Giant peritoneal loose body and its protein composition: a case report.

Peritoneal loose body (PLB) is a kind of lesions located in the abdominal cavity or pelvic cavity, which is rare and difficult to diagnose. The diameter of PLB is mostly 0.5-2.5 cm. Most PLBS are asymptomatic. Here we reported a case of giant PLB in the pelvis and analyzed its structure and protein composition. Surgical exploration revealed a white oval mass (4.5*4*3 cm) in the pelvic cavity. After the mass was removed, the symptoms of hematuria disappeared and the patient was discharged on the second postoperative day. Histochemical staining showed that PLB was mainly composed of collagen and scattered calcification. The protein components of PLB were detected by proteome analysis, and a variety of proteins related to collagen deposition and calcification were identified in PLB.

FOXM1/KIF20A axis promotes clear cell renal cell carcinoma progression via regulating EMT signaling and affects immunotherapy response.

Background: The correlation between FOXM1 and KIF20A has not been revealed in clear cell renal cell carcinoma (ccRCC). Methods: Public data was downloaded from The Cancer Genome Atlas (TCGA) database. R software was utilized for the execution of bioinformatic analysis. The expression levels of specific molecules (mRNA and protein) were detected using real-time quantitative PCR (qRT-PCR) and Western blot assays. The capacity of cell growth was assessed by employing CCK8 and colony formation assay. Cell invasion and migration ability were assessed using transwell assay. Results: In our study, we illustrated the association between FOXM1 and KIF20A. Our results indicated that both FOXM1 and KIF20A were associated with poor prognosis and clinical performance. The malignant characteristics of ccRCC cells can be significantly suppressed by inhibiting FOXM1 and KIF20A, as demonstrated by in vitro experiments. Moreover, we found that FOXM1 can upregulate KIF20A. Then, EMT signaling was identified as the underlying pathway FOXM1 and KIF20A are involved. WB results indicated that FOXM1/KIF20A axis can activate EMT signaling. Moreover, we noticed that FOXM1 and KIF20A can affect the immunotherapy response and immune microenvironment of ccRCC patients. Conclusions: Our results identified the role of the FOXM1/KIF20A axis in ccRCC progression and immunotherapy, making it the underlying target for ccRCC.

Integrative analysis of the ST6GALNAC family identifies GATA2-upregulated ST6GALNAC5 as an adverse prognostic biomarker promoting prostate cancer cell invasion.

BACKGROUND: ST6GALNAC family members function as sialyltransferases and have been implicated in cancer progression. However, their aberrant expression levels, prognostic values and specific roles in metastatic prostate cancer (PCa) remain largely unclear. METHODS: Two independent public datasets (TCGA-PRAD and GSE21032), containing 648 PCa samples in total, were employed to comprehensively examine the mRNA expression changes of ST6GALNAC family members in PCa, as well as their associations with clinicopathological parameters and prognosis. The dysregulation of ST6GALNAC5 was further validated in a mouse PCa model and human PCa samples from our cohort (n = 64) by immunohistochemistry (IHC). Gene Set Enrichment Analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and drug sensitivity analyses were performed to enrich the biological processes most related to ST6GALNAC5. Sulforhodamine B, transwell, luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to examine the PCa cell proliferation, invasion and transcriptional regulation, respectively. RESULTS: Systematical investigation of six ST6GALNAC family members in public datasets revealed that ST6GALNAC5 was the only gene consistently and significantly upregulated in metastatic PCa, and ST6GALNAC5 overexpression was also positively associated with Gleason score and predicted poor prognosis in PCa patients. IHC results showed that (1) ST6GALNAC5 protein expression was increased in prostatic intraepithelial neoplasia and further elevated in PCa from a PbCre;PtenF/F mouse model; (2) overexpressed ST6GALNAC5 protein was confirmed in human PCa samples comparing with benign prostatic hyperplasia samples from our cohort (p < 0.001); (3) ST6GALNAC5 overexpression was significantly correlated with perineural invasion of PCa. Moreover, we first found transcription factor GATA2 positively and directly regulated ST6GALNAC5 expression at transcriptional level. ST6GALNAC5 overexpression could partially reverse GATA2-depletion-induced inhibition of PCa cell invasion. The GATA2-ST6GALNAC5 signature exhibited better prediction on the poor prognosis in PCa patients than GATA2 or ST6GALNAC5 alone. CONCLUSIONS: Our results indicated that GATA2-upregulated ST6GALNAC5 might serve as an adverse prognostic biomarker promoting prostate cancer cell invasion.

CD44 Is a Prognostic Biomarker Correlated With Immune Infiltrates and Metastasis in Clear Cell Renal Cell Carcinoma.

BACKGROUND/AIM: CD44 is a critical cell-surface glycoprotein. However, its prognostic significance and correlation with tumor-infiltrating lymphocytes in clear cell renal cell carcinoma (ccRCC) are not well-understood. MATERIALS AND METHODS: The mRNA and protein levels of CD44 in ccRCC were assessed. The prognostic value of CD44 was analyzed in the TCGA and PrognoScan databases. The functional enrichment and immune infiltrates analyses were conducted. The STRING database was used to analyze the protein interactions of CD44. Tissue array, western blot, qRT-PCR, and transwell assay were performed to determine the expression and biological function of CD44 in ccRCC cells. RESULTS: CD44 was highly expressed in ccRCC and correlated with poor prognosis. CD44 mRNA and protein expression was associated with TNM stage, pathologic stage, and histologic grade. Functional enrichment analyses revealed CD44 is involved in extracellular matrix organization, metastasis, IL6/JAK/STAT3 signaling and so on. Moreover, CD44 expression was positively correlated with infiltrating levels of macrophages, Th2 cells and Th1 cells in ccRCC. Combining the immune infiltration analysis and immunohistochemistry, the SPP1/CD44 axis might participate in immune escape through regulating PD-L2 expression. Experiments indicated that CD44 was increased in ccRCC and inhibition of CD44 could suppress the migration of ccRCC cells. CONCLUSION: High expression of CD44 in ccRCC was associated with metastasis, poor prognosis, and high infiltrating levels of macrophages. The SPP1/CD44 axis potentially contributes to the regulation of PD-L2. These results demonstrated that targeting the SPP1/CD44 axis or inhibiting CD44 expression may be a new therapy to suppress ccRCC progression.

Hsa_circ_0003596 enhances the development of cell renal clear cell carcinoma through the miR-502-5p/IGF1/PI3K/AKT axis.

Accumulating research findings have shown that circular RNAs (circRNAs) play an indispensable role in tumorigenesis and tumor progression. The current study aimed to explore the role and modulatory mechanism of hsa_circ_0003596 in clear cell renal cell carcinoma (ccRCC). Quantitative real-time polymerase chain reaction was adopted to detect the expression of hsa_circ_0003596 in ccRCC tissue and cell lines. 5-Ethynyl-2'-deoxyuridine, cell counting kit 8 and the colony formation assay were utilized to assess the proliferation potential of the ccRCC cells. Transwell along with wound healing assays were adopted to quantify infiltration coupled with the migration potential of the cells. The current research study found that the circRNA hsa_circ_0003596 was overexpressed in ccRCC tissue and cell lines. Further, result showed that hsa_circ_0003596 was associated with distant metastasis of renal cancer. Notably, the knockdown of hsa_circ_0003596 can lower the proliferation, infiltration and migration potential of ccRCC cells. The results of in vivo experiments found that the reduction of hsa_circ_0003596 significantly hampered the growth of tumors in mice. In addition, it was evident that hsa_circ_0003596 acts as a "molecular sponge" for miR-502-5p to upregulate the expression of the microRNA-502-5p (miR-502-5p) target insulin-like growth factor 1 (IGF1R). Furthermore, it was found that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling was the downstream cascade of hsa_circ_0003596/miR-502-5p/IGF1R cascade, which is partly responsible for the cancer-promoting effect. Overall, the results of the present study showed that hsa_circ_0003596 facilitated the proliferation, infiltration and migration of ccRCC through the miR-502-5p/IGF1R/PI3K/AKT axis. Therefore, it was evident that hsa_circ_0003596 can serve as a possible biomarker and therapeutic target against ccRCC.

LncRNA SPRY4­IT1 is upregulated and promotes the proliferation of prostate cancer cells under hypoxia in vitro.

The incidence and mortality rate of prostate cancer are among the highest for all cancers worldwide; this disease has a high cancer mortality rate in males, following lung cancer. Sprouty4-intron 1 (SPRY4-IT1) has been shown to play a variety of roles in tumors. Our previous study demonstrated that SPRY4-IT1 sponges microRNA-101-3p to promote the proliferation and metastasis of bladder cancer cells by upregulating enhancer of zeste homolog 2 expression; however, the role of SPRY4-IT1 in prostate cancer has not been fully established. In the present study, the expression levels, effects and mechanism of action of SPRY4-IT1 were investigated in prostate cancer tissues and cell lines using reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8 and flow cytometry assays. The results indicated that SPRY4-IT1 expression was upregulated in prostate cancer tissues and cell lines. Furthermore, hypoxia increased the expression levels of SPRY4-IT1 in prostate cancer cells. Knockdown of SPRY4-IT1 expression led to S-phase arrest, decreased expression levels of the cell cycle-associated proteins CDK2 and cyclin D1. AKT phosphorylation was also reduced by SPRY4-IT1 knockdown. In summary, the findings indicate the elevation of SPRY4-IT1 expression in prostate cancer. Under hypoxic conditions in vitro, SPRY4-IT1 overexpression promoted prostate cancer cell proliferation via a mechanism involving regulation of the cell cycle and the PI3K/AKT signaling pathway. Therefore, it may provide a basis for the development of targeted therapies.

Antireflux Ureteral Stent Improves Stent-Related Symptoms and Quality of Life: A Prospective Randomized Controlled Trial.

Objectives: To compare the effectiveness of antireflux ureteral stents on improving symptoms and quality of life of patients with ureteral stents. Materials and Methods: We randomized 120 patients with ureteral stone who required ureteral stent placement after ureteroscopic lithotripsy, of which 107 (56 in standard ureteral stent group and 51 in antireflux ureteral stent group) entered the final analysis. Severity of flank pain and suprapubic pain, visual analog scale (VAS), analgesic used after hospitalization, back soreness during micturition, gross hematuria, creatinine abnormality, hydronephrosis grade, symptomatic urinary tract infection (UTI), and quality of life were compared between the two groups. Results: There were no serious complications after operation in all 107 cases. The antireflux ureteral stent group had less flank pain and suprapubic pain (p < 0.05), analgesic used after hospitalization (p < 0.05), back soreness during micturition (p < 0.05), and lower VAS (p < 0.05). The health status index scores (p < 0.05), dimensions of usual activities, and pain/discomfort (p < 0.05) in the antireflux ureteral stent group were statistically better than those in the standard ureteral stent group. There were no significant differences between the groups in creatinine abnormality, hydronephrosis grade, gross hematuria, and symptomatic UTI. Conclusions: The antireflux ureteral stent has the same safety and efficacy as the standard ureteral stent, and is significantly better than the standard ureteral stent in flank pain and suprapubic pain, VAS, analgesic used after hospitalization, back soreness during micturition, and quality of life.

Identification of hexosamine biosynthesis pathway as a novel prognostic signature and its correlation with immune infiltration in bladder cancer.

Background: Urinary bladder cancer (UBC) is one of the common urological malignancies, lacking reliable biomarkers to predict clinical outcomes in UBC patients. Thus, it is needed to identify the novel diagnostic/prognostic biomarkers to stratify the high-risk UBC patients. As a shunt pathway of glycolysis, the hexosamine biosynthesis pathway (HBP) has been implicated in carcinogenesis. However, its prognostic value in UBC remains unclear. Methods: The RNA sequencing and mRNA microarray datasets were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus databases. The expression levels of five HBP genes were analyzed in normal and UBC samples, and their associations with stage, grade and survival were plotted. The performance of HBP risk group was evaluated by receiver-operating characteristics (ROC) curve. The HBP signature was generated by Gene Set Variation Analysis (GSVA) and its association with clinicopathological parameters and survival were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to examine the potential biological functions of HBP using DAVID online tool. The infiltration estimation fraction of immune cells was performed using CIBERSORT-ABS algorithm. Gene set enrichment analysis (GSEA) was used to explore the potential function of HBP in tumor immunoregulation. Results: Four HBP genes were upregulated in UBCs compared to normal tissues in TCGA-BLCA dataset. The upregulation of all five HBP genes was significantly associated with tumor grade and stage of UBC in three independent UBC datasets. The expression of HBP genes predicted poor clinical outcomes in UBC patients in both TCGA-BLCA and GSE13507 datasets. The high-risk group based on HBP genes showed a poor prognosis. Furthermore, HBP signature was positively associated with tumor grade and stage in TCGA-BLCA dataset and with tumor grade, stage, distal metastasis and poor survival in GSE13507 dataset. Interestingly, high-HBP signature group exhibited a high infiltration of immune cells, particularly the macrophage population. Conclusion: We identified that HBP was a promising prognostic biomarker in UBC patients and strongly associated with immune infiltration.

Identification of ST3GAL5 as a prognostic biomarker correlating with CD8+ T cell exhaustion in clear cell renal cell carcinoma.

Aberrant sialylation is frequently observed in tumor development, but which sialyltransferases are involved in this event are not well known. Herein, we performed comprehensive analyses on six ST3GAL family members, the α-2,3 sialyltransferases, in clear cell renal cell carcinoma (ccRCC) from public datasets. Only ST3GAL5 was consistently and significantly overexpressed in ccRCC (n = 791 in total), compared with normal kidney tissues. Its overexpression was positively correlated with tumor stage, grade, and the poor prognosis in ccRCC patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated the involvement of ST3GAL5 in tumor immunoregulation. Then we revealed that ST3GAL5 expression showed a positive correlation with CD8+ T cell infiltration, using multiple tools on TIMER2.0 web server. Notably, ST3GAL5 overexpression was further identified to be associated with expression signature of CD8+ T cell exhaustion in ccRCC samples from three datasets (n = 867 in total; r > 0.3, p < 0.001). In our own ccRCC cohort (n = 45), immunohistochemistry and immunofluorescence staining confirmed that ST3GAL5 overexpression was accompanied by high CD8+ T cell infiltration with the increased exhaustion markers. Altogether, ST3GAL5 as a promising prognostic biomarker with CD8+ T cell exhaustion in ccRCC is indicated.

Insights into homeobox B9: a propeller for metastasis in dormant prostate cancer progenitor cells.

BACKGROUND: Metastasis is the major cause of treatment failure and cancer-related deaths in prostate cancer (PCa) patients. Our previous study demonstrated that a CD44+ subpopulation isolated from PCa cells or tumours possesses both stem cell properties and metastatic potential, serving as metastatic prostate cancer stem cells (mPCSCs) in PCa metastasis. However, the underlying mechanisms remain unknown. METHODS: In this study, we established PCa models via the orthotopic and subcutaneous implantation of different human PCa cancer cell lines, and compared the metastatic efficacy, after which process function analysis of target genes was pinpointed. RESULTS: Several novel differentially expressed genes (DEGs) between orthotopic and ectopic tumours were identified. Among them, human homeobox B9 (HOXB9) transcription factor was found to be essential for PCa metastasis, as evidenced by the diminished number of lung metastatic foci derived from orthotopic implantation with HOXB9-deficient CWR22 cells, compared with the control. In addition, HOXB9 protein expression was upregulated in PCa tissues, compared with paracancer and benign prostate hyperplasia tissues. It was also positively correlated with Gleason scores. Gain- and loss-of-function assays showed that HOXB9 altered the expression of various tumour metastasis- and cancer stem cell (CSC) growth-related genes in a transforming growth factor beta (TGFß)-dependent manner. Moreover, HOXB9 was overexpressed in an ALDH+CD44+CXCR4+CD24+ subpopulation of PCa cells that exhibited enhanced TGFß-dependent tumorigenic and metastatic abilities, compared with other isogenic PCa cells. This suggests that HOXB9 may contribute to PCa tumorigenesis and metastasis via TGFß signalling. Of note, ALDH+CD44+CXCR4+CD24+-PCa cells exhibited resistance to castration and antiandrogen therapy and were present in human PCa tissues. CONCLUSION: Taken together, our study identified HOXB9 as a critical regulator of metastatic mPCSC behaviour. This occurs through altering the expression of a panel of CSC growth- and invasion/metastasis-related genes via TGFß signalling. Thus, targeting HOXB9 is a potential novel therapeutic PCa treatment strategy.

Roles of NANOGP8 in cancer metastasis and cancer stem cell invasion during development of castration-resistant prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of the most common types of cancer and the emerging resistance to androgen deprivation therapy in PCa aggravates disease progression. In this study, we examined the potential pro-tumorigenic functions of NANOGP8 in prostate cancer development. METHODS: Quantitative RT-PCR confirmed higher NANOGP8 expression in androgen independent tumors, as well as a recurrent prostate tumor in patient samples. We then established a novel two-way inducible NANOGP8-short hairpin RNA experimental system, in which the NANOGP8 expression was transiently induced by adding doxycycline in the diet of NOD/SCID mice. RESULTS: The knockdown of NANOGP8 inhibited implanted tumor growth and the progression of castration-resistant PCa. NANOGP8-deficient PCa cells lost their cancer stem cell and gene expression programs. To further investigate the functions of NANOGP8 in PCa stem cells, real-time cell tracking was used to monitor the cell division modes and differentiation patterns of NANOGP8+ cells. The expression level of NANOGP8 markedly influenced the cell division mode of NANOGP8+ PCa cells and was strongly correlated with their pluripotency, reflected by robust telomerase activity and longer telomere length. NANOGP8 expression was also associated with the metastatic capacity of PCa cells. CONCLUSIONS: Based on these findings, we propose that NANOGP8 could serve as an effective therapeutic target for the treatment of PCa.

Phage display screening identifies a prostate specific antigen (PSA)-/lo prostate cancer cell specific peptide to retard castration resistance of prostate cancer.

Patients with prostate cancer (PCa) will eventually progress to castrate-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) treatment. Prostate-specific antigen (PSA)-/lo cells which harbor self-renewing long-term tumor-propagating cells that can be enriched using ALDH+CD44+α2ß1+ and can initiate tumor development may represent a critical source of CRPC cells. Our purpose was to find a peptide that specifically targets PSA-/lo PCa cells to retard the development of CRPC. PSA+ and PSA-/lo cells were successfully separated from LNCaP xenograft tumors after prostate- PSAP-GFP vector infection and FACS. A variety of PSA-/lo cells specifically targeting peptide (named as "TAP1" targeted affinity peptide 1) was identified by using phage display library screening. The highest binding rate in TAP1 binding cell subpopulations are identified to be among ALDH+CD44+CXCR4+CD24+ cells. TAP1 significantly inhibited PCa growth both in vitro and in vivo. TAP1 significantly improved the anti-proliferation effect of the anti-androgens (Charcoal dextran-stripped serum (CDSS)+Bicalutamide, Enzalutamide) and chemotherapeutic agents (Abiraterone, Docetaxel, Etoposide) in vitro. TAP1 treatment shortens the length of telomeres in ALDH+CD44+CXCR4+CD24+ cells and significantly reduces the expression of Homeobox B9 (HOXB9) and TGF-ß2. In conclusion, PSA-/lo PCa cell-specific targeting peptide (TAP1) that suppressed PCa cell growth both in vitro and in vivo and improved the drug sensitivities of anti-androgens and chemotherapeutic agents at least through shortening the length of telomere and reducing the expression of HOXB9 and TGF-ß2. Therapeutic peptides that specifically target prostate cancer stem cell might be a very valuable and promising approach to overcome chemoresistance and prevent recurrence in patients with PCa.

Carcinoembryonic antigen related cell adhesion molecule 6 promotes the proliferation and migration of renal cancer cells through the ERK/AKT signaling pathway.

BACKGROUND: Carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6) is a versatile glycoprotein and a member of the CEACAM family. Studies suggested that it served as a diagnostic and prognostic biomarker in some malignancies. In addition, it is involved in tumorigenesis by stimulating proliferation, suppressing apoptosis, facilitating migration and invasion, promoting angiogenesis, and inducing drug resistance. In the present study, we demonstrated the oncogenic effects of CEACAM6 in clear cell renal cell carcinoma (ccRCC). METHODS: CEACAM6 expression was detected by quantitative real-time PCR (qRT-PCR), immunohistochemical staining and western blot in ccRCC tumor tissues and cell lines. Survival analysis was performed using the data of TCGA database. Cell proliferation and migration were detected by CCK-8 and transwell assays with the overexpression or silencing of CEACAM6. LY294002 was used to block the activation of PI3K/AKT pathway. Associated pathway proteins were detected by western blot. RESULTS: CEACAM6 was upregulated in ccRCC cell lines and tumor tissues. Longer overall survival was observed in patients with relatively low CEACAM6 levels. Furthermore, overexpression of CEACAM6 promoted the proliferation and migration of ccRCC cells. Conversely, shRNA-mediated CEACAM6 depletion modulated those changes. Further investigation demonstrated that the ERK/AKT signaling pathway activation played a pivotal role. In addition, PI3K/AKT pathway blockade abrogated the effects of CEACAM6 overexpression. CONCLUSIONS: Aberrantly high expression of CEACAM6 is a stimulus for the formation and progression of ccRCC.

Epidemic investigation of benign prostatic obstruction with coexisting overactive bladder in Shanghai Pudong New Area and its impact on the health-related quality of life.

BACKGROUND: We aimed to investigate the prevalence, relative risk factors, and the impact on the health-related quality of life (HRQoL) of benign prostatic obstruction (BPO) with coexisting overactive bladder (OAB) in men aged over 50 and living in Shanghai Pudong New Area. METHODS: Using a multi-stage sampling and descriptive epidemiological method, 1632 men were selected from among the general population. Participants completed an evaluation of lower urinary tracts symptoms (LUTS), including international prostate symptom score (IPSS) and quality of life (QoL) questionnaires. Erectile function was assessed using the International Index of Erectile Function-5 (IIEF-5) questionnaire. In addition, the Overactive Bladder Symptom Score (OABSS) and King's health questionnaire (KHQ) were used to assess the impact of BPO with coexisting OAB on the HRQoL. Maximum flow rate (Qmax), postvoid residual urine volume (PVR) and prostate-specific antigen (PSA) were also recorded. RESULTS: A total of 1476 men with complete data were analyzed. The overall prevalence of BPO with coexisting OAB was 39.6%. Age and prostate volume were associated risk factors for BPO with coexisting OAB. In addition, BPO with coexisting OAB negatively impacted the HRQoL, with increased IPSS, QoL, OABSS, and KHQ scores and decreased IIEF-5 scores compared to that in patients with BPO without OAB. CONCLUSIONS: Qmax, PVR and serum PSA did not predict whether the patients had a combined BPO + OAB or not. The prostate volume and age were associated risk factors for BPO with coexisting OAB. BPO is a progressive disease and may be one of the risk factors for OAB.

Upregulation of TRPV1 in spinal dorsal root ganglion by activating NGF-TrkA pathway contributes to pelvic organ cross-sensitisation in rats with experimental autoimmune prostatitis.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the prostate gland inflammation characterised as genitourinary pain in the pelvic region. The rat experimental autoimmune prostatitis (EAP) was achieved to mimic CP/CPPS. The expressions of transient receptor potential vanilloid 1 (TRPV1) in the prostate, bladder and spinal dorsal root ganglion (DRG) were analysed by Western blotting. Tropomyosin receptor kinase A (TrkA) and nerve growth factor (NGF) in the DRG were also analysed by Western blotting. Measurements of inflammatory cytokines were carried out according to the instructions of the corresponding kits. The expressions of TRPV1 in the prostate, bladder and DRG in the EAP group were significantly higher than those in the control group. The expressions of NGF and TrkA in the DRG in the EAP group were significantly higher than those in the control group. The levels of serum TNF-α and IL-1ß in the EAP group were significantly higher than those in the control group. We conclude that CP/CPPS may participate in the pathological activation of neurons in the L5-S1 segment of DRG by activating NGF-TrkA pathway and cause pelvic organ cross-sensitisation by upregulating the expression of TRPV1 in the prostate, bladder and DRG.

A positive feed-forward loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma.

BACKGROUND: The aberrant expression of long noncoding RNAs (lncRNAs) has recently emerged as key molecules in human cancers; however, whether lncRNAs are implicated in the progression of clear cell renal cell carcinoma (ccRCC) remains unclear. METHODS: Candidate lncRNAs were selected using microarray analysis and quantitative real-time PCR (qRT-PCR) was performed to detect lncRNAs expression in human ccRCC tissues. Overexpression and knocking down experiments in vivo and in vitro were performed to uncover the biological roles of lncRNA-URRCC on ccRCC cell proliferation and invasion. Microarray, chromatin immunoprecipitation, Luciferase reporter assay and western blot were constructed to investigate the molecular mechanisms underlying the functions of lncRNA-URRCC. RESULTS: The microarray analysis and qRT-PCR identified a new lncRNA, URRCC, whose expression is upregulated in RCC samples and associated with poor prognosis, leading to promote ccRCC cell proliferation and invasion. Mechanistically, URRCC enhances the expression of EGFL7 via mediating histone H3 acetylation of EGFL7 promoter, activation of P-AKT signaling, and suppressing P-AKT downstream gene, FOXO3. In return, FOXO3 could inhibit the transcription of URRCC via binding to the special region on the promoter of URRCC. CONCLUSIONS: Our data suggests that targeting this newly identified feed-back loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling may enhance the efficacy of existing therapy and potentially imparts a new avenue to develop more potent therapeutic approaches to suppress RCC progression.

Tetracycline attenuates calcifying nanoparticles-induced renal epithelial injury through suppression of inflammation, oxidative stress, and apoptosis in rat models.

BACKGROUND: Calcifying nanoparticles (CNPs) has been associated with the occurrence and development of kidney stones, but the exact mechanism is not clear. This study aimed to establish a rat model of CNP-induced renal epithelial injury and assess the efficacy of tetracycline in preventing this injury. METHODS: Kidney stones from patients after percutaneous nephrolithotomy (PCNL) were collected to isolate and culture CNPs. Thirty Sprague-Dawley rats were divided into three groups: the sham group (G1), the CNP group (G2), and the CNP + tetracycline group (G3). Rats in G2 and G3 were given an intravenous injection of CNPs via the tail vein, while rats in G1 were given saline. Meanwhile, rats in G3 were given tetracycline by gavage twice a day at a dose of 25 mg/kg. After 8 weeks, the 24-h urine of all rats was collected, and all rats were sacrificed to obtain blood and kidneys. RESULTS: The results revealed that in G2, activities of antioxidant enzymes such as superoxide dismutase and catalase were significantly lower than those in G1, while malondialdehyde activity in G2 was significantly higher than that in G1 and both of them were inhibited by tetracycline co-treatment in G3. CNPs significantly increased expression of inflammatory cytokines, including monocyte chemotactic protein 1 and interleukin 6, which were largely alleviated in G3. CNPs significantly increased TUNEL-positive cells and the apoptosis activity of Bcl2-associated X protein but decreased B-cell lymphoma-2 level compared with that in G1, and was limited by tetracycline co-treatment in G3. Furthermore, CNPs led to notable renal tubular epithelial cell damage, hyaline cast formation, desquamation, swelling, vacuolization in histology, all of which were alleviated by tetracycline. CONCLUSIONS: Tetracycline can attenuate CNP-induced renal epithelial injury through suppression of inflammation, oxidative stress, and apoptosis.

MiR-532-5p suppresses renal cancer cell proliferation by disrupting the ETS1-mediated positive feedback loop with the KRAS-NAP1L1/P-ERK axis.

BACKGROUND: Despite the fact that miRNAs play pivotal roles in various human malignancies, their molecular mechanisms influencing RCC are poorly understood. METHODS: The expression of miRNAs from RCC and paired normal renal specimens was analysed by a combined computational and experimental approach using two published datasets and qRT-PCR assays. The functional role of these miRNAs was further identified by overexpression and inhibition assays in vivo and in vitro. Western blots, luciferase assays, and chromatin immunoprecipitation were performed to investigate the potential mechanisms of these miRNAs. RESULTS: Bioinformatics analysis and qRT-PCR revealed that miR-532-5p was one of the most heavily downregulated miRNAs. Overexpression of miR-532-5p inhibited RCC cell proliferation, while knockdown of miR-532-5p promoted cell proliferation. Mechanistic analyses indicated that miR-532-5p directly targets KRAS and NAP1L1. Interestingly, ETS1 suppressed the transcription of miR-532-5p by directly binding a special region of its promoter. Moreover, high levels of ETS1, as an oncogene in RCC, were significantly associated with poor survival in a large cohort of RCC specimens. CONCLUSIONS: Our work presents a road map for the prediction and validation of a miR-532-5p/KRAS-NAP1L1/P-ERK/ETS1 axis feedback loop regulating cell proliferation, which could potentially provide better therapeutic avenues for treating RCC.

Role of leptin and the leptin receptor in the pathogenesis of varicocele-induced testicular dysfunction.

The present study investigated the expression of leptin and its receptor in the left testis and hypothalamus of rats with varicocele and clarified their roles in the pathogenesis of varicocele­induced testicular dysfunction. A total of 40 male rats were divided randomly into four groups. Groups 1 (G1) and 3 (G3) underwent a sham operation. Groups 2 (G2) and 4 (G4) underwent operations to form a varicocele created by partial ligation of the left renal vein. G1 and G2 rats were euthanized 4 weeks after the operation while G3 and G4 rats were euthanized at 8 weeks. The expression of leptin and its receptor was analyzed by immunohistochemistry. The mRNA levels of leptin, its receptor, kisspeptin (KiSS­1), G­protein coupled receptor 54 (GPR54), gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), and follicle­stimulating hormone (FSH) were measured by reverse transcription­quantitative polymerase chain reaction. Testicular spermatogenesis function and gonadal hormone levels were measured. Compared with G1 and G3, the expression of leptin and its receptor in rat testis was significantly higher in G2 and G4, respectively. Leptin expression was inversely associated with the number of sperm in the left epididymis, thickness of the seminiferous epithelium and the diameter of seminiferous tubules. The expression of leptin receptors in the hypothalamus of G2 and G4 was significantly increased compared with that in G1 and G3, respectively. The mRNA levels of KiSS­1, GPR54, GnRH, LH and FSH in G2 and G4 were significantly increased compared with that in G1 and G3, respectively. Serum testosterone levels in G2 and G4 rats were significantly lower than those in G1 and G3 rats, respectively. There was no significant difference between the serum levels of FSH, LH and leptin. These results suggest that leptin and its receptor may serve significant roles in the pathogenesis of varicocele-induced testicular dysfunction.

Cryptotanshinone inhibits proliferation yet induces apoptosis by suppressing STAT3 signals in renal cell carcinoma.

It has been established that signal transducer and activator of transcription 3 serves as an oncoprotein in various human cancers; targeting it is therefore a reasonable approach for emerging cancer therapies. Cryptotanshinone, a natural compound extracted from the root of Salvia miltiorrhiza Bunge, has been identified as a potential STAT3 inhibitor. However, its functional role in renal cell carcinomas remains largely unknown. Therefore, we investigated the mode of action for cryptotanshinone. We found that cryptotanshinone substantially suppressed cancer cell growth while it promoted cell apoptosis by inhibiting the phosphorylation of STAT3 at Tyr705 and its blocking nuclear translocation. Coordinately, P-AKT, CyclinD1, C-MYC, MEKK2, and HGF were down-regulated and cell cycle progression was arrested at the G0/G1 phase, thereby attenuating cell proliferation. Moreover, the level of Cleaved-Caspase-3 was elevated while Bcl-2 and Survivin were down-regulated, accounting for the increased apoptosis. Furthermore, in vivo results revealed that cryptotanshinone effectively inhibits tumorigenesis in an A498-xenografted mouse model. Taken together, our data gives a more comprehensive understanding of how cryptotanshinone functions in renal cell carcinomas and demonstrates its potential as a powerful therapeutic approach to treat renal cell carcinomas.