CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway.

Systemic therapy for muscle-invasive bladder cancer (BC) remains dominated by cisplatin-based chemotherapy. However, resistance to cisplatin therapy greatly limits long-term survival. Resistance to cisplatin-based chemotherapy still needs to be addressed. In this study, we established three cisplatin-resistant BC cell lines by multiple cisplatin pulse treatments. Interestingly, after exposure to cisplatin, all cisplatin-resistant cell lines showed lower reactive oxygen species (ROS) levels than the corresponding parental cell lines. Using proteomic analysis, we identified 35 proteins that were upregulated in cisplatin-resistant BC cells. By knocking down eleven of these genes, we found that after CAB39 knockdown, BC cisplatin-resistant cells were more sensitive to cisplatin. Overexpression of CAB39 had the opposite effect. Then, the knockdown of six genes downstream of CAB39 revealed that CAB39 promoted cisplatin resistance in BC through LKB1. Moreover, a key cause of cisplatin-induced cell death is damage to mitochondria and increased ROS levels. In our study, cisplatin-resistant cells exhibited higher autophagic flux and healthier mitochondrial status after cisplatin exposure. We demonstrated that the CAB39-LKB1-AMPK-LC3 pathway plays a critical role in enhancing autophagy to maintain the health of mitochondria and reduce ROS levels. In addition, the autophagy inhibitor chloroquine (CQ) can significantly enhance the killing effect of cisplatin on BC cells. Compared with gemcitabine plus cisplatin (GC), GC plus CQ significantly reduced tumor burden in vivo. In conclusion, our study shows that CAB39 counteracts the killing of cisplatin by enhancing the autophagy of BC cells to damaged mitochondria and other organelles to alleviate the damage of cells caused by harmful substances such as ROS.

ADAM12 promotes gemcitabine resistance by activating EGFR signaling pathway and induces EMT in bladder cancer

Background Gemcitabine (GEM)-based chemotherapy regimens is widely used in bladder cancer (BC) patients. However, GEM resistance may occur and result in treatment failure and disease progression. A disintegrin and metalloprotease 12 (ADAM12) plays a critical role in many cancers. However, the role of ADAM12 in GEM resistance of BC remains unclear. Methods We analyzed the relationship between ADAM12 expression and tumor characteristics using the data downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Then, we established GEM resistant BC cell lines and used quantitative real-time PCR, western blot, cell counting kit-8, immunohistochemistry, and xenograft mouse model to investigate the role of ADAM12 in GEM resistance. Results In general, ADAM12 was found to be upregulated in GEM resistant BC cells. ADAM12 knockdown increased the chemosensitivity of BC cells. We further proved that ADAM12 could promote GEM resistance by activating the epidermal growth factor receptor (EGFR) signaling pathway in BC. Furthermore, the epithelial–mesenchymal transition (EMT) phenotype was observed in GEM resistant BC cells. ADAM12 induced EMT process and promotes tumor progression in BC. Conclusion Our findings suggested that ADAM12 was a key gene for GEM resistance and positively correlated with malignancy of BC. It might serve as a novel and valuable therapeutic target for BC (AU)

ADAM12 promotes gemcitabine resistance by activating EGFR signaling pathway and induces EMT in bladder cancer.

BACKGROUND: Gemcitabine (GEM)-based chemotherapy regimens is widely used in bladder cancer (BC) patients. However, GEM resistance may occur and result in treatment failure and disease progression. A disintegrin and metalloprotease 12 (ADAM12) plays a critical role in many cancers. However, the role of ADAM12 in GEM resistance of BC remains unclear. METHODS: We analyzed the relationship between ADAM12 expression and tumor characteristics using the data downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Then, we established GEM resistant BC cell lines and used quantitative real-time PCR, western blot, cell counting kit-8, immunohistochemistry, and xenograft mouse model to investigate the role of ADAM12 in GEM resistance. RESULTS: In general, ADAM12 was found to be upregulated in GEM resistant BC cells. ADAM12 knockdown increased the chemosensitivity of BC cells. We further proved that ADAM12 could promote GEM resistance by activating the epidermal growth factor receptor (EGFR) signaling pathway in BC. Furthermore, the epithelial-mesenchymal transition (EMT) phenotype was observed in GEM resistant BC cells. ADAM12 induced EMT process and promotes tumor progression in BC. CONCLUSION: Our findings suggested that ADAM12 was a key gene for GEM resistance and positively correlated with malignancy of BC. It might serve as a novel and valuable therapeutic target for BC.

Efficacy and safety of robot-assisted laparoscopic, laparoscopic and open surgery in ureteral reimplantation: a network meta-analysis and systematic review.

To compare the efficacy and safety between open ureteral replantation (OUR), laparoscopic ureteral replantation (LUR) and robot-assisted laparoscopic ureteral replantation (RALUR). This review produced by the R3.5.0 software with "gemtc" program package and JAGS3.4.0 software based on the Bayesian model. A comprehensive search was done in databases including PubMed, Web of Science, Embase, Cochrane library, Cnki, CBM and WANFANG DATA. Studies that compared OUR, LUR OR RALUR were selected. Summary of Conclusions by ranking of Outcomes. A total of 3949 patients from 29 studies were included. The success rate in OUR, LUR and RALUR was 97.72%, 94.68% and 95.82%. The OR (95% CI) of LUR and RALUR was 0.76 (0.42,1.7) and 0.76 (0.30, 2.6), respectively, compared with OUR. The rate of complications in OUR, LUR and RALUR was 12.78%, 7.94% and 16.32%. The OR (95% CI) of LUR and RALUR was 0.28 (0.16, 0.48) and 0.61 (0.24,1.3), respectively, compared with OUR. The MD (95% CI) of LUR and RALUR for operation time was 22 (2,40) and 46 (7.5,84), respectively, compared with OUR. The MD (95% CI) of LUR and RALUR for hospital stay was - 3.6 (- 4.5, - 2.7) and - 1.1 (- 2.9, 0.58), respectively, compared with OUR. There is no significant difference in the success rates of OUR, LUR, and RALUR. RALUR and OUR has similar complication rates and time of hospital stay, while LUR has fewer complications and faster time to discharge compared to RALUR and OUR. The operative time of OUR is significantly less compared to LUR and RALUR.

Association of TERT gene polymorphisms with clinical benign prostatic hyperplasia in a Chinese Han population of the Northwest region.

BACKGROUND: To investigate the association between single nucleotide polymorphisms (rs10078761, rs12696304, rs2853669, rs16847897, rs2736100, rs10069690) of telomerase gene (TERT) and the risk clinical benign prostatic hyperplasia (BPH) in a Chinese Han population of the Northwest region. METHODS: A total of 150 BPH patients and 150 healthy older males from the northwest Chinese Han population were included in this study. The sample size for this unmatched case-control study was estimated by the look-up table method. Meanwhile, the general information and disease data of patients were collected. Age was only collected in healthy control subjects for statistical correction. Genotypes were detected using a multiplex PCR + ligase detection reaction (LDR). Typing results and clinical data were statistically analyzed using multiple linear regression and logistic regression. Pearson correlation was used for Hardy-Weinberg equilibrium. RESULTS: The included population is in Hardy-Weinberg equilibrium. There was no significant association between SNP and the risk of BPH by correlation analysis. However, 4 haplotypes (TCTGGT, TCTGTC, TGCCTC, and TGTGTC) were identified as risk factors of BPH by haplotype analysis. The SNP rs2853669 is an independent risk factor for smooth muscle type of hyperplasia. Besides, rs2736100, rs10078761, and rs10069690 which are in linkage disequilibrium are associated with the severity of BPH. CONCLUSIONS: Polymorphism of the TERT gene determines the different disease development and pathological manifestations of BPH in the Chinese Han population the Northwest region.

Diagnostic and prognostic role of BTA, NMP22, survivin and cytology in urothelial carcinoma.

BACKGROUND: Cytology is a recommended noninvasive urine test for the detection and surveillance of bladder cancer and upper-tract urothelial carcinoma. It is however characterized by poor sensitivity in low-grade tumors. This study aims to determine the diagnostic and prognostic role of BTA, BTA-stat, NMP22, and Survivin. METHODS: Urine samples were collected from a total of 105 patients (bladder cancer (n=61), upper-tract urothelial carcinoma (n=44), and controls (n=52). The samples were directly assessed using cytology, BTA-stat (Qualitative test), BTA (chemiluminescence test), NMP22 (Qualitative test), and Survivin (enzyme-linked immunosorbent assay). Cancer progression and recurrence were assessed after a median follow-up of 32 months (4-47 months). Univariate and multivariate analyses were performed using Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: The triple combination of Survivin + BTA + Cytology was the most promising model for discriminating bladder cancer or upper-tract urothelial carcinoma from controls (UTUC group: the area under the curve value 0.97, sensitivity 86%, specificity 96%; BC group: the area under the curve value 0.86 sensitivity 67%, specificity 96%). Univariate survival analysis, showed Cytology (P=0.02; HR=5.35) and Survivin (HR=3.24; P=0.03) to have a significant association with the progression-free survival, while Survivin (HR=4.15; P=0.04) was statistically associated with cancer-specific survival in the bladder cancer group. The multivariable analysis did not show any of these markers as independent prognostic factors. CONCLUSIONS: These biomarkers showed a higher sensitivity than cytology, but a poorer specificity. All biomarkers exhibited good diagnostic performance in both bladder cancer and upper-tract urothelial carcinoma. Combining Survivin + BTA + Cytology was superior to the use of a single marker or combining other biomarkers.

[Genetic polymorphisms in benign prostatic hyperplasia: Progress in studies].

BPH is a common and frequently-occurring disease of the urinary system. The single nucleotide polymorphism (SNP) is the most common mutation in the genome and has an impact on the pathogenesis, progression and prognosis of BPH in different populations. We reviewed the published literature on BPH-related SNPs, expounded the roles of different SNPs in the development and progression of BPH, and summarized the current status and existing problems in the related studies and the prospects of its clinical application.

[Methods for androgen receptor splice variant-7 detection: Advances in studies].

Treatment strategies for castration-resistant prostate cancer (CRPC) mainly include taxane-based chemotherapy, novel endocrine therapy, and immunotherapy with radium 233. At present, there have been no clinical biomarkers for the prediction of the therapeutic effects and guidance with the medication in the treatment of CRPC. A large number of studies have shown that the androgen receptor splice variant-7 (AR-V7) is associated with the resistance to abiraterone and enzalutamide but not to Taxanes. So AR-V7 is expected to become a clinically useful tumor marker for predicting the clinical efficacy and guiding medication selection. However, the methods for the detection of AR-V7 present a challenge before its clinical application. This review introduces different methods of AR-V7 detection in the existing studies and looks forward to the clinical application of AR-V7 in order to move AR-V7 from the bench to the bedside.

Helicobacter pylori infection enhances heparanase leading to cell proliferation via mitogen­activated protein kinase signalling in human gastric cancer cells.

Helicobacter pylori (H. pylori) infection is the most important factor in the development of gastric cancer. Heparanase (HPA) is involved in tissue remodelling and cell migration, which leads to inflammation and tumour metastasis. The current study aimed was to explore whether a H. pylori infection leads to an increase in the level of HPA in gastric cancer and to investigate the specific mechanism underlying this association. Reverse transcription­polymerase chain reaction and western blotting were used to detect HPA mRNA and protein expression, respectively, in MKN­45 cells infected by H. pylori, MKN­45 cells treated with the mitogen­activated protein kinase (MAPK) inhibitor SB203580 and MKN­45 cells transfected with small interfering RNA against HPA. MAPK and nuclear factor (NF)­κB expression were determined by western blotting in the different cells group. Cell Counting Kit­8, Transwell method, and Scratch and Clone tests were conducted to detect proliferation, invasion, migration and clone formation ability of gastric cancer cells. It was demonstrated that HPA mRNA expression was highest at 6 h post­infection, while the expression of the HPA protein was highest at 24 h post­infection in H. pylori­infected gastric cancer cells. Furthermore, it was demonstrated that H. pylori infection significantly enhanced the expression of MAPK and NF­κB in MKN­45 cells at the mRNA and protein levels. SB203580 significantly decreased the expression of NF­κB in MKN­45 cells infected with H. pylori. Exposure to SB203580 also significantly decreased the expression of HPA. In the present study, the inhibition of HPA significantly lowered H. pylori­induced cell proliferation, suggesting that H. pylori infection induces the proliferation of gastric cancer cells through the upregulation of HPA. Taken together, the results of the present study demonstrated that HPA serves a critical role in the development of gastric cancer in H. pylori­infected cells, which may be an important mechanism through which H. pylori infection leads to gastric cancer. In addition, H. pylori infection promotes the proliferation, invasion and metastasis of gastric cancer cells through the upregulation of HPA expression, and this is likely mediated via the MAPK and NF­κB signalling pathways. These data suggest that HPA can be used as a therapeutic target in gastric cancer, particularly in cases induced by H. pylori infection.