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1.
Heliyon ; 9(12): e22408, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38107280

ABSTRACT

Background: As an important kidney-sparing treatment for upper urothelial carcinoma (UTUC), whether endoscopic excision can be performed without sacrificing oncologic outcomes remains indefinite. This study aimed to investigate the prevalence and efficacy of endoscopic excision, in patients with non-muscle invasive UTUC (NMIUTUC) and compare them to those of radical nephroureterectomy (RNU). Methods: Using the Surveillance, Epidemiology, and End Results database, we reviewed 4347 cases with NMIUTUC (cTis/Ta/T1-N0-M0,≤ 5.0 cm) between 2004 and 2020. Surgical treatment modalities included endoscopic excision and RNU. Propensity score matching analysis was used to minimize the selection bias between endoscopic excision and RNU, selecting 1:1 matched patients in the two group. Results: A total of 794 patients with NMIUTUC were included after matching (397:397). Patients who underwent endoscopic excision had worse survival outcomes compared with those of patients who underwent RNU (5-year OS: 65.3 % vs. 80.3 %, p < 0.0001; 5-year DSS: 83.2 % vs. 94.0 %, p = 0.00021). After stratification by anatomical sites, the effect of endoscopic excision for NMI renal pelvis cancer was worse than RNU (5-year OS, 62.9 % vs. 82.8 %; 5-year DSS, 78.8 % vs. 91.6 %), while in NMI ureteral cancer, there is no statistically significant difference in OS and DSS between endoscopic excision and RNU. Further stratification according to tumor grade revealed equivalent tumor control effects of endoscopic excision and RNU in low-grade NMI ureteral cancer (5-year OS: 67.7 % vs. 72.5 %, p = 0.23; 5-year DSS: 87.2 % vs. 93.1 %, p = 0.17); while for renal pelvis tumor and high-grade ureteral tumor, endoscopic excision was related with significantly inferior prognosis. Conclusions: Only for low-grade NMI ureteral cancer, endoscopic excision and RNU are oncologically equivalent, indicating that endoscopic excision might be an effective option for low-grade NMI ureteral cancer. This result needs to be further verified in randomized controlled trials.

2.
Front Oncol ; 13: 1130680, 2023.
Article in English | MEDLINE | ID: mdl-37207146

ABSTRACT

Background: For metastatic prostate cancer (mPCa), radical prostatectomy (RP) and radiation therapy (RT) may improve overall survival (OS) and cancer-specific survival (CSS). Compared with RT, RP shows significant advantages in improving patient outcomes. External beam radiation therapy (EBRT) even slightly elevates CSM with no statistical difference in OS compared with no local treatment (NLT). Objective: To evaluate OS and CSS after local treatment (LT) (including RP and RT) versus NLT in mPCa. Design, setting, and participants Within the Surveillance, Epidemiology and End Results (SEER) database (2000-2018), 20098 patients with metastatic prostate cancer were selected in this study, of which 19433 patients had no local treatment, 377 patients with radical prostate treatment, and 288 patients with RT. Outcome measurements and statistical analysis: Multivariable competing risks regression analysis after propensity score matching (PSM) was used to calculate CSM. Multivariable Cox regression analysis was used to identify the risk factors. Kaplan-Meier methods were used to calculate OS. Results and limitations: A total of 20098 patients were included: NLT (n = 19433), RP (n=377) and RT (n=288). In a competing risk regression analysis after PSM (ratio 1:1), RP resulted in a significantly lower CSM (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.29-0.45) than NLT, while RT showed a slightly lower CSM (HR 0.77, 95% CI 0.63-0.95). In a competing risk regression analysis after PSM (ratio 1:1), RP led to a lower CSM (HR 0.56, 95% CI 0.41-0.76) versus RT. As for all-cause mortality (ACM), RP (HR 0.37, 95% CI 0.31-0.45) and RT (HR 0.66, 95% CI 0.56-0.79). also showed a downward trend. In terms of OS, RP and RT significantly improved the survival probability compared with NLT, with the effect of RP being more pronounced. Obviously, older age, Gleason scores ≥8, AJCC T3-T4 stage, AJCC N1, AJCC M1b-M1c were all associated with higher CSM (P <0.05). The same results held true for ACM. The limitation of this article is that it is not possible to assess the effect of differences in systemic therapy on CSM in mPCa patients and clinical trials are needed to verify the results. Conclusions: For patients with mPCa, both RP and RT are beneficial to patients, and the efficacy of RP is better than RT from the perspective of CSM and ACM. Older age, higher gleason scores and the more advanced AJCC TNM stage all put patients at higher risk of dying. Patient summary: A large population-based cancer database showed that in addition to first-line therapy (hormonal treatment), RP and radiotherapy can also benefit patients with mPCa.

3.
Aging Dis ; 14(5): 1757-1774, 2023 Oct 01.
Article in English | MEDLINE | ID: mdl-37196108

ABSTRACT

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. It is characterized by the loss of androgen receptor (AR) signaling in neuroendocrine transdifferentiation, and finally, resistance to AR-targeted therapy. With the application of a new generation of potent AR inhibitors, the incidence of NEPC is gradually increasing. The molecular mechanism of neuroendocrine differentiation (NED) after androgen deprivation therapy (ADT) remains largely unclear. In this study, using NEPC-related genome sequencing database analyses, we screened RACGAP1, a common differentially expressed gene. We investigated RACGAP1 expression in clinical prostate cancer specimens by IHC. Regulated pathways were examined by Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation, and immunoprecipitation assays. The corresponding function of RACGAP1 in prostate cancer was analyzed by CCK-8 and Transwell assays. The changes of neuroendocrine markers and AR expression in C4-2-R and C4-2B-R cells were detected in vitro. We confirmed that RACGAP1 contributed to NE transdifferentiation of prostate cancer. Patients with high tumor RACGAP1 expression had shorter relapse-free survival time. The expression of RACGAP1 was induced by E2F1. RACGAP1 promoted neuroendocrine transdifferentiation of prostate cancer by stabilizing EZH2 expression in the ubiquitin-proteasome pathway. Moreover, overexpression of RACGAP1 promoted enzalutamide resistance of castration-resistant prostate cancer (CRPC) cells. Our results showed that the upregulation of RACGAP1 by E2F1 increased EZH2 expression, which drove NEPC progression. This study explored the molecular mechanism of NED and may provide novel methods and ideas for targeted therapy of NEPC.

4.
Am J Transl Res ; 15(4): 2515-2527, 2023.
Article in English | MEDLINE | ID: mdl-37193192

ABSTRACT

OBJECTIVES: Kidney cancer is one of the top ten cancers worldwide, and clear cell renal cell carcinoma (ccRCC) is the most common pathohistological type of kidney cancer. This study aimed to decipher the diagnostic and prognostic value of NCOA2 for ccRCC survival based on its expression and methylation. METHODS: We explored the mRNA and protein expression, DNA methylation, prognosis, cell function, and relevant immune infiltration of NCOA2 in ccRCC using data from public databases. Furthermore, GSEA (Gene Set Enrichment Analysis) was used to dissect the cell functions and signal pathways associated with NCOA2 involved in ccRCC and evaluated the close correlation between NCOA2 expression and immune cells. Finally, RT-qPCR (quantitative reverse transcription PCR) and IHC (immunohistochemistry) were utilized to verify the expression of NCOA2 in ccRCC among the tumor and adjacent normal tissues collected from patients. RESULTS: NCOA2 was lowly expressed in ccRCC tissue, which resulted from its methylation. High NCOA2 expression and low beta value of one of the CpG sites predicted better prognosis in patients with ccRCC. GSEA results and analysis of immune infiltration revealed that NCOA2 was associated with PD-1/PD-L1 expression and infiltration of other immune cells in ccRCC. CONCLUSIONS: NCOA2 has great potential to serve as a novel biomarker that can predict prognosis in ccRCC and may become a new therapeutic target in patients with late-stage ccRCC.

6.
Front Oncol ; 12: 914875, 2022.
Article in English | MEDLINE | ID: mdl-35847902

ABSTRACT

Purpose: Little is known about the detailed spectrum of the cause of death associated with prostate cancer (PCa). This study systematically characterized the cause of death among patients with PCa. Methods: Patients aged 40 years and older with primary PCa were identified from the Surveillance, Epidemiology, and End Results program. Mortality rates were estimated. Standardized mortality ratios (SMRs) of non-cancer deaths were calculated to evaluate the risk of death and to compare with the cancer-free population. Results: This study included 1,170,489 patients with PCa. There were 501,262 deaths, of which 27.4% were due to PCa and 57.0% were due to non-cancer causes. Non-cancer deaths increased over time from 1975 to 2016, and index cancer death decreased continually. The risk of non-cancer deaths was 1.45 times (SMR, 1.45; 95% confidence interval [CI], 1.45-1.46) that of the general population. Cardiovascular disease was the most common non-cancer cause of death, accounting for 30.2% of all deaths among PCa patients. Alzheimer's disease (SMR, 3.92; 95% CI, 3.85-4.00) had the highest risk of death. The mortality rate and SMR of non-cancer deaths increased with increased follow-up after diagnosis. Conclusion: Instead of the index cancer, non-cancer comorbidities were the leading cause of death among patients with PCa, and the risk of non-cancer deaths was much higher than among the general population. Clinicians and researchers should be aware of this trend to conduct timely and targeted interventions.

8.
Front Oncol ; 11: 678694, 2021.
Article in English | MEDLINE | ID: mdl-34367965

ABSTRACT

Ferroptosis is a novel form of cell death and plays a role in various diseases, especially tumors. It has been reported that ferroptosis is involved in the growth and progression of clear cell renal cell carcinoma (ccRCC); however, the specific molecular mechanisms are still unclear. In this study, we constructed a four-gene signature (FeSig) of ferroptosis-related genes via Cox regression analysis. ROC and survival analyses indicated that FeSig had good diagnostic and prognostic value. Further analysis revealed that ferroptosis was associated with tumor immunity in ccRCC. Next, weighted gene co-expression network analysis was performed to identify the potential regulatory mechanisms. Combined with correlation and survival analyses, the TAZ/WNT10B axis was identified as a tumor immune-related regulatory pathway. In conclusion, these findings suggest that ferroptosis is correlated with tumor immunity. The TAZ/WNT10B axis may be a novel biomarker and therapeutic target for immunotherapy in ccRCC.

9.
Transl Androl Urol ; 10(5): 2133-2139, 2021 May.
Article in English | MEDLINE | ID: mdl-34159094

ABSTRACT

The aim of the present study was to report the initial clinical experience of robot-assisted laparoscopic retroperitoneal leiomyosarcoma resection with inferior vena cava graft replacement. The patient was a 45-year-old female with abdominal pain. She was referred to our hospital and found to be with a retroperitoneal mass (46 mm × 45 mm). The inferior vena cava and the distal part of left renal vein were invaded by the tumor and compression was obviously seen from magnetic resonance imaging. The serum level of potassium, epinephrine, norepinephrine, cortisol, adrenocorticotropic hormone and renin angiotensin aldosterone system were all in normal ranges before the surgery. The operation was performed via a six port, robot assisted, transperitoneal laparoscopic approach. The tumor was completely resected and adherent part of inferior vena cava (approximately 5 cm) was dissected. Considering severe impairment of the great vessel, we decided to replace excised caval segment with an extended polytetrafluoroethylene graft and undertook the inferior vena cava reconstruction. The patient was discharged 11 days postoperatively with embolus in the graft. Anticoagulants were routinely administrated and the thrombus seemed to be smaller 3 months after operation. Abdominal pain was resolved and pathological examination finally confirmed that the tumor was leiomyosarcoma with negative margins free from tumor. Leiomyosarcoma of inferior vena cava present a technical challenge to surgeons. Comprehensive preparation should be made preoperatively to facilitate tumor resection and vascular management. In specific cases, robotic resection of leiomyosarcoma from great vessels and vascular repairment might be feasible options in experienced hands.

10.
Front Oncol ; 11: 649761, 2021.
Article in English | MEDLINE | ID: mdl-34084746

ABSTRACT

Renal cell carcinoma (RCC) is the most frequent malignant tumor of the kidney. 30% of patients with RCC are diagnosed at an advanced stage. Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of RCC. Currently, advanced ccRCC lacks reliable diagnostic and prognostic markers. We explored the potential of SAA1 as a diagnostic and prognostic marker for advanced ccRCC. In this study, we mined and analyzed the public cancer databases (TCGA, UALCAN and GEPIA) to conclude that SAA1 was up-regulated at mRNA and protein levels in advanced ccRCC. We further found that hypomethylation of SAA1 promoter region was responsible for its high expression in ccRCC. Receiver operating characteristic curve (ROC) indicated that high SAA1 levels could distinguish advanced ccRCC patients from normal subjects (p < 0.0001). Kaplan-Meier curve analysis showed that high SAA1 levels predicted poor overall survival time (p < 0.0001) and poor disease-free survival time (p = 0.0003). Finally, the functional roles of SAA1 were examined using a si-SAA1 knockdown method in RCC cell lines. Our results suggest that SAA1 may possess the potential to serve as a diagnostic and prognostic biomarker for advanced ccRCC patients. Moreover, targeting SAA1 may represent as a novel therapeutic target for advanced ccRCC patients.

11.
Front Genet ; 12: 609174, 2021.
Article in English | MEDLINE | ID: mdl-34122497

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is characterized by its insensitivity to chemoradiotherapy and lacks effective diagnostic and prognostic biomarkers. In this study, we focused on the role of m6A RNA methylation regulators for tumor immunity. Based on the expression of 20 m6A regulators, consensus clustering was performed to divide patients into cluster1/cluster2 and showed that there was a survival difference between the two clusters. Through cox regression analysis, five hub m6A regulators were screened to construct a risk model. Further analysis showed that the risk score was an independent prognostic factor. GSEA, GSVA, and KEGG analysis revealed that immune cell pathways played a critical role between the high risk group and low risk group. Combined with CIBERSORT and survival analysis, five hub tumor-infiltrating immune cells (TIICs) were identified for further study. Meanwhile, correlation analysis indicated that IGF2BP2 was positively associated with activated memory CD4 T cell and METTL14 was negatively correlated to the regulatory T cell. Therefore, IGF2BP2 and METTL14 were regarded as key genes. Further study verified that only METTL14 possessed good diagnostic and prognostic value. Then, GSEA exhibited that METTL14 was mainly enriched in chemokine related pathways. We also found that CCL5 was negatively correlated to METTL14 and might serve as a potential target of METTL14. In conclusion, these findings suggest that the METTL14/CCL5/Tregs axis is a potential signaling pathway for regulating tumor immunity, and might become novel therapeutic targets for ccRCC.

12.
Cancer Immunol Res ; 9(7): 838-852, 2021 07.
Article in English | MEDLINE | ID: mdl-34011528

ABSTRACT

Tumor cells can evade immune surveillance and immune killing during the emergence of endocrine therapy resistance in prostate cancer, but the mechanisms underlying this phenomenon are still unclear. Flightless I homolog (FLII) is a coregulator for transcription factors in several malignancies. Here, we have demonstrated that endocrine therapy resistance can induce an immunosuppressive prostate tumor microenvironment and immune evasion through FLII downregulation, which leads to activation of the YBX1/PD-L1 signaling pathway. FLII expression negatively correlated with expression of PD-L1 in tumors. Mechanism studies demonstrated that FLII physically interacted with YBX1 to inhibit nuclear localization of YBX1 and thereby suppress transcription of PDL1 in enzalutamide-resistant tumors. Restoration of FLII expression reversed enzalutamide resistance through activation of T-cell responses in the tumor microenvironment through inhibition of the YBX1/PD-L1 pathway. We also found that reversal of endocrine therapy resistance and immune evasion was mediated by proliferation of effector CD8+ T cells and inhibition of tumor infiltration by regulatory T cells and myeloid-derived suppressor cells. Taken together, our results demonstrate a functional and biological interaction between endocrine therapy resistance and immune evasion mediated through the FLII/YBX1/PD-L1 cascade. Combination therapy with FLII expression and endocrine therapy may benefit patients with prostate cancer by preventing tumor immune evasion.


Subject(s)
Androgen Receptor Antagonists/pharmacology , Benzamides/pharmacology , Drug Resistance, Neoplasm/genetics , Microfilament Proteins/genetics , Nitriles/pharmacology , Phenylthiohydantoin/pharmacology , Prostatic Neoplasms/drug therapy , Trans-Activators/genetics , Androgen Receptor Antagonists/therapeutic use , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Benzamides/therapeutic use , Cell Line, Tumor , Coculture Techniques , Datasets as Topic , Disease Models, Animal , Down-Regulation/immunology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/immunology , Humans , Leukocytes, Mononuclear , Male , Mice , Microfilament Proteins/metabolism , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Primary Cell Culture , Prostate/immunology , Prostate/pathology , Prostatic Neoplasms/immunology , Prostatic Neoplasms/pathology , Signal Transduction/genetics , Signal Transduction/immunology , Tissue Array Analysis , Trans-Activators/metabolism , Tumor Escape/genetics , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
13.
Aging (Albany NY) ; 12(17): 17459-17479, 2020 Sep 13.
Article in English | MEDLINE | ID: mdl-32921632

ABSTRACT

Patients with advanced renal cell carcinoma who are resistant to sunitinib currently have limited clinical options for treatment. Therefore, it is necessary to explore the biological basis of sunitinib resistance and to uncover new targets for the intervention of sunitinib resistance. In this study, we identified that LINC00160 was associated with sunitinib resistance in renal cell carcinoma. Resistant tumor cells highly expressed LINC00160 to recruit transcriptional factor TFAP2A, which bound to SAA1 promoter regions and activated its expression. On one hand, SAA1 linked to ABCB1 protein, which facilitated sunitinib cellular efflux and diminished drug accumulation. On the other hand, SAA1 stimulated JAK-STAT signaling pathways, which countered cellular survival inhibition from drug. All these regulatory networks were well organized and collaborated, thus promoting sunitinib resistance in renal cell carcinoma. LINC00160 mediates sunitinib resistance in renal cell carcinoma via SAA1 that is implicated in STAT3 activation and compound transportation, which offers an opportunity for targeted intervention and molecular therapies in the future.

14.
Oncogene ; 39(38): 6113-6128, 2020 09.
Article in English | MEDLINE | ID: mdl-32814829

ABSTRACT

VHL mutations are the most common tumorigenic lesions in clear cell renal cell carcinoma (ccRCC) and result in continued activation of the HIF/VEGF pathway and uncontrolled cancer progression. Receptor tyrosine kinase (RTK) inhibitors such as sunitinib have been demonstrated to target tumorigenic signaling pathways, delay tumor progression, and improve patient prognosis in metastatic renal cell carcinoma (mRCC). Although several mechanisms of sunitinib resistance have been reported, the solutions to overcome this resistance remain unclear. In our study, we found that increased expression of Y-box binding protein 1 (YB1, a multidrug resistance associated protein) and EphA2 (a member of the erythropoietin-producing hepatocellular (Eph) receptor family, belonging to the RTK family) mediated sunitinib resistance and mRCC exhibited a large phenotypic dependence on YB1 and EphA2. In addition, our findings confirm that YB1 promotes the invasion, metastasis and sunitinib resistance of ccRCC by regulating the EphA2 signaling pathway. Furthermore, pharmacological inhibition of EphA2 through the small molecule inhibitor ALW-II-41-27 reduced the proliferation of sunitinib-resistant tumor cells, suppressed tumor growth in vivo, and restored the sensitivity of sunitinib-resistant tumor cells to sunitinib in vitro and in vivo. Mechanistically, YB1 increases the protein levels of EphA2 by maintaining the protein stability of EphA2 through inhibition of the proteasomal degradation pathway. Collectively, our findings provide the theoretical rationale that ccRCC metastasis and RTK-directed therapeutic resistance could be prospectively and purposefully targeted.


Subject(s)
Carcinoma, Renal Cell/metabolism , Drug Resistance, Neoplasm , Kidney Neoplasms/metabolism , Receptor, EphA2/metabolism , Signal Transduction , Y-Box-Binding Protein 1/metabolism , Adult , Aged , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Movement , Computational Biology/methods , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Profiling , Gene Knockdown Techniques , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Male , Middle Aged , Models, Biological , Neoplasm Metastasis , Neoplasm Staging , Phenotype , Protein Stability , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/metabolism
15.
Crit Rev Eukaryot Gene Expr ; 30(2): 153-168, 2020.
Article in English | MEDLINE | ID: mdl-32558494

ABSTRACT

Prostate cancer (PCa) is one of the most common malignancies affecting men's health worldwide. The aim of this study is to identify key genes and their regulatory networks and evaluate the usefulness of these genes on diagnosis of and prognosis for prostate cancer. The gene expression microarray dataset GSE55945 was downloaded for analysis. The differentially expressed genes (DEGs) were accessed with RStudio. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the database for annotation, visualization and integrated discovery (DAVID) database. A protein-protein interaction network was carried out using STRING. The survival and diagnostic analysis of hub genes were conducted using the cancer genome atlas (TCGA) data. Finally, we identified 387 DEGs. GO and KEGG analyses reveled that the DEGs in PCa were mainly enriched in the bone morphogenetic protein (BMP) signaling pathway and cytochrome P450. Among 15 hub genes, we found that only a different expression level of MYH11 affected patient survival. And further gene set enrichment analysis (GSEA) showed that low expression of MYH11 was associated with the cell cycle, DNA replication, TGF-P1 signal pathway, and PCa. In conclusion, we identified 387 DEGs that may be involved in core pathways such as the BMP pathway and cytochrome P450, which may contribute to the progression of PCa. In addition, hub gene MYH11 has the potential to be a novel biomarker for diagnosing and determining the prognosis for PCa.


Subject(s)
Biomarkers, Tumor/genetics , Myosin Heavy Chains/genetics , Prognosis , Prostatic Neoplasms/genetics , Disease-Free Survival , Gene Expression Regulation, Neoplastic/genetics , Gene Ontology , Gene Regulatory Networks/genetics , Humans , Male , Prostatic Neoplasms/pathology , Protein Interaction Maps/genetics , Transcriptome
16.
Mol Ther ; 28(5): 1299-1313, 2020 05 06.
Article in English | MEDLINE | ID: mdl-32209435

ABSTRACT

Recently, cytoophidium, a nonmembrane-bound intracellular polymeric structure, has been shown to exist in various organisms, including tumor tissues, but its function and mechanism have not yet been examined. Examination of cytoophidia-assembled gene inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase (CTPS) mRNA levels showed that only IMPDH1 levels were significantly higher in the clear cell renal cell carcinoma (ccRCC). IMPDH1 was positively correlated with the metastasis-related gene Y-box binding protein 1 (YB-1) and served as an independent prognostic factor in ccRCC. Kaplan-Meier analysis indicated that patients with tumors that expressed high IMPDH1 levels had a shorter overall survival (OS) and disease-free survival (DFS). Furthermore, detection of cytoophidia by immunofluorescence staining in ccRCC tissues showed that IMPDH1-assembled cytoophidia are positively associated with tumor metastasis. Mechanistically, IMPDH1 and YB-1 formed an autoregulatory positive feedback loop: IMPDH1 maintained YB-1 protein stabilization; YB-1 induced IMPDH1 expression by binding to the IMPDH1 promoter motif. Functionally, IMPDH1-assembled cytoophidia physically interacted with YB-1 and translocated YB-1 into the cell nucleus, thus correlating with ccRCC metastasis. Our findings provide the first solid theoretical rationale for targeting the IMPDH1/YB-1 axis to improve metastatic renal cancer treatment.


Subject(s)
Carcinoma, Renal Cell/metabolism , Feedback, Physiological , IMP Dehydrogenase/metabolism , Kidney Neoplasms/metabolism , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Y-Box-Binding Protein 1/metabolism , Animals , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Nucleus/metabolism , Disease-Free Survival , Female , Humans , IMP Dehydrogenase/genetics , Kaplan-Meier Estimate , Kidney Neoplasms/pathology , Male , Mice , Mice, Nude , Middle Aged , Plasmids/genetics , RNA, Messenger/metabolism , Transfection , Tumor Burden/genetics , Xenograft Model Antitumor Assays , Y-Box-Binding Protein 1/genetics
17.
Aging (Albany NY) ; 12(2): 1808-1827, 2020 01 30.
Article in English | MEDLINE | ID: mdl-32003757

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies and lacks reliable biomarkers for diagnosis and prognosis, which results in high incidence and mortality rates of ccRCC. In this study, ISG20, HJURP, and FOXM1 were identified as hub genes via weighted gene co-expression network analysis (WGCNA) and Cox regression analysis. Samples validation showed that only ISG20 was up-regulated in ccRCC. Therefore, ISG20 was selected for further study. High ISG20 expression was associated with poor overall survival and disease-free survival. Furthermore, the expression of ISG20 could effectively differentiate ccRCC from normal tissues and was positively correlated to clinical stages. Functional experiments proved that knockdown of ISG20 expression could obviously inhibit cell growth, migration, and invasion in ccRCC cells. To find the potential mechanisms of ISG20, gene set enrichment analysis (GSEA) was performed and revealed that high expression of ISG20 was significantly involved in metastasis and cell cycle pathways. In addition, we found that ISG20 could regulate the expression of MMP9 and CCND1. In conclusion, these findings suggested that ISG20 promoted cell proliferation and metastasis via regulating MMP9/CCND1 expression and might serve as a potential biomarker and therapeutic target in ccRCC.


Subject(s)
Biomarkers, Tumor , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Exoribonucleases/genetics , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Oncogenes , Computational Biology , Disease Progression , ELAV-Like Protein 2/genetics , ELAV-Like Protein 2/metabolism , Exoribonucleases/metabolism , Gene Expression Profiling , Humans , Models, Biological , Neoplasm Grading , Neoplasm Staging , Prognosis , Proportional Hazards Models , Transcriptome
18.
J Cell Physiol ; 235(2): 1235-1246, 2020 02.
Article in English | MEDLINE | ID: mdl-31267540

ABSTRACT

Prostate cancer (PCa) is the second leading cause of death among American men. Increasing evidence has shown that long noncoding RNAs (lncRNAs) play important roles in tumorigenesis of PCa. In this study, we explored the biological functions of small nucleolar RNA host gene 12 (SNHG12) and investigated the interaction between miR-133b and SNHG12 in the progression of PCa. Data was downloaded from The Cancer Genome Atlas and Human Cancer Metastasis Database, and clinicopathological characteristics were analyzed with relapse-free survival rate. We detected SNHG12 expression level in PCa cells and tissues, and then analyzed its clinical significance, which revealed that SNHG12 has the potent to predict prognosis of PCa. Bioinformatic analysis revealed that SNHG12 was closely related to the progression of PCa and could target candidate microRNA (miR-133b). After transfecting SNHG12 silencing plasmid and miR-133b mimic/sponge, biological function assays were conducted and results illustrated that SNHG12 associated with miR-133b exerted biological effects on cancer cell growth, migration, and invasion. Direct interactions between miR-133b and SNHG12 have been found and SNHG12 acts as an oncogene to promote tumorigenesis of PCa by sponging tumor suppressor gene miR-133b.


Subject(s)
Carcinogenesis , MicroRNAs/metabolism , Prostatic Neoplasms/metabolism , RNA, Long Noncoding/metabolism , Biomarkers, Tumor , Cell Line, Tumor , Cell Movement , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasm Invasiveness , Prognosis , Prostatic Neoplasms/genetics , RNA, Long Noncoding/genetics , Up-Regulation
19.
Clin Cancer Res ; 26(6): 1516-1528, 2020 03 15.
Article in English | MEDLINE | ID: mdl-31796514

ABSTRACT

PURPOSE: Emerging evidence indicates that castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor (AR) or its V7 splice variant (AR-V7) and commonly becomes resistant to endocrine therapy. The aim of this work is to evaluate the function of a kinesin protein, KIF4A, in regulating AR/AR-V7 in prostate cancer endocrine therapy resistance. EXPERIMENTAL DESIGN: We examined KIF4A expression in clinical prostate cancer specimens by IHC. Regulated pathways were investigated by qRT-PCR, immunoblot analysis, immunoprecipitation, and luciferase reporter and chromatin immunoprecipitation (ChIP) assays. A series of functional analyses were conducted in cell lines and xenograft models. RESULTS: Examination of the KIF4A protein and mRNA levels in patients with prostate cancer showed that increased expression of KIF4A was positively correlated with androgen receptor (AR) levels. Patients with lower tumor KIF4A expression had improved overall survival and disease-free survival. Mechanistically, KIF4A and AR form an auto-regulatory positive feedback loop in prostate cancer: KIF4A binds AR and AR-V7 and prevents CHIP-mediated AR and AR-V7 degradation; AR binds the promoter region of KIF4A and activates its transcription. KIF4A promotes castration-sensitive and castration-resistant prostate cancer cell growth through AR- and AR-V7-dependent signaling. Furthermore, KIF4A expression is upregulated in enzalutamide-resistant prostate cancer cells, and KIF4A knockdown effectively reverses enzalutamide resistance and enhances the sensitivity of CRPC cells to endocrine therapy. CONCLUSIONS: These findings indicate that KIF4A plays an important role in the progression of CRPC and serves as a crucial determinant of the resistance of CRPC to endocrine therapy.


Subject(s)
Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Kinesins/antagonists & inhibitors , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Receptors, Androgen/chemistry , Aged , Aged, 80 and over , Androgen Receptor Antagonists/pharmacology , Animals , Benzamides , Cell Line, Tumor , Cell Proliferation , Databases, Genetic/statistics & numerical data , Humans , Kinesins/metabolism , Male , Mice , Mice, Nude , Middle Aged , Nitriles , Phenylthiohydantoin/pharmacology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Androgen/metabolism , Survival Rate , Xenograft Model Antitumor Assays
20.
Aging (Albany NY) ; 11(24): 12165-12176, 2019 12 16.
Article in English | MEDLINE | ID: mdl-31844035

ABSTRACT

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney, and its diagnosis and prognosis still lack reliable biomarkers. Glutathione peroxidase 1 (GPX1) has been identified to be highly expressed in a variety of human malignancies. However, few studies have studied the expression of GPX1 and its biological functions in RCC. We attempted to assess the potential of GPX1 as a promising biomarker for RCC diagnosis and prognosis. In this study, we analyzed and explored the public cancer databases (TCGA and ONCOMINE) to conclude that GPX1 is highly expressed in RCC. Meanwhile, we evaluated the expression of GPX1 at the levels of RCC cells and tissues to verify the results of the database. Moreover, high GPX1 levels were positively correlated with short overall survival time, distant metastasis, lymphatic metastasis, and tumor stage. Receiver operating characteristic curve (ROC) analysis showed that high GPX1 levels could distinguish RCC patients from normal subjects (p < 0.0001). Kaplan-Meier curve analysis revealed that high GPX1 levels predicted shorter overall survival time (p = 0.0009). Finally, the functional roles of GPX1 were examined using a GPX1 sh-RNA knockdown method in RCC cell lines. In summary, our results suggest that GPX1 may have the potential to serve as a diagnostic and prognostic biomarker for RCC patients. Moreover, targeting GPX1 may represent as a new therapeutic strategy and direction for RCC patients.


Subject(s)
Carcinoma, Renal Cell/metabolism , Glutathione Peroxidase/metabolism , Kidney Neoplasms/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Disease Progression , Female , Humans , Kidney/pathology , Kidney Neoplasms/diagnosis , Kidney Neoplasms/pathology , Male , Middle Aged , Prognosis , Glutathione Peroxidase GPX1
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