[Bioinformatics-based identification of the key genes associated with prostate cancer].

OBJECTIVE: To identify the key genes associated with the pathogenesis of PCa using the bioinformatics approach for a deeper insight into the molecular mechanisms underlying the development and progression of PCa. METHODS: The microarray datasets GSE70770, GSE32571 and GSE46602 were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEG) in the normal prostate tissue and PCa were identified with the GEO2R tool, followed by functional enrichment analysis. A protein-protein interaction (PPI) network of DEGs was constructed by STRING and visualized with the Cytoscape software. RESULTS: A total of 235 DEGs were identified, including 61 up-regulated and 174 down-regulated genes, which were mainly enriched in focal adhesion kinase (FAK), ECM-receptor interaction, and other signaling pathways. From the PPI network were screened out 12 highly connected hub genes, including MYH11, TPM1, TPM2, SMTN, MYL9, VCL, ACTG1, CNN1, CALD1, ACTC1, MYLK and SORBS1, which were shown by hierarchical cluster analysis to be capable of distinguishing prostate cancer from non-cancer tissue. CONCLUSIONS: A total of 235 DEGs and 12 hub genes were identified in this study, which may contribute to a further understanding of the molecular mechanisms of the development and progression of PCa, and provide new candidate targets for the diagnosis and treatment of the malignancy.

Mitochondrial E3 ubiquitin ligase 1 promotes autophagy flux to suppress the development of clear cell renal cell carcinomas.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors in the urinary system. Surgical intervention is the preferred treatment for ccRCC, but targeted biological therapy is required for postoperative recurrent or metastatic ccRCC. Autophagy is an intracellular degradation system for misfolded/aggregated proteins and dysfunctional organelles. Defective autophagy is associated with many diseases. Mul1 is a mitochondrion-associated E3 ubiquitin ligase and involved in the regulation of divergent pathophysiological processes such as mitochondrial dynamics, and thus affects the development of various diseases including cancers. Whether Mul1 regulates ccRCC development and what is the mechanism remain unclear. Histochemical staining and immunoblotting were used to analyze the levels of Mul1 protein in human renal tissues. Statistical analysis of information associated with tissue microarray and The Cancer Genome Atlas (TCGA) database was conducted to show the relationship between Mul1 expression and clinical features and survival of ccRCC patients. Impact of Mul1 on rates of cell growth and migration and autophagy flux were tested in cultured cancer cells. Herein we show that Mul1 promoted autophagy flux to facilitate the degradation of P62-associated protein aggresomes and adipose differentiation-related protein (ADFP)-associated lipid droplets and suppressed the growth and migration of ccRCC cells. Levels of Mul1 protein and mRNA were significantly reduced so that autophagy flux was likely blocked in ccRCC tissues, which is potentially correlated with enhancement of malignancy of ccRCC and impairment of patient survival. Therefore, Mul1 may promote autophagy to suppress the development of ccRCC.

Metastatic prostate cancer-associated P62 inhibits autophagy flux and promotes epithelial to mesenchymal transition by sustaining the level of HDAC6.

BACKGROUND: P62 (also named sequestosome-1, SQSTM1) is involved in autophagy regulation through multiple pathways. It interacts with autophagosomes-associated LC3-II and ubiquitinated protein aggregates to engulf the aggregates in autophagosomes, interacts with HDAC6 to inhibit its deacetylase activity to maintain the levels of acetylated α-tubulin and stabilities of microtubules to enhance autophagosome trafficking, and regulates autophagy initiation and cell survival. We performed immunohistochemistry staining of P62 in prostate tissues from prostate cancer patients and found that levels of P62 in patients with prostate adenocarcinomas (PCA) are significantly higher than those in patients with benign prostate hyperplasia (BPH). High levels of P62 predict high tumor grade and high intensity of metastasis. METHODS: We created prostate cancer cell lines stably overexpressing P62 and then suppress the expression of P62 in the cell line stably overexpressing P62 with CRISPR technology. Cell proliferation assay with crystal violet, cell migration assay, cell invasion assay, Western blot analysis, and confocal fluorescent microscopy were conducted to test the impact of altered levels of P62 on the growth, migration, invasion, epithelial-to-mesenchymal transition, autophagy flux, HDAC6 activity, and microtubular acetylation of cancer cells. RESULTS: P62 increased the levels of HDAC6 and reduced the acetylation of α-tubulin and the stability of microtubules. Consequently, high levels of P62 caused a promotion of epithelial-to-mesenchymal transition in addition to an impairment of autophagy flux, and further led to an enhancement of proliferation, migration, and invasion of prostate cancer cells. CONCLUSION: P62 promotes metastasis of PCA by sustaining the level of HDAC6 to inhibit autophagy and promote epithelial-to-mesenchymal transition.

SOX4 induces tumor invasion by targeting EMT-related pathway in prostate cancer.

SOX4 (sex-determining region Y-related high-mobility group box 4) is associated with tumor progression and poor clinical outcome in several cancers. This study aims to evaluate whether SOX4 affects the biological behaviors of prostate cancer and further elucidate whether this effect works through the epithelial-mesenchymal transition pathway. We investigated the expression of SOX4 in a series of prostate cancer tissues and adjacent noncancerous tissues, as well as in a panel of prostate cancer cell lines. Cell proliferation, migration, and invasion were evaluated in SOX4 knockdown prostate cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assay. Our results showed that the expression of SOX4 was remarkably upregulated both in prostate cancer tissues and in cell lines. Knockdown of SOX4 repressed the ability of cell proliferation and migration of DU145 cells. Moreover, inhibition of SOX4 could reverse the epithelial-mesenchymal transition processes through upregulation of E-cadherin and downregulation of vimentin. This study provided evidence that SOX4 could serve as a potential therapeutic target in prostate cancer.

The roles of long non­coding RNAs in renal cell carcinoma (Review).

Long non-coding RNAs (lncRNAs) are involved in the gene expression regulation and usually play important roles in various human cancers, including the renal cell carcinoma (RCC). Dysregulation of certain lncRNAs are associated with the prognosis of patients with RCC. In the present review, several recently studied lncRNAs were discussed and their critical roles in proliferation, migration, invasion, apoptosis and drug resistance of renal cancer cells were revealed. The research on lncRNAs further increases our understanding on the development and progression of RCC. It is suggested that lncRNAs can be used as biomarkers or therapeutic targets for diagnosis or treatment of renal cancer.

Association of ulcerative colitis and acute gastroenteritis with prostate specific antigen: results from National Health and Nutrition Examination Survey from (2009 to 2010) and Mendelian randomization analyses.

Background: An increasing number of studies have demonstrated that gastrointestinal inflammation may increase prostate cancer risk and raise the prostate-specific antigen (PSA) level. However, the association between ulcerative colitis (UC) and acute gastroenteritis (AGE) with PSA remains unclear and complicated. Herein, we evaluated the relationship between UC and AGE with PSA concentration using the National Health and Nutrition Examination Survey (NHANES) database and Mendelian randomization (MR) analyses. Materials and methods: A total of 1,234 participants fit into the study after conducting the screening based on the NHANES survey conducted from 2009 to 2010. UC and AGE were the independent variables, and PSA was the dependent variable. Weighted multiple linear regressions were utilized to estimate the association of UC and AGE with PSA concentration. To detect the causal relationship between UC and AGE with PSA, a two-sample Mendelian randomized analysis was conducted. Results: After controlling for all covariates, PSA (log2 transform) concentrations in the UC group were increased by 0.64 (0.07, 1.21). AGE was not independently associated with PSA levels after adjusting potential confounders. In patients with coronary artery disease, AGE promotes elevated PSA (log2 transform) concentrations (ß = 1.20, 95% CI: 0.21-2.20, p < 0.001). Moreover, an IVW MR analysis indicated that genetically predicted UC was associated with increased PSA, and that AGE was not associated with PSA. Conclusion: This study indicated that a positive causal association exists between UC and the PSA level. However, there is no evidence to support the relationship between AGE and the PSA level.

The tuberous sclerosis complex-associated giant renal angiomyolipoma: A case report.

Renal angiomyolipoma (RAML), also referred to as renal hamartoma, is a rare benign tumor. There are two types of RAML, which include the tuberous sclerosis complex (TSC)-associated type and the sporadic type. TSC is an autosomal dominant genetic disease characterized by the growth of benign tumors in the skin, brain, kidneys, lung and heart. TSC leads to organ dysfunction, as the normal parenchyma is replaced by a variety of cell types. The current study presents a case of giant RAML in a 20-year-old female, who was hospitalized for epileptic seizures. Large abdominal lesions were detected during hospitalization. Subsequently, she underwent open mass resection and right kidney partial resection. Postoperative pathological examination confirmed that the mass was angiomyolipoma.

Bladder Paraganglioma: Three Cases Report and Literature Review.

BACKGROUND: Bladder paraganglioma (BPG) is one of the rare neuroendocrine neoplasms that develops from neural crest cells. It categorizes into functional and non-functional types based on the catecholamines secretion. Currently, functional BPG is predicted in advance based on signs and symptoms of catecholamine excess, such as hypertension and "micturition attacks". However, it is often overlooked because of its rareness. Misdiagnosis of a functional tumor may increase the risk of surgical intervention. CASE PRESENTATION: We reported 3 cases of BPG that they were admitted to the hospital due to abdominal pain or gross hematuria. Computed tomography (CT) scans showed space-occupying lesions in the bladders with diameters less than 3cm. There were no typical catecholamine excess symptoms before surgical intervention. Postoperative pathology confirmed BPG after removal of the tumor. We also analyze 69 cases of BPG that has been reported and found that 78.0% cases were functional among the tumors larger than 3cm. CONCLUSION: Bladder tumors larger than 3cm in diameter can serve as an additional predictor of functional BPG. Patients who are suspected should undergo magnetic resonance imaging (MRI) scans, 123/131 metaiodobenzylguanidine (MIBG) scan, and have their catecholamine levels tested. Once the diagnosis is confirmed, patients should be started on fluid replacement therapy and adrenergic blockade to abate the disorders associated with catecholamine excess.

Long non-coding RNAs in prostate tumorigenesis and therapy (Review).

Prostate cancer (PCa) is one of the most frequently diagnosed malignancy. Although there have been many advances in PCa diagnosis and therapy, the concrete mechanism remains unknown. Long non-coding RNAs (lncRNAs) are novel biomarkers associated with PCa, and their dysregulated expression is closely associated with risk stratification, diagnosis and carcinogenesis. Accumulating evidence has suggested that lncRNAs play important roles in prostate tumorigenesis through relevant pathways, such as androgen receptor interaction and PI3K/Akt. The present review systematically summarized the potential clinical utility of lncRNAs and provided a novel guide for their function in PCa.

Erratum: MicroRNA-429 inhibits cancer cell proliferation and migration by targeting AKT1 in renal cell carcinoma.

[This corrects the article DOI: 10.3892/mco.2019.1940.].

MicroRNA-429 inhibits cancer cell proliferation and migration by targeting AKT1 in renal cell carcinoma.

MicroRNAs (miRNAs or miR) serve as oncogenes and tumor suppressors. In a previous study, it was revealed that has-miRNA-429 (miR-429) is a tumor suppressor in 786-O renal cell carcinoma (RCC) cells. However, its mechanism in RCC remains to be determined. The present study aimed to explain the functional role and mechanism of miR-429 in RCC pathogenesis. Luciferase reporter assays demonstrated that miR-429 overexpression reduced the transcriptional activity of AKT serine/threonine kinase 1 (AKT1). Reverse transcripton-quantitative (RT-q) PCR and western blot analysis indicated that the mRNA and protein expression of AKT1 was downregulated in 786-O RCC cell lines when miR-429 was overexpressed, indicating that miR-429 may directly target AKT1 in RCC. Therefore, miR-429 overexpression enhanced the inhibition of tumor size and weight in nude mice in vivo. The current study indicated that the novel miR-429-regulated pathway may provide insights into RCC oncogenesis and metastasis.

p62 promotes proliferation, apoptosis­resistance and invasion of prostate cancer cells through the Keap1/Nrf2/ARE axis.

Prostate cancer poses a public health threat to hundreds of people around the world. p62 has been identified as a tumor suppressor, however, the mechanism by which p62 promotes prostate cancer remains poorly understood. The present study aimed to investigate whether p62 promotes proliferation, apoptosis resistance and invasion of prostate cancer cells via the Kelch­like ECH­associated protein 1/nuclear factor erytheroid­derived 2­like 2/antioxidant response element (Keap1/Nrf2/ARE) axis. Immunohistochemical staining and immunoblotting were performed to determine the protein levels. Rates of proliferation, invasion and apoptosis of prostate cancer cells were assessed using an RTCA system and flow cytometric assays. Levels of reactive oxygen species (ROS) were assessed using Cell ROX Orange reagent and mRNA levels of Nrf2 target genes were detected by qRT­PCR. It was revealed that p62 increased the levels and activities of Nrf2 by suppressing Keap1­mediated proteasomal degradation in prostate cancer cells and tissues, and high levels of p62 promoted growth of prostate cancer through the Keap1/Nrf2/ARE system. Silencing of Nrf2 in DU145 cells overexpressing p62 led to decreases in the rate of cell proliferation and invasion and an increase in the rate of cell apoptosis. p62 activated the Nrf2 pathway, promoted the transcription of Nrf2­mediated target genes and suppressed ROS in prostate cancer. Therefore, p62 promoted the development of prostate cancer by activating the Keap1/Nrf2/ARE pathway and decreasing p62 may provide a new strategy to ameliorate tumor aggressiveness and suppress tumorigenesis to improve clinical outcomes.

Elevated expression of PTCD3 correlates with tumor progression and predicts poor prognosis in patients with prostate cancer.

Pentatricopeptide repeat domain protein 3 (PTCD3) is a mitochondrial RNA­binding protein that serves a role in mitochondrial translation. PTCD3 was originally reported as an oncogene that is involved in breast cancer and lymphoma. However, the expression and function of PTCD3 in prostate cancer (PCa) are unknown. Therefore, the aim of the present study was to investigate the expression of PTCD3 and its clinical significance in PCa. Immunohistochemistry and dataset analyses revealed that PTCD3 protein expression levels were enhanced in human PCa tissues and mouse PCa models. PTCD3 expression levels were positively correlated with advanced PCa pathological grade and clinical stage. Additionally, PTCD3 mRNA expression was positively correlated with tissue malignancy, high Gleason score and distant metastasis in The Cancer Genome Atlas dataset. Kaplan­Meier analysis revealed that high PTCD3 levels can predict the increased biochemical recurrence (BCR)­free survival in all patients with or without metastasis. The overexpression of PTCD3 could be used as an independent prognostic marker of poor BCR­free survival. Immunofluorescence and western blot analysis in human PCa cell lines further confirmed that PTCD3 levels were associated with the hormone independence of PCa. Therefore, the present study revealed that PTCD3 levels may serve as a novel biomarker for PCa prognosis.

Design of Friction Stir Spot Welding Tools by Using a Novel Thermal-Mechanical Approach.

A simple thermal-mechanical model for friction stir spot welding (FSSW) was developed to obtain similar weld performance for different weld tools. Use of the thermal-mechanical model and a combined approach enabled the design of weld tools for various sizes but similar qualities. Three weld tools for weld radii of 4, 5, and 6 mm were made to join 6061-T6 aluminum sheets. Performance evaluations of the three weld tools compared fracture behavior, microstructure, micro-hardness distribution, and welding temperature of welds in lap-shear specimens. For welds made by the three weld tools under identical processing conditions, failure loads were approximately proportional to tool size. Failure modes, microstructures, and micro-hardness distributions were similar. Welding temperatures correlated with frictional heat generation rate densities. Because the three weld tools sufficiently met all design objectives, the proposed approach is considered a simple and feasible guideline for preliminary tool design.

Bellini's duct carcinoma: A report of two cases and a review of the literature.

Bellini's duct carcinoma (BDC) is a rare and aggressive variant of renal cell carcinoma that possesses an extremely poor prognosis. The greater the grade or stage of disease, the poorer the prognosis tends to be. This study presents two cases of BDC; one case of low grade BDC and one case of high grade BDC in a 47-year-old male and 74-year-old female, respectively. The 47-year-old male patient presented with painless gross hematuria, which had lasted for 3 weeks and subsequently underwent purely laparoscopic nephroureterectomy. After 4-years of follow-up, the patient remained disease-free. By contrast, a right renal tumor was identified in the 74-year-old female patient during a routine examination. Radical right nephrectomy and lymph node dissection were performed, however, 10 months after surgery the patient succumbed due to wide-spread metastasis. The two cases reported in the present study not only represent excellent examples of the disease spectrum, but also act as a reminder of the possibility of detecting BDC in an early stage of disease. Therefore, the epidemiology of BDC has been discussed, and the aggressive growth pattern of BDC has been presented in terms of signs, symptoms and imaging examinations, including ultrasonography, computed tomography (CT), angiography and single photon emission CT, in the early stage of disease.

Xp11.2 translocation renal cell carcinoma with multiple bone metastases: A case report.

Xp11.2 translocation/transcription factor enhancer 3 (TFE3) fusion gene associated with renal cell carcinoma (Xp11.2 translocation RCC) is rare and occurs predominantly in children and adolescents. The current study reports the case of a 14-year-old male with Xp11.2 translocation RCC, who presented with chest pain that had persisted for 1 month. A solid neoplasm was located in the left kidney of the patient. Contrast-enhanced computed tomography revealed the presence of a solid mass in the kidney, with uneven enhancement. Destruction of multiple bones was also observed. The patient was treated with a radical nephrectomy. The pathological examination of the tumor revealed that the tumor cells contained an eosinophilic cytoplasm in the renal interstitial tissue. Immunohistochemistry revealed that the tumor cells expressed P504S, cluster of differentiation 10, pan-cytokeratin, vimentin and TFE3. In conclusion, Xp11.2 translocation RCC is a rare type of kidney cancer. Diagnosing this disease prior to surgery is challenging, and providing a definite diagnosis requires histopathological and immunohistochemical examination, while genetic analysis may also be required.

MicroRNA-20b-5p functions as a tumor suppressor in renal cell carcinoma by regulating cellular proliferation, migration and apoptosis.

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and is associated with a poor prognosis due to a lack of early­warning signs, protean clinical manifestations, and resistance to radiotherapy and chemotherapy. Recently, increasing evidence has suggested that microRNAs (miRNAs) are involved in the proliferation, invasion and apoptosis of various types of human cancer cells. In a previous study, miRNA expression profiles from renal cell carcinoma (RCC) revealed that expression of miR­20b­5p was significantly downregulated in RCC tissues. The aim of this study was to investigate the expression and functional significance of miR­20b­5p in RCC. The expression of miR­20b­5p was quantified in 48 paired RCC tissues and cell lines, and compared with adjacent normal tissues and the 293T cell line by reverse transcription­quantitative polymerase chain reaction. The functional impact of miR­20b­5p on cell proliferation, cell migration and apoptosis in the 786­O and ACHN RCC cell lines, was determined by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a scratch assay and flow cytometry. To the best of our knowledge, the present study was the first to reveal that miR­20b­5p was downregulated in RCC tissues and cell lines. It also demonstrated that upregulation of miR­20b­5p inhibited cellular migration and proliferation, and promoted cellular apoptosis, suggesting that miR­20b­5p functioned as a potential tumor suppressor. However, further studies are required to fully determine the effects of miR­20b­5p and the miR­20b­5p­mediated molecular pathway in RCC and other types of cancer. In conclusion, these results imply that miR­20b­5p may be a biomarker for early detection and prognosis prediction, as well as a therapeutic target for RCC.

Tumor suppressive microRNA­429 regulates cellular function by targeting VEGF in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the predominant and most aggressive type of kidney malignancy, however, the mechanism underlying its carcinogenesis remains to be elucidated. The present study aimed to determine the expression and function of microRNA (miR)­429 in ccRCC carcinogenesis. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to detect the expression of miR­429 in ccRCC specimens. Following transfection of miR­429 synthetic mimics, the expression of miR­429 was examined and cell proliferation, cell migration, apoptosis and luciferase assays were conducted in ccRCC cell lines. The results demonstrated that expression of miR­429 was decreased in ccRCC cells. In addition, upregulation of miR­429 by transfection of mimics reduced cellular proliferation and migration, and induced apoptosis in ACHN and 786­0 cell lines. Furthermore, miR­429 decreased the 3'UTR luciferase activity of vascular endothelial growth factor (VEGF) and c­MYC, and RT­qPCR analysis demonstrated that the cancer cells transfected with miR­429 mimics exhibited decreased expression of VEGF, but not c­MYC. To the best of our knowledge, the present study was the first to reveal that downregulated miR­429 functioned as a tumor suppressor by restraining cellular proliferation and migration, and inducing apoptosis, as well as targeting VEGF in ccRCC cells.

miR-362-3p targets nemo-like kinase and functions as a tumor suppressor in renal cancer cells.

MicroRNAs (miRNAs) have been demonstrated to exhibit abnormal expression patterns in various types of human cancer. The aim of the present study was to identify a novel tumor suppressor microRNA (miR) and investigate its physiological function and mechanism in renal cell carcinoma (RCC). The expression levels of miRNA (miR)­362­3p expres were measured in 47 pairs of RCC and adjacent normal tissue samples, using reverse transcription-quantitative polymerase chain reaction analysis. In addition, miR­362­3p was transfected into renal cancer cells to investigate its role in the regulation of cell proliferation, migration, invasion, apoptosis and cell cycle. Identification of the target gene of miR­362­3p was performed using luciferase reporter assays and western blot analyses. The results demonstrated that the expression levels of miR­362­3p were downregulated in the RCC tissue samples, compared with the adjacent normal tissue samples. The upregulation of miR­362­3p using a synthesized mimic suppressed the proliferation, migration and invasion of the renal cancer cells, and induced cell apoptosis and G1 phase arrest. Further experiments demonstrated that the overexpression of miR­362­3p resulted in decrease expression levels of nemo-like kinase. These results suggested that miR-362-3p functions as a tumor suppressor in RCC, and may serve as a potential molecular target in the treatment of RCC.

Tumor suppressive miR-196a is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma.

Certain microRNAs (miRs) are implicated in the genesis and progression of various cancers by regulating multiple cellular processes, including apoptosis, proliferation and migration. The aim of the present study was to explore the functions of miR­196a in renal cell carcinoma (RCC). RCC and paired normal tissues we assessed for miR­196a expression by reverse-transcription quantitative PCR. Furthermore, the effects of miR­196a on renal cell proliferation, apoptosis and migration were determined using an MTT assay, flow cytometry and a scratch wound assay following restoration of miR-196a with synthetic mimics. miR­196a was found to be significantly downregulated in RCC tissues compared with that in normal tissues (P<0.05). In addition, miR­196a suppressed cell proliferation, apoptosis and migration of the 786­O and ACHN RCC cell lines. To the best of our knowledge, the present study was the first to report this tumor suppressor role of miR­196a in RCC. The results indicated that miR­196a may be a potential diagnostic biomarker for RCC and that transfection of miR-196a mimics may represent a novel treatment strategy for RCC.