(s)
Cellular Senescence , Neoplasms , Oxidative Stress , Humans , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/genetics , Neoplasms/drug therapy , Animals , Senescence-Associated Secretory Phenotype , Signal TransductionABSTRACT
BACKGROUND: A three-dimensional (3D) reconstruction of the kidney, parapelvic cyst and the collecting system was conducted using the 3D Slicer software. The reconstructed image was used to form a virtual endoscope to assist flexible ureteroscopic incision and drainage was performed with a holmium laser for treating parapelvic cysts. The effectiveness of this assistive technique was assessed. METHODS: This was a retrospective cohort study. The clinical information of 59 patients undergoing flexible ureteroscopic incision and drainage for parapelvic cysts in two medical centers was collected. 3D Slicer software reconstruction and virtual endoscopic imaging were performed for 28 cases. Before the operation, the best point for incision on the collecting system's mucosa was assessed by virtual endoscope imaging. Propensity score matching was adopted for the reconstructive and non-reconstructive groups. RESULTS: After matching, the reconstructive group and non-reconstructive group both had 21 cases each. The operation time in the reconstructive and non-reconstructive groups was 38.81±5.01 and 51.00±18 minutes, respectively. Statistically significant differences existed between the two groups (t=7.024, P<0.001). No statistical significance was found in postoperative fever, immediate postoperative C reactive protein (CRP), length of postoperative hospital stay and cyst diameter three months after the operation. CONCLUSIONS: The operator was provided with a more direct and real vision when 3D Slicer software reconstruction was adopted via virtual endoscopic imaging to assist flexible ureteroscopic parapelvic cyst incision. This helped reduce the operation time. Further follow-ups and observations are required to assess the long-term efficacy of flexible ureteroscopic parapelvic cyst incision.
Subject(s)
Ureteroscopy , Humans , Retrospective Studies , Ureteroscopy/methods , Female , Male , Middle Aged , Cohort Studies , Imaging, Three-Dimensional/methods , Adult , Aged , Kidney Diseases, Cystic/surgery , Kidney Diseases, Cystic/diagnostic imaging , Drainage/methods , Lasers, Solid-State/therapeutic use , Kidney Pelvis/surgery , Kidney Pelvis/diagnostic imagingABSTRACT
OBJECTIVES: RC48 is an antibody-drug conjugate (ADC) that targets HER2. In China, RC48 is approved for patients with HER-2-positive metastatic urothelial carcinoma (mUC) who have failed at least platinum-based chemotherapy. This study aimed to evaluate RC48 for mUC in a cohort of real-world patients. MATERIALS AND METHODS: We retrospectively collected data from 103 mUC patients from 12 centers between July 2021 and August 2023 in China. RC48 alone or with immunotherapy was administered until disease progression, intolerable toxicity, death, or other reasons. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TRAEs) were evaluated. RESULTS: The median age of the patients was 68 years, and 68.0% were men. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) received RC48 combination therapy. The response rates were as follows: complete response in 2 (1.9%) patients, partial response in 50 (48.5%) patients, stable disease in 30 (29.1%) patients. The ORR was 50.5%. In patients with ≥80 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and creatinine clearance rate (CCr) <30 mL/min, the ORR was 75%, 48.6%, and 40.0%, respectively. The median PFS was 6 (3.9-8.1) months, and the median OS was not reached. The most reported TRAEs were peripheral sensory neuropathy (53.4%), alopecia (42.7%), asthenia (38.8%), decreased appetite (35.9%) and weight loss (35.9%) and TRAE did not increase in patients with poor condition or impaired renal function. CONCLUSION: Administration of RC48 for real-world patients is both effective and safe. mUC patients can benefit from RC48-based therapy, regardless of their poor condition or impaired renal function.
Subject(s)
Immunoconjugates , Humans , Male , Female , Aged , Retrospective Studies , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , China , Middle Aged , Aged, 80 and over , Receptor, ErbB-2/metabolism , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/secondary , Progression-Free Survival , Urologic Neoplasms/drug therapy , Urologic Neoplasms/pathology , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Treatment Outcome , AdultSubject(s)
Global Health , Urinary Tract Infections , Humans , Female , Urinary Tract Infections/epidemiology , Prevalence , Adult , Young Adult , Time Factors , AdolescentABSTRACT
Numerous research works have emphasized the critical role that circadian rhythm plays in the tumor microenvironment (TME). The goal of clarifying chrono-pharmacological strategies for improving cancer treatment in clinical settings is a continuous endeavor. Consequently, to enhance the use of time-based pharmaceutical therapies in oncology, combining existing knowledge on circadian rhythms' roles within the TME is essential. This perspective elucidates the functions of circadian rhythms in the TME across various stages of cancer development, progression, and metastasis. Specifically, aging, angiogenesis, and inflammation are implicated in modulating circadian rhythm within the TME. Furthermore, circadian rhythm exerts a profound influence on current cancer treatments and thereby generates chronotheray to manage tumors. From a TME perspective, circadian rhythm offers promising opportunities for cancer prevention and treatment; nevertheless, further study is needed to address unanswered scientific problems.
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Prostatic Neoplasms , Signal Transduction , Male , Humans , Prognosis , Cells, Cultured , BiomarkersABSTRACT
Background: During the COVID-19 pandemic, public transport was restricted in many countries because of the transmission risk. According to the risk compensation theory, travellers post-COVID-19 vaccination may encounter higher risks; however, no real-world studies provide such evidence. Therefore, we conducted a survey to assess whether risk compensation would occur among travellers' health-related behaviours after COVID-19 vaccination, potentially aggravating the transmission of the virus. Materials and Methods: A self-administered online survey was designed and distributed over WeChat to identify the difference in health behaviours before and after COVID-19 vaccination among travellers at a train station in Taizhou, China, from 13 February to 26 April 2022. Results: A total of 602 individuals completed the questionnaire. The results revealed no statistical difference between the health behaviours reported by the vaccinated and unvaccinated groups. Participants who received the first dose of the vaccine earlier showed no statistical difference in harmful health behaviours (hand washing frequency decreased by 4.1% (P=0.145) and the duration of public transport travel increased by 3.4% (P=0.437)), but showed better protective health behaviours (mask-wearing duration increased by 24.7% (P=0.014)). Compared to those vaccinated less than three times, participants vaccinated against COVID-19 three times showed no statistical differences in harmful health behaviours mask-wearing duration decreased by 7.0% (P=0.927), their hand washing frequency decreased by 4.8% (P=0.905), and the duration of public transport travel increased by 2.5% (P=0.287). After vaccination, when compared to themselves before vaccination, participants exhibited better health behaviours (increased hand washing frequency and mask-wearing duration, and decreased duration of public transport travel) to some extent. Conclusion: In conclusion, this study found no evidence of risk compensation among travellers. After being vaccinated, health behaviours partly improved among travellers.
ABSTRACT
Purpose: To elucidate the clinical and prognostic role of PDZ and LIM domain protein (PDLIM) genes and the association to epithelial-mesenchymal transition (EMT) and immune cell infiltration in patients with prostate cancer (PRAD). Methods: The data of RNA-seq, DNA methylation, and clinical features of PRAD patients were collected from The Cancer Genome Atlas (TCGA) database to define the prognostic value of PDLIM gene expression and the association with EMT and immune cell infiltration. A tissue microarray including 134 radical prostatectomy specimens was served as validation by immunohistochemistry (IHC) staining analysis. Results: The mRNA levels of PDLIM1/2/3/4/6/7 were significantly downregulated, while PDLIM5 was upregulated in PRAD (P < 0.05). High expression of PDLIM2 mRNA suggests poor progression free interval in PRAD patients. DNA methylation of PDLIM2 was correlated with its mRNA expression level, and that the cg22973076 methylation site in PDLIM2 was associated with shorter PFI (P < 0.05) in PRAD. Single-sample gene-set enrichment and gene functional enrichment results showed that PDLIM2 was correlated with EMT and immune processes. Spearman's test showed a significant correlation with six reported EMT signatures and several EMT signature-related genes. Tumor microenvironment analysis revealed that the PDLIM2 mRNA expression was positively correlated with the immune score, stromal score, and various tumor infiltrating immune cells. Additionally, the results showed that patients in the high-PDLIM2 mRNA expression group may be more sensitive to immune checkpoint blockade therapy. Finally, IHC analysis further implicated the protein level of PDLIM2 was upregulated in PRAD and acts as a novel potential biomarker in predicting tumor progression. Conclusion: Our study suggests that PDLIM family genes might be significantly correlated with oncogenesis and the progression of PRAD. PDLIM2 correlated with EMT and immune cell infiltration by acting as an oncogene in PRAD, which may serve as a potential prognostic biomarker for PRAD patients.
Subject(s)
Epithelial-Mesenchymal Transition , LIM Domain Proteins , Microfilament Proteins , Prostatic Neoplasms , Epithelial-Mesenchymal Transition/genetics , Humans , LIM Domain Proteins/genetics , Male , Microfilament Proteins/genetics , Prognosis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA, Messenger/genetics , Tumor Microenvironment/geneticsABSTRACT
BACKGROUND: Specificity protein 1 (Sp1) is a transcription factor that exerts key functions in the carcinogenesis and progression of various types of cancer. However, its expression and prognostic value in bladder urothelial carcinoma (BUC) have yet to be completely elucidated. METHODS: The present study performed reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to examine Sp1 mRNA expression in 12 pairs of urothelial carcinoma and adjacent normal bladder tissues. Immunohistochemistry (IHC) was performed in 113 paraffin-embedded urothelial carcinoma tissues to detect the expression of Sp1. Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the correlation between Sp1 expression and patient prognosis. RESULTS: The mRNA expression of Sp1 was elevated in the urothelial carcinoma by RT-qPCR compared with their paired normal bladder tissues. Among 113 cases of patients with urothelial carcinoma, there were 39 low histological grade and 74 high histological grade, 61 unifocal tumor and 52 multifocal tumor, 78 cases in Ta, T1, and T2 stages, and 35 cases in T3 and T4 stages. The enhanced expression of Sp1 mRNA was observed in tumors with a high histological grade, and invasive and metastatic samples. Immunohistochemistry revealed that Sp1 high expression was significantly correlated with the histological grade, tumor stage, vascular invasion, lymph node metastasis and distant metastasis (P < 0.05). Kaplan-Meier analysis demonstrated that elevated Sp1 expression in cancer tissue was correlated with a significantly poor overall survival (OS) and disease-free survival (DFS) compared with samples with low Sp1 expression (P < 0.05). Multivariate analyses by Cox's proportional hazard model also revealed that the expression of Sp1 was an independent prognostic factor in urothelial carcinoma. CONCLUSION: Sp1 expression is significantly elevated in urothelial carcinoma and may be used to identify a subset of patients with aggressive behaviors and poor clinical outcomes. Sp1 is a potential novel independent prognostic biomarker for patients with urothelial carcinoma following surgery.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Carcinoma, Transitional Cell/pathology , Humans , Kaplan-Meier Estimate , Neoplasm Staging , Prognosis , RNA, Messenger , Sp1 Transcription Factor/genetics , Urinary Bladder/pathology , Urinary Bladder Neoplasms/pathologyABSTRACT
Background: Transurethral split of the prostate (TUSP) is effective in treating benign prostatic hyperplasia (BPH). However, there is still a lack of research focusing on the optimal target population for TUSP. This study aimed to compare the efficacy of TUSP in patients with different prostate volumes or ages. Methods: The study was a multicenter retrospective study. The outcomes of TUSP in BPH patients with different prostate volumes or different ages were compared. A total of 439 patients were included in the study. Patients were divided into two groups according to prostate volume, with a cut-off value of 50 mL. Similarly, the cut-off value for the age groups was 70 years. Baseline patient characteristics and perioperative outcomes were recorded. Follow-up was performed at 1, 6, and 12 months after surgery. Results: The mean age of the patients was 73.4 years, and the mean prostate volume was 51.2 mL. At 12-month follow-up after TUSP treatment, the patients' International Prostate Symptom Scores (IPSS), quality of life (QoL) scores, and postvoid residual (PVR) volumes decreased significantly, while peak urinary flow rate (Qmax) increased significantly. Intraoperative hemoglobin (Hb) reduction was significantly lower in the small volume group than in the large volume group. The incidence of postoperative urinary urgency and transient incontinence was lower in the small volume group. IPSS score, PVR, and Qmax in the small volume group showed more remarkable changes at several time points compared to the preoperative period. Postoperative pain scores were higher in the small volume group than in the large volume group. There were no differences between the two groups in terms of long-term complications. The younger group showed greater variation in PVR and Qmax at some time points but less variation in QoL than the older group. Conclusions: TUSP is overall safe and effective in treating BPH. This study showed differences in the outcomes of TUSP in treating different prostate volumes or ages of BPH patients. The optimal surgical approach for BPH patients might be selected clinically based on a combination of prostate volume or patient age.
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BACKGROUND: This study aimed to systematically evaluate the efficacy of laparoscopic radical cystectomy (LRC) surgical therapy in patients with bladder cancer (BC), and to provide evidence for the clinical treatment of BC. METHODS: The Embase, Ovid, PubMed, Medline, Springer, and Web of Sciences database were searched to screen articles with clinical controlled trials on LRC treatment of BC. The Cochrane Handbook 5.0.2 software and Review Manager 5.3 software were adopted to evaluate the risk of bias and to perform a meta-analysis of the included articles in this study. RESULTS: A total of 12 articles were obtained, including 1,283 research cases. The meta-analysis results showed that relative to the control group (Ctrl), the observation group (Observ group) had significantly lower intraoperative blood loss (IBL) after LRC [mean difference (MD) =-458.75; 95% confidential interval (CI): -505.75 to -411.76; Z=19.13; P<0.00001], blood transfusion rate (BTR) (odds ratio =0.36; 95% CI: 0.13-0.94; Z=2.08; and P=0.04), use of analgesics (MD =-24.53; 95% CI: -39.04 to -10.01; Z=3.31; and P=0.0009), and incidence of postoperative complications (Risk ratio =0.58; 95% CI: 0.39-0.85; Z=2.77; and P=0.006). However, and the length of hospital stay could not be shortened (MD =-2.43; 95% CI: -4.83 to -0.02; Z=1.98; and P=0.05). DISCUSSION: LRC treatment of BC could effectively reduce the amount of IBS, and lower the intraoperative BTR, use of analgesics, and incidence of postoperative complications. Therefore, it could be used in the clinical surgical treatment of BC patients.
ABSTRACT
Cystitis glandularis is characterized by chronic inflammation and hyperproliferation of bladder mucosa, and contributes to progression of bladder adenocarcinoma. TPRG1 (Tumor Protein P63 Regulated 1) is related to cellular inï¬ammatory response, and dysregulation of TPRG1 in tumor tissues is associated with tumor early recurrence. The effect of TPRG1 on cystitis glandularis was investigated in this study. Firstly, bladder specimen were isolated from patients with cystitis glandularis and E. coli-induced cystitis rat. Expression of TPRG1 was found to be up-regulated in the bladder specimen. Moreover, adeno-associated virus (AAV)-mediated silence of TPRG1 was delivered into rat, and data from hematoxylin and eosin (H and E) staining showed that injection with AAV-shTPRG1 ameliorated E. coli-induced histological changes in bladder tissues of rats, and suppressed the inflammatory response. Secondly, TPRG1 was also increased in primary cystitis glandularis cells. Knockdown of TPRG1 decreased cell proliferation of primary cystitis glandularis cells, and suppressed the migration. Thirdly, cyclooxygenase-2 (COX-2) was up-regulated in the bladder specimen isolated from patients with cystitis glandularis and E. coli-induced cystitis rat. Injection with AAV-shTPRG1 reduced protein expression of COX-2, p65 and prostaglandin E2 (PGE2) in the bladder specimen. Lastly, interference of COX-2 attenuated TPRG1 over-expression-induced increase of cell proliferation and migration in the primary cystitis glandularis cells. In conclusion, TPRG1 promoted inflammation and cell proliferation of cystitis glandularis through activation of NF-кB/COX2/PGE2 axis.
Subject(s)
Cystitis , Proteins/genetics , Urinary Bladder Neoplasms , Animals , Cell Proliferation , Cyclooxygenase 2/genetics , Cystitis/genetics , Cystitis/pathology , Dinoprostone/genetics , Escherichia coli , Humans , Inflammation , NF-kappa B/genetics , Neoplasm Recurrence, Local , Rats , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathologyABSTRACT
BACKGROUND: Pelvic lipomatosis (PL) is a rare benign condition with characteristic overgrowth of histologically benign fat and invasion and compression of pelvic organs, often leading to non-specific lower urinary tract symptoms (LUTS). Approximately 40% of patients with PL have cystitis glandularis (CG). The cause of PL combined with CG is poorly understood, and there is currently no effective treatment. Refractory CG with upper urinary tract obstruction even requires partial or radical bladder resection. CASE SUMMARY: In this case, a patient suffering from PL with CG was treated by transurethral resection of bladder tumour (TUR-BT) and oral administration of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor. The LUTS were alleviated, and the cystoscopy results improved significantly. Immunohistochemistry showed up-regulated COX-2 expression in the epithelium of TUR-BT samples, suggesting that COX-2 may participate in the pathophysiological process of PL combined with CG. CONCLUSION: We report for the first time that celecoxib may be an effective treatment strategy for PL combined with refractory CG.
ABSTRACT
Bladder cancer (BC) is the most common malignant disease. The developing of economically sustainable and available agents for the treatment of BC is required. Purple sweet potato anthocyanin (PSPA) has been shown to have antitumor abilities. The present study aimed to evaluate the potential role of PSPA in BC treatment. CCK-8 assay was used to assess the viability of BC cells. Flow cytometry assays were performed to evaluate the mitochondrial membrane potential (MMP), cell apoptosis and cell-cycle distribution. Real-time PCR (RT-PCR) and western blot analysis were performed to determine the expression of the target genes. The results of this study revealed that PSPA reduced the viability of BC in a dose-dependent manner. The MMP collapse was aggravated by the PSPA treatment. The apoptosis rate was higher in the PSPA groups than that in the control group. The expression of the pro-apoptosis genes, including cleaved caspase-3, Fas, Fasl, Bcl-2-associated X proteins (Bax) and anti-apoptotic gene (Bcl-2) was induced and decreased by PSPA, respectively. The cell-cycle progression was suppressed by the presence of PSPA. The activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) signaling pathway was suppressed by PSPA treatment during BC treatment. The PI3K/Akt signaling was closely related to the antitumor effect of PSPA in BC. The present study provided evidence regarding the treatment of BC and enhanced the understanding of the potential role that PSPA plays in cancer prevention.
Subject(s)
Anthocyanins/pharmacology , Ipomoea batatas/chemistry , Neoplasm Proteins/genetics , Urinary Bladder Neoplasms/drug therapy , Anthocyanins/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Flow Cytometry , Gene Expression Regulation, Neoplastic/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Signal Transduction/drug effects , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathologyABSTRACT
Smad ubiquitin regulatory factor 1 (SMURF1), a recently identified E3 ubiquitin ligase, targets substrate proteins for ubiquitination and proteasomal degradation. Previous studies have reported that SMURF1 also functions as an oncogene in human cancers. However, the clinical value of SMURF1 and its role in clear cell renal cell carcinoma (ccRCC) are unknown. SMURF1 expression was analyzed in 100 cases of ccRCC and matched tumor-adjacent specimens. SMURF1 was prominently overexpressed in ccRCC specimens compared with tumor-adjacent specimens. Increased levels of SMURF1 were also observed in ccRCC cell lines. Clinicopathological detection verified that SMURF1 expression was associated with advanced tumor node metastasis stage, large tumor size and vascular invasion of ccRCC patients. Moreover, Kaplan-Meier analysis found that SMURF1 elevation led to adverse overall survival and disease-free survival. Multivariate Cox regression analysis revealed that SMURF1 expression was an independent marker for prognosis prediction. Further experiments illustrated that SMURF1 knockdown significantly inhibited growth and metastasis of 769P cells, while SMURF1 overexpression promoted proliferation, migration and invasion in OSRC-2 cells. Mechanistically, SMURF1 inversely regulated the expression of DAB2 interacting protein, which negatively mediated the activation of both the ERK/RSK1 and PI3K/AKT/mTOR pathways in ccRCC cells. Taken together, these results suggest that SMURF1 might be a promising biomarker and target for novel treatment of human ccRCC.