Deubiquitinating enzyme USP46 suppresses the progression of hepatocellular carcinoma by stabilizing MST1.

The deubiquitinating enzyme USP46 (ubiquitin-specific protease 46) is implicated in various cancers. However, its role and regulatory mechanism in HCC (hepatocellular carcinoma) are still unknown. In this study, we showed that USP46 is downregulated in HCC tissues and that low USP46 levels are associated with poor prognosis in HCC patients. In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo. Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1. Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression. Mechanistically, USP46 promotes the degradation of YAP1 by increasing expression of MST1, and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression. Finally, we demonstrated that USP46 stabilizes the MST1 protein by directly binding to it and decreasing its ubiquitination. Taken together, our results demonstrated that USP46 may be a novel tumor suppressor in HCC. Moreover, USP46 acts as a deubiquitinating enzyme of MST1 to potentiate MST1 kinase activity to suppress tumor growth and metastasis, indicating that USP46 activation may represent a potential treatment strategy for HCC.

Dysregulated Serum Cytokine Production in Pediatric Patients with ß-Thalassemia Major.

ß-Thalassemia major (ß-TM) is an inherited disorder of hemoglobin (Hb) production, which can cause severe anemia. A compromised immune system has been observed in patients with ß-TM, whereas cytokines have a major role in immune modulation. Interleukin-4 (IL-4), IL-8, IL-13 and transforming growth factor-ß (TGF-ß) are critical in initiating pro-inflammatory responses, and the serum levels of those cytokines may be involved in the pathophysiology of ß-thalassemia (ß-thal). To assess this hypothesis, we studied 23 pediatric patients with ß-TM by measuring serum levels of IL-4, IL-8, IL-13 and TGF-ß, as well as evaluating infection frequency per year, total number of transfusions and serum ferritin (SF) levels, together with age-matched healthy controls. We found that patients with ß-thal had higher IL-8, IL-13 and TGF-ß concentrations than normal controls, whereas markedly decreased serum IL-4 level was documented in patients with ß-TM. Serum IL-4 level of ß-thal patients showed a negative significant correlation with infection frequency, total number of transfusions and SF levels. On the contrary, serum levels of IL-8, IL-13 and TGF-ß exerted a positive relationship with those clinical parameters. Taken together, our study implies that dysregulated cytokine profile might contribute to iron overloads and impair immune cell functions, thus serving as useful biomarkers for diagnosis and evaluation of ß-TM in the future. Our study sheds new light on the pathogenesis of ß-TM.

Partial nephrectomy provides equivalent oncologic outcomes and better renal function preservation than radical nephrectomy for pathological T3a renal cell carcinoma: A meta-analysis.

PURPOSE: Radical nephrectomy (RN) is the standard surgical type for pathological stage T3a (pT3a) renal cell carcinoma (RCC). Recently, some studies have suggested equivalence between partial nephrectomy (PN) and RN for oncologic control and have shown the benefits of PN for better renal function. We conducted this meta-analysis to assess oncologic outcomes, perioperative outcomes and renal function between two groups among patients with pT3a RCC. MATERIALS AND METHODS: PubMed, Scopus, Web of Science, Science Direct, Ovid MEDLINE, The Cochrane Library, Embase and Google Scholar were searched for eligible articles. The endpoints of the final analysis included overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), surgical complications, operative time, estimated blood loss (EBL), serum creatinine and estimated glomerular filtration rate (eGFR). RESULTS: Twelve studies of moderate to high quality, including 14.152 patients, were examined. PN showed superiority for renal functional preservation, providing higher eGFR (WMD=12.48mL/min; 95%CI: 10.28 to 14.67; P < 0.00001) and lower serum creatinine (WMD=-0.31mg/dL; 95%CI: -0.40 to -0.21; P < 0.00001). There were no significant differences between PN and RN regarding operative time, EBL, surgical complications, OS, RFS and CSS. Despite inherent selection bias, most pooled estimates were consistent in sensitivity analysis and subgroup analysis. More positive margins were found in the PN group (RR=2.42; 95%CI: 1.25-4.68; P=0.009). CONCLUSIONS: PN may be more suitable for treating pT3a RCC than RN because it provides a similar survival time (OS or RFS) and superior renal function. Nevertheless, this result is still disputed, and more high-quality studies are required.

Long non-coding RNA CASC2 regulates Sprouty2 via functioning as a competing endogenous RNA for miR-183 to modulate the sensitivity of prostate cancer cells to docetaxel.

Prostate cancer (PC) is the most common cancer in men; however, limited effect is obtained due to the therapy resistance. CASC2 acts as a tumor suppressor in human malignancies serving as a ceRNA for miRNAs; Sprouty2 (SPRY2), a key antagonist of RTK signaling, also serves as a tumor suppressor. Herein, CASC2 and SPRY2 expression was down-regulated in PC tissues and cell lines; the overexpression of CASC2 and SPRY2 could suppress PC cell proliferation, promote PC cell apoptosis, and enhance the sensitivity of PC cells to docetaxel. CASC2 positively regulated SPRY2 expression and inhibited downstream extracellular regulated protein kinases (ERK) signaling activation through SPRY2. By using online tools, miR-183 might be a direct target of CASC2, and might simultaneously bind to the 3'UTR of SPRY2. The direct binding between CASC2, miR-183 and SPRY2 was then validated; miR-183 inhibition enhanced the cytotoxicity of docetaxel on PC cells, which could be partially attenuated by SPRY2 knockdown. In summary, CASC2 competes with SPRY2 for miR-183 binding to rescue the expression of SPRY2 in PC cells, thus enhancing the sensitivity of PC cells to docetaxel through SPRY2 downstream ERK signaling pathway; CASC2 and SPRY2 might be novel adjuvants for docetaxel-based chemotherapy for PC.

Pazopanib has equivalent anti-tumor effectiveness and lower Total costs than Sunitinib for treating metastatic or advanced renal cell carcinoma: a meta-analysis.

BACKGROUND: Sunitinib and pazopanib are extensively used as first-line treatment of metastatic renal cell carcinoma (mRCC). We performed this meta-analysis to assess the anti-tumor effectiveness, toxicity, and total costs of the two drugs among patients with mRCC/advanced RCC (aRCC). MATERIALS AND METHODS: PubMed, ScienceDirect, Scopus, Web of Science, Ovid MEDLINE, the Cochrane Library, Embase, and Google Scholar were searched to obtain eligible articles. The endpoints included progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and per-patient-per-month (PPPM) costs. RESULTS: We included 14 medium- to high-quality studies. Both drugs were valid for mRCC/aRCC, with equivalent PFS (hazard ratio (HR) =1.06, 95% confidence interval [CI]: 0.98-1.15, P = 0.13), OS (HR = 0.92, 95% CI: 0.79-1.07, P = 0.29), objective response rate (ORR, risk ratio (RR) =1.03, 95% CI: 0.93-1.13, p = 0.58), and disease control rate (DCR, RR = 1.03, 95% CI: 0.94-1.22, P = 0.54). Sunitinib had more dosage reductions and higher PPPM (weighted mean difference = - 1.50 thousand US dollars, 95% CI: - 2.27 to - 0.72, P = 0.0002). Furthermore, more incidences of severe fatigue, thrombocytopenia, and neutropenia were recorded for sunitinib, but pazopanib had more liver toxicity. In subgroup analysis, studies from the US reported longer OS (HR = 0.86, 95% CI: 0.77-0.95, P = 0.004) and higher ORR (RR = 1.24, 95% CI: 1.03-1.51, P = 0.03). CONCLUSIONS: Pazopanib provides equivalent anti-tumor effectiveness and lower PPPM as compared with sunitinib for mRCC/aRCC. Great care should be given to pazopanib-treated patients with abnormal liver function. Nevertheless, more large-scale, high-quality studies are required.

Erectile Dysfunction Predicts Cardiovascular Events as an Independent Risk Factor: A Systematic Review and Meta-Analysis.

INTRODUCTION: Previous studies demonstrating that erectile dysfunction (ED) predicts the risk of further cardiovascular events (CV) events are insufficient to make recommendations for cardiologists, diabetologists, urologists, and more, and the association between CV events and ED degree is unclear. AIM: To assess whether ED was a risk factor for CV events in a comprehensive literature review and meta-analysis. METHODS: PubMed, EMBASE, the Cochrane Library, Medline, and the Web of Science were searched for eligible studies. The protocol for this meta-analysis is available from PROSPERO (CRD42018086138). MAIN OUTCOME MEASURES: The main outcomes included cardiovascular disease (CVD), coronary heart disease (CHD), stroke, and all-cause mortality. Subgroup and sensitivity analyses were conducted to detect potential bias. RESULTS: 25 eligible studies involving 154,794 individuals were included in our meta-analysis. Compared with those of men without ED, the CVD risk of ED patients was significantly increased by 43% (relative risk [RR] =1.43; P < .001), CHD was increased by 59% (RR = 1.59; P < .001), stroke was increased by 34% (RR = 1.34; P < .001), and all-cause mortality was increased by 33% (RR = 1.33; P < .001). Older individuals with ED (≥55 years), those with ED of a shorter duration (<7 years), and those with higher rates of diabetes (≥20%) and smoking (≥40%) were more prone to develop CVD. Additionally, severe ED was proven to predict higher CVD and all-cause mortality risk. The standardized model proposed here can be properly applied for screening early CV events. CLINICAL IMPLICATIONS: The evidence prompts the diligent observation of at-risk men and reinforces the importance of early treatment to prevent CV events. STRENGTHS & LIMITATIONS: Larger sample sizes from recent prospective cohort studies were included to provide more up-to-date, reliable, and comprehensive results. Moreover, the results were robust regarding consistency across sensitivity and subgroup analyses and remained consistent; even pre-excluded retrospective or cross-sectional studies were included. We constructed a standardized model that addresses the study's innovations and implications for the first time. However, not all included studies were randomized controlled trials, which might downgrade this evidence. CONCLUSIONS: Risk of total CVD, CHD, stroke, and all-cause mortality was significantly increased in populations with ED, and severe ED is of particular concern. The evidence suggests the need for diligent observation of at-risk men and reinforces the importance of early treatment to prevent CV events. Zhao B, Hong Z, Wei Y, et al. Erectile Dysfunction Predicts Cardiovascular Events as an Independent Risk Factor: A Systematic Review and Meta-Analysis. J Sex Med 2019;16:1005-1017.

Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway.

BACKGROUND/AIMS: Renal cell carcinoma (RCC) is currently the ninth most common cancer in men. Interleukin (IL)-33 expression has previously been associated with a number of cancers; however, its biological role in RCC is poorly understood. In this study, we sought to elucidate the role of IL-33 in RCC. METHODS: Serum IL-33 levels were measured by ELISA. IL-33 expression in clinical RCC samples was examined by immunocytochemistry. The proliferation and apoptosis rate of RCC were determined by CCK8 and flow cytometry. Mcl1 and Bcl-2 expression were measured by quantitative real-time PCR and western blotting. JNK expression were measured by western blotting and flow cytometry. The in vivo role of IL-33 in RCC tumorigenesis was examined by animal models. RESULTS: We found that increased expression of IL-33 in RCC was associated with tumor-lymph node-metastasis (TNM) stage and inversely correlated with prognosis. IL-33 enhances RCC cell growth in vivo and stimulates RCC cell proliferation and prevents chemotherapy-induced tumor apoptosis in vitro. Furthermore, we demonstrated that IL-33 promotes RCC cell proliferation and chemotherapy resistance via its receptor ST2 and the JNK signaling activation in tumor cells. CONCLUSION: Our findings suggest that targeting IL-33/ST2 and JNK signaling may have potential value in the treatment of RCC.

Speckle-Type POZ Protein Down-Regulates Matrix Metalloproteinase 2 Expression via Sp1/PI3K/Akt Signaling Pathway in Colorectal Cancer.

BACKGROUND: Elevated expression of matrix metalloproteinases (MMPs) is correlated with invasion and metastasis of colorectal cancer (CRC). Recently, a previous study has suggested that speckle-type POZ protein (SPOP) could inhibit cancer cell proliferation and migration through down-regulation of MMP2 and MMP7, with a mechanism remaining unknown. AIM: In this study, we, by using both CRC cells and normal colorectal cells, aimed to investigate the causal relationship between SPOP and MMP2, as well as the potential signaling pathways. METHODS: The causal relationship between SPOP and MMP2 was determined by both RT-PCR and Western blot in cells with SPOP expression or siRNA interference. The signaling pathway involved in MMP2 down-regulation by SPOP was subsequently identified by determination on the expression and phosphorylation of key signaling pathway proteins. Transcription factor involving in this MMP2 regulation was identified by determination on expression, phosphorylation, and nuclear translocation of key transcription factors. RESULTS: SPOP overexpression could significantly decrease MMP2 expression, while the knockdown of SPOP, in contrast, resulted in enhanced MMP2 level. Measurement of expression and phosphorylation of key signaling pathway proteins revealed that SPOP could inhibit PI3K and p-Akt level. Further tests on transcription factors showed that SPOP could inhibit SP1 phosphorylation and nuclear translocation. CONCLUSIONS: SPOP could down-regulate MMP2 expression in CRC, and this regulation is mediated by inhibiting SP1 phosphorylation and nuclear translocation through PI3K/Akt signaling pathway. Our findings in this study provide understanding of MMP2 regulation in CRC and may also shed lights on the development of anti-CRC treatments.

CSN5 promotes renal cell carcinoma metastasis and EMT by inhibiting ZEB1 degradation.

CSN5 (also known as COPS5) is a newly characterized oncogene involved in various types of cancer. However, its expression pattern and biological functions in renal cell carcinoma (RCC) is unknown. Here, we found that CSN5 expression was elevated in RCC tissues than those in paired normal renal tissues. Additionally, we demonstrated that high CSN5 level was closely correlated with tumor progression and poor survival in RCC patients. Our results showed that increased expression of CSN5 was observed in RCC cell lines and knockdown of CSN5 significantly suppressed the migration and invasion of RCC cells in vitro and in vivo. Additionally, CSN5 contributes to the metastasis and EMT (epithelial-mesenchymal transition) of RCC cells. Further investigation revealed that CSN5 led to the metastasis and EMT activation of RCC cells through increasing ZEB1 expression. Mechanistically, we found that CSN5 directly bound ZEB1 and decreased its ubiquitination to enhance the protein stability of ZEB1 in RCC cells. Taken together, our data identified CSN5 as a critical oncoprotein involved in migration and invasion of RCC cells, which could serve as a potential therapeutic target in RCC patients.

Rock2 promotes RCC proliferation by decreasing SCARA5 expression through ß-catenin/TCF4 signaling.

Rho-associated coiled-coil forming protein kinase 2 (Rock2), as a key effector of the small GTPase RhoA, is involved in tumor development. Scavenger receptor class A member 5 (SCARA5) is an important regulator of biological processes in cancer cells. However, the roles and relationship of Rock2 and SCARA5 in renal cell carcinoma (RCC) remain unclear. In this study, we found that Rock2 expression was markedly increased in clinical RCC tissues compared with that in adjacent non-cancerous tissues. High expression of Rock2 was inversely correlated with patient survival in RCC, which indicated that Rock2 may be a prognostic marker in human RCC. In addition, Rock2 knockdown increased SCARA5 expression and suppressed RCC cell proliferation both in vitro and in vivo. Furthermore, we found that the ß-catenin/TCF4 pathway contributed to the effect of Rock2 on SCARA5-mediated RCC proliferation. Taken together, these results suggest that this newly identified Rock2-ß-catenin/TCF4-SCARA5 axis will provide novel insight into the understanding of the regulatory mechanisms of proliferation in human RCC.

MiR-21 inhibitor suppressed the progression of retinoblastoma via the modulation of PTEN/PI3K/AKT pathway.

MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.

Linc00239 Facilitates the Progress of Clear Cell Renal Cell Carcinoma via the miR-204-5p/RAB22A Axis.

Long intergenic non-coding RNA 239 (Linc00239) acts as an oncogene in colorectal cancer (CRC), esophageal squamous cell carcinoma, and acute myeloid leukemia cells. However, its role and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain unknown. We used StarBase and The Cancer Genome Atlas databases to evaluate Linc00239 expression and its effect on ccRCC. Furthermore, the function of Linc00239 in ccRCC proliferation and metastasis was analyzed using Cell Counting Kit-8 and Transwell assays following Linc00239 knockdown. Subsequently, the Linc00239-miRNA-mRNA regulatory associations were selected based on miRanda, miTarbase, and previous references, and their expression levels and binding relationship were further validated using quantitative real-time polymerase chain reaction, western blotting and dual-luciferase reporter gene assay. Additionally, we transfected a miRNA inhibitor to evaluate whether the miR-204-5p/RAB22A (Ras-related proteins in brain 22a) axis was involved in Linc00239 function. Linc00239 was elevated in ccRCC and correlated with poor prognosis. Linc00239 knockdown inhibited ccRCC progression. Additionally, Linc00239 inhibition elevated miR-204-5p expression and repressed RAB22A levels. Moreover, miR-204-5p inhibitors attenuated this inhibitory effect on proliferation, migration, invasion, and RAB22A level when Linc00239 was knocked down. Linc00239 promotes ccRCC proliferation and metastasis by elevating RAB22A expression through the adsorption of miR-204-5p, which provides a clue for the diagnosis and treatment of ccRCC.

Silence of linc00023 inhibits pyroptosis and promotes cell proliferation via regulating p53.

OBJECTIVE: The objective of our study is to investigate the role and potential mechanism of linc00023 in the development of pyroptosis in clear cell renal cell carcinoma (ccRCC). METHODS: We assessed the expression of linc00023 in cells using qRT-PCR. Following linc00023 knockdown, we monitored cell proliferation and the pyroptosis marker using MTS, qRT-PCR, western blot analysis, and ELISA assays. Additionally, we performed RNA sequencing after linc00023 knockdown and validated the involvement of p53 using western blot analysis. Furthermore, we evaluated the potential mechanism by assessing cell proliferation and the expression of the pyroptosis marker after treatment with a p53 activator in linc00023-inhibited cells. RESULTS: Linc00023 expression was downregulated in ccRCC cells. Among them, ACHN cells exhibited higher linc00023 expression and were selected for further investigation. Knockdown of linc00023 resulted in increased cell proliferation and decreased pyroptosis. Furthermore, inhibition of linc00023 led to changes in the expression of numerous mRNAs, including p53. Importantly, the p53 activator ReACp53 reversed the effects of linc00023 knockdown on cell proliferation and pyroptosis. CONCLUSION: In conclusion, our findings suggested that linc00023 regulates pyroptosis in ccRCC by modulating p53 expression.

ROCK2-RNA interaction map reveals multiple biological mechanisms underlying tumor progression in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common form of kidney cancer in adults. Despite new therapeutic modalities, the outcomes for RCC patients remain unsatisfactory. Rho-associated coiled-coil forming protein kinase 2 (ROCK2) has previously been shown to be upregulated in RCC, and its expression was negatively correlated with patient survival. However, the precise molecular function of ROCK2 has remained unclear. Herein, using RNA-seq analysis of ROCK2 knockdown and control cells, we identified 464 differentially expressed genes, and 1287 alternative splicing events in 786-O RCC cells. Furthermore, mapping of iRIP-seq reads in 786-O cells showed a biased distribution at 5' UTR, intronic and intergenic regions. By comparing ROCK2-regulated alternative splicing and iRIP-seq data, we found 292 overlapping genes that are enriched in multiple tumorigenic pathways. Taken together, our work defined a complex ROCK2-RNA interaction map on a genomic scale in a human RCC cell line, which deepens our understanding of the molecular function of ROCK2 in cancer development.

Comprehensive analysis of the expression and prognosis of YPEL family members in clear cell renal cell cancer.

The Yippee­like (YPEL) gene family is composed of five members encoding a protein containing a zinc finger­like metal­binding domain. Due to its structure and location in cells, this domain is considered to be involved in cell multiplication and numerous types of cancer. However, the relationship between the protein and the prognosis of clear cell renal cell carcinoma (ccRCC) remains unknown. In the present study, using pan­cancer data from the updated public database, the expression and correlation of YPEL genes in 33 types of cancer was systematically and comprehensively analyzed. The prognostic value of YPEL genes was evaluated by survival and Cox regression analysis. Considering the relationship between the tumor microenvironment and stem cell indices, the function of superoxide dismutase was evaluated. Tumor Immune Assessment Resources (TIMER) and CIBERSORT algorithm analysis were used to evaluate the correlation between YPEL genes and tumor immune infiltrating cells (TIICs). Furthermore, knockdown experiments of YPEL genes were developed to explore their effects on ccRCC cell proliferation, migration and invasion in ccRCC cell lines. Members of the YPEL family were differentially expressed in ccRCC. Increased expression levels of YPEL1, YPEL2, and YPEL5 were associated with improved overall survival and disease­specific survival. TIMER and CIBERSORT analyses showed remarkable correlation between YPEL family members and TIICs. More importantly, the results of Cell Counting Kit­8, EdU and Transwell assays revealed that the multiplication, migration and invasion abilities of ccRCC cell lines could be promoted by knocking out YPEL1, YPEL2 and YPEL5. In conclusion, the present study provided new insight into the different roles of YPEL1, YPEL2 and YPEL5 in ccRCC, and the relationship between YPEL1 and immune infiltration may offer new options for future clinical treatment.

miR-5590-3p inhibits the proliferation and metastasis of renal cancer cells by targeting ROCK2 to inhibit proliferation, migration and invasion.

The present study aimed to clarify the role of microRNA (miR)-5590-3p in the progression of renal cell carcinoma (RCC) and investigate the underlying mechanisms. The expression levels of miR-5590-3p, Rho-associated protein kinase (ROCK)2 and ß-catenin in RCC cells were measured by reverse transcription-quantitative PCR and western blot analysis. Following overexpression of miR-5590-3p and ROCK2 by transfection of miR-5590-3p mimics and GV367-ROCK2, respectively, changes in the proliferation, migration and invasion of RCC cells were determined through colony-formation, wound-healing and Transwell assays, respectively. The direct binding interaction between miR-5590-3p and ROCK2, initially predicted using Targetscan, was validated by a dual-luciferase reporter assay. The results indicated that miR-5590-3p was downregulated in RCC. Overexpression of miR-5590-3p led to downregulation of ROCK2 and ß-catenin and inhibited the proliferation, migration and invasion of RCC cells. The dual-luciferase reporter assay confirmed the binding relationship between miR-5590-3p and ROCK2. Of note, overexpression of ROCK2 effectively reversed the regulatory effects of miR-5590-3p on RCC cells. In conclusion, miR-5590-3p inhibits the proliferation, migration and invasion of RCC cells by targeting ROCK2, which is a potential molecular biomarker and therapeutic target for RCC.

Nc886 promotes renal cancer cell drug-resistance by enhancing EMT through Rock2 phosphorylation-mediated ß-catenin nuclear translocation.

Drug resistance is a significant challenge in the present treatment regimens of renal cell carcinoma (RCC). Our previous study confirmed that nc886 functions as an oncogene in RCC. Nevertheless, the role and underlying mechanism of nc886 in RCC drug resistance are unclear. In the present study, Sunitinib and Everolimus treatment, respectively, downregulated nc886 expression in a dose-dependent manner in all four renal cancer cell lines. Nc886 overexpression in 786-O cells and ACHN cells significantly reduced the sensitivity of cancer cells to both Sunitinib and Everolimus treatment, respectively, by promoting cell viability and inhibiting cell apoptosis, whereas nc886 silencing increased cancer cell sensitivity. In renal cancer cell line with the highest drug-resistance, 786-O cells, Sunitinib, or Everolimus treatment enhanced the cellular EMT and was further enhanced by nc886 overexpression while attenuated by nc886 silencing. In 786-O cells, nc886 overexpression significantly promoted EMT, ROCK2 phosphorylation, and ß-catenin nucleus translocation under Sunitinib or Everolimus treatment. Moreover, ROCK2 silencing significantly reversed the effects of nc886 overexpression on EMT, ROCK2 phosphorylation, and ß-catenin nucleus translocation, as well as drug-resistant renal cancer cell viability and apoptosis. In conclusion, it was demonstrated that nc886 promotes renal cancer cell proliferation, migration, and invasion, as demonstrated previously. nc886 also promotes renal cancer cell drug-resistance to Sunitinib or Everolimus by promoting EMT through Rock2 phosphorylation-mediated nuclear translocation of ß-catenin.

Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells and its implication in therapy resistance.

Neuroendocrine (NE)-like tumors secrete various signaling molecules to establish paracrine communication within the tumor milieu and to create a therapy-resistant environment. It is important to identify molecular mediators that regulate this secretory phenotype in NE-like cancer. The current study highlights the importance of a cell surface molecule, Neuropilin-2 (NRP2), for the secretory function of NE-like prostate cancer (PCa). Our analysis on different patient cohorts suggests that NRP2 is high in NE-like PCa. We have developed cell line models to investigate NRP2's role in NE-like PCa. Our bioinformatics, mass spectrometry, cytokine array, and other supporting experiments reveal that NRP2 regulates robust secretory phenotype in NE-like PCa and controls the secretion of factors promoting cancer cell survival. Depletion of NRP2 reduces the secretion of these factors and makes resistant cancer cells sensitive to chemotherapy in vitro and in vivo. Therefore, targeting NRP2 can revert cellular secretion and sensitize PCa cells toward therapy.

The deubiquitinating enzyme ATXN3 promotes the progression of anaplastic thyroid carcinoma by stabilizing EIF5A2.

Ataxin-3 (ATXN3) is a ubiquitous deubiquitinating enzyme that plays an essential role in the carcinogenesis of numerous tumors and stabilizes the expression of substrates by deubiquitination. However, the functional role of ATXN3 in anaplastic thyroid carcinoma (ATC) remains unknown. In this research, we report that ATXN3 was overexpressed in ATC compared to that in paracancerous samples. Moreover, various gain/loss functional assays were performed to indicate that ATXN3 overexpression enhanced ATC cell proliferation and metastasis. We also found that ATXN3 and eukaryotic translation initiation factor 5A2 (EIF5A2) protein levels in ATC tissues are positively correlated, and ATXN3 promotes the proliferation and metastasis of ATC cells through EIF5A2. Mechanistically, ATXN3 promotes EIF5A2 expression by directly binding to EIF5A2 to reduce its ubiquitination and degradation. Therefore, for the first time, we clarified the role of ATXN3 in the carcinogenesis of ATC cells, which provides novel insights into potential therapeutic targets for ATC progression.

Circular RNA circFLNA inhibits the development of bladder carcinoma through microRNA miR-216a-3p/BTG2 axis.

Recent studies have shown that circular RNA circFLNA is abnormally expressed in a variety of malignant tumors, but its role and mechanism in bladder carcinoma (BCa) are still unclear. The present paper aims to contribute to research on the effects and mechanism of circFLNA on the malignant phenotype of BCa. In this study, the expressions of circFLNA, miR-216a-3p and BTG2 in BCa and BCa cells (EJ, T24, 5637, TCC-SUP) were detected by qRT-PCR. EdU staining, colony formation, Transwell assay, wound healing assays, and sphere formation assay were used to measure the cell proliferation, viability, invasion, migration, and cell stemness of BCa cells after circFLNA overexpression. In addition, the correlation existed between miR-216a-3p and circFLNA or BTG2 was confirmed by Dual-Luciferase Reporter assay and RNA pull-down. Western blot was utilized to determine the expression of BTG2, MMP2, epithelial-mesenchymal transition (EMT)-related proteins (vimentin, E-cadherin) and stem cell-specific proteins (CD34, OCT4, SOX2). Our study confirmed that downregulated circFLNA and BTG2 expression and upregulated miR-216a-3p were found in both BCa tissues and cell lines. Meanwhile, upregulated circFLNA inhibited proliferation, invasion and migration, EMT and stemness of BCa cells. MiR-216a-3p was a target gene of circFLNA and could target BTG2. Further analysis finally demonstrated that circFLNA sponged miR-216a-3p and indirectly promoted BTG2 expression, ultimately regulating proliferation, migration, invasion and EMT of BCa cells. In conclusion, circFLNA inhibits the malignant phenotype of BCa cells and their stemness through miR-216a-3p/BTG2, thus suppressing BCa progression.