ZNF692 promote proliferation through transcriptional repression of essential genes in clear cell renal carcinoma.

Transcription deregulation is recognized as a prominent hallmark of carcinogenesis. However, our understanding of the transcription factors implicated in the dysregulated transcription network of clear cell renal carcinoma (ccRCC) remains incomplete. In this study, we present evidence that ZNF692 drives tumorigenesis in ccRCC through the transcriptional repression of essential genes. We observed overexpression of ZNF692 in various cancers, including ccRCC, and found that the knockdown or knockout of ZNF692 suppressed the growth of ccRCC. Genome-wide binding site analysis using ChIP-seq revealed that ZNF692 regulates genes associated with cell growth, Wnt signaling, and immune response in ccRCC. Furthermore, motif enrichment analysis identified a specific motif (5'-GCRAGKGGAKAY-3') that is recognized and bound by ZNF692. Subsequent luciferase reporter assays demonstrated that ZNF692 transcriptionally represses the expression of IRF4 and FLT4 in a ZNF692 binding motif-dependent manner. Additionally, we observed MYC binding to the promoter regions of ZNF692 in most cancer types, driving ZNF692 overexpression specifically in ccRCC. Overall, our study sheds light on the functional significance of ZNF692 in ccRCC and provides valuable insights into its therapeutic potential as a target in cancer treatment.

TRIM38 triggers the uniquitination and degradation of glucose transporter type 1 (GLUT1) to restrict tumor progression in bladder cancer.

BACKGROUND: Loss-of-function mutations or abnormal expressions of E ubiquitin ligases contributes to tumorigenesis. TRIM38 was reported to regulate immunity, inflammatory responses or apoptosis, but its roles in tumor progression remain inconclusive. This study aimed to investigate the functional roles of TRIM38 in bladder cancer to identify effective targets. METHODS: Firstly, the expression data of ubiquitination-associated genes were derived from the TCGA-BLCA cohort. Univariate Cox regression method was utilized to screen prognostic genes. Colony formation assay, Transwell assay, sphere formation assays were used to assess functional roles of TRIM38. TAP/MS assay was used to identify downstream substrates of TRIM38. Fresh clinical BLCA tissues were collected to evaluate the clinicopathological features of patients with different TRIM38 expression. The subcutaneous tumor models were established to determine the drug efficacy of BAY-876. RESULTS: A list of ubiquitination-associated signature was identified based on the screening in TCGA-BLCA cohort. Subsequent validations revealed that TRIM38 was a significant suppressor in tumors, which was expressed lowly in BLCA. Kaplan-Meier analysis and correlation analysis suggested that patients with low TRIM38 expressions had shorter survival time and advanced clinical characteristics. Targeting TRIM38 reinforced BLCA cells proliferation, migration and stemness. Mechanistically, TRIM38 interacted with GLUT1, thereby promoting its ubiquitinoylation and degradation. Furthermore, TRIM38 deficiency relied on accumulated GLUT1 proteins to enhance BLCA malignant features and cellular glycolytic capacity. We accordingly investigated the efficacy of GLUT1 inhibitor (BAY-876) in BLCA and determined its IC50 values across cell lines. Tumor xenograft models further validated that BAY-876 could effectively suppress the in vivo growth of TRIM38low/- BLCA. CONCLUSIONS: Our results suggested that TRIM38 plays a tumor suppressive role in BLCA pathogenesis and TRIM38/GLUT1 axis is a therapeutic vulnerability for clinical treatment, which possessing great translational significance.

Chelerythrine induces apoptosis via ROS-mediated endoplasmic reticulum stress and STAT3 pathways in human renal cell carcinoma.

Renal cell carcinoma (RCC) is a heterogeneous histological disease and it is one of the most common kidney cancer. The treatment of RCC has been improved for the past few years, but its mortality still remains high. Chelerythrine (CHE) is a natural benzo[c]phenanthridine alkaloid and a widely used broad-range protein kinase C inhibitor which has anti-cancer effect on various types of human cancer cells. However, its effect on RCC has not been fully elucidated. In this study, we evaluated the effect and mechanism of CHE on RCC cells. Our study showed that CHE induced colony formation inhibition and G2/M cell cycle arrest in a dose-dependent manner in RCC cells. In addition, CHE increased cellular ROS level, leading to endoplasmic reticulum (ER) stress, inactivating STAT3 activities and inducing apoptosis in RCC cells which were suppressed by NAC, a special ROS inhibitor. We further found that both knockdown of ATF4 protein and overexpression of STAT3 protein could reduce CHE-induced apoptosis in Caki cells. These results demonstrated that the apoptosis induced by CHE was mediated by ROS-caused ER stress and STAT3 inactivation. Collectively, our studies provided support for CHE as a potential new therapeutic agent for the management of RCC.

Retrospective analysis of variant venous anatomy in 303 laparoscopic adrenalectomies and its clinical implications.

BACKGROUND AND OBJECTIVES: To clarify the correlation of variant venous anatomy with adrenal tumor phenotype and surgical outcomes. PATIENTS AND METHODS: This retrospective study included 303 consecutive minimally invasive adrenalectomies from 301 patients. All adrenal veins were identified. We compared the preoperative, intraoperative, and postoperative data between patients with and without variant adrenal venous anatomy. We also explored the factors associated with venous variants. RESULTS: We found variant venous anatomy in 62 of 303 adrenalectomies (20.5%). Compared with patients with normal anatomy, those with variant anatomy were associated with larger tumor size, larger adrenal veins, more adrenal medullary tumors, longer operation time, more estimated intraoperative blood loss, longer length of hospitalization, and more transfusion. Computed tomography (CT) images may improve the identification of venous anatomy. Tumor size and diagnosis of pheochromocytoma were independently related to variant venous anatomy, whereas sex, tumor size, and venous variant influenced hemorrhage. For pheochromocytoma with variant venous anatomy operated on by a single surgeon, robot-assisted laparoscopic adrenalectomy was associated with shorter postoperative hospitalization. CONCLUSIONS: Adrenal vein variants are associated with worse outcomes in adrenal tumors and an optimized surgery strategy should be applied to this group of patients.

Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling.

The goal of this research was to study the relationships between maternally expressed gene 3 (MEG3), microRNA-7 (miR-7), and RASL11B, and explore their influence on the progression of clear cell renal cell carcinoma (CCRCC). Microarray analysis was conducted using the data provided by The Cancer Genome Atlas. The expression levels of MEG3 and miR-7 in CCRCC and adjacent tissue samples were ascertained by quantitative real-time polymerase chain reaction (qRT-PCR). The cell proliferation activity was unmasked by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell apoptosis and cell cycle were investigated by flow cytometry. A dual luciferase reporter assay was used to verify target relationships. Wound healing assay and transwell assay were used to detect cell migration and invasion ability. Decreased MEG3 expression was observed in CCRCC tissues and cells. Overexpression of MEG3 accelerated apoptosis; inhibited cell proliferation, migration and invasion; and induced G0/G1 phase cell cycle arrest in CCRCC. MiR-7, directly binding to MEG3, was overexpressed in the CCRCC tissues and could inhibit the apoptosis and promote the migration and invasion of CCRCC cells. RASL11B, lowly expressed in CCRCC, was a target of miR-7. After the overexpression of RASL11B, G0/G1 phase cell cycle arrest was induced; cell apoptosis was promoted; and the proliferation, invasion, and migration of CCRCC cells were inhibited. MEG3 could up-regulate RASL11B to inhibit the cell proliferation, invasion, and migration; induce G0/G1 cell cycle arrest; and promote cell apoptosis by suppressing miR-7 in CCRCC.

Silencing of MED27 inhibits adrenal cortical carcinogenesis by targeting the Wnt/ß-catenin signaling pathway and the epithelial-mesenchymal transition process.

This study aimed to explore the effect of MED27 on the expression of epithelial-mesenchymal transition (EMT)-related proteins and ß-catenin in adrenal cortical carcinoma (ACC). The functional mechanism of MED27 on ACC processes was also explored. The expression of MED27 was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). siRNA was utilized to knockdown the expression of MED27. CCK8 assays were performed to evaluate SW-13 cell proliferation. Transwell assays were performed to assess the invasion ability, and wound healing assays were utilized to detect migration. A tumor xenograft mouse model was established to investigate the impact of silencing MED27 on tumor growth and metastasis. MED27 was highly expressed in ACC tissues and cells. Down-regulation of MED27 induced ACC cell apoptosis, and significantly attenuated ACC cell proliferation, invasion and metastasis in vivo and in vitro. MED27 knockdown regulated the expression of EMT-related proteins and Wnt/ß-catenin signaling pathway-related proteins. Our study investigated the function and mechanism of MED27 and validated that MED27 plays a negative role in ACC occurrence and progression and could be utilized as a new therapeutic target in ACC prevention and treatment.

ABCG2 is a potential prognostic marker of overall survival in patients with clear cell renal cell carcinoma.

BACKGROUND: ATP-binding cassette sub-family G member 2 (ABCG2) is a semi-transport protein that plays a major role in multidrug resistance. We aimed to evaluate the prognostic significance of ABCG2 expression in patients with clear cell renal cell carcinoma. METHODS: From 2008 to 2013, 120 patients with clear cell kidney cancer underwent surgery with paraffin-embedded specimens and necessary clinical information available. Immunohistochemistry staining was performed to grade the expression of ABCG2 as ABCG2(-): less than 10% of tumor cells stained; ABCG2(+): weak membrane staining; and ABCG2(++): moderate or strong membrane staining. The overall survival was analyzed using Kaplan-Meier method. Multivariable Cox regression evaluated the independent predictors for overall survival. RESULTS: ABCG2(-) was diagnosed in 57 (48%) patients, ABCG2(+) in 52 (43%) patients, and ABCG2 (++) in 11(9.2%) patients. ABCG2 expression significantly correlated with the five-year survival (p < 0.001) and distant metastasis (p = 0.001). In the multivariable analysis, besides Fuhrman grade, the ABCG2 expression was an independent prognostic marker for overall survival (p < 0.001) when incorporating other relevant tumor and clinical parameters (HR = 3.84, 95% CI: 1.92-7.70). CONCLUSION: The current data suggests that ABCG2 may serve as a prognostic marker for overall survival in patients with clear cell renal cell carcinoma. Further studies with large cohorts of patients will be essential for validating these findings and defining the clinical utility of ABCG2 in the patient population.

[Radical retropubic prostatectomy for prostate cancer with pelvic lymph node metastasis].

OBJECTIVE: To investigate the safety and effectiveness of radical retropubic prostatectomy (RRP) with adjuvant androgen deprivation or external radiotherapy in the treatment of prostate cancer (PCa) with pelvic lymph node metastasis (PLNM). METHODS: Twenty PCa patients underwent bilateral pedal lymphangiography (PLG) preoperatively, and 11 of them received lymph node aspiration for examination of the mRNA expressions of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) in the lymph fluid by real-time RT-PCR. All the patients were treated by RRP with extended dissection of pelvic lymph nodes, and 3 of them by external radiotherapy in addition after recovery from urinary incontinence because of positive surgical margins, followed by adjuvant androgen deprivation therapy. RESULTS: Real-time RT-PCR showed positive mRNA expressions of PSA and PSMA in the lymph fluid of the 11 patients, all pathologically confirmed with PLNM. The median intraoperative blood loss was 575 ml, with blood transfusion for 5 cases. Positive surgical margin was found in 3 cases, lymphorrhagia in 2 and urinary leakage in another 2 each. There were no such severe complications as vascular injury and rectum perforation. The patients were followed up for 6－48 (mean 42) months, during which, biochemical recurrence was observed in 12 cases at a median of 12 months postoperatively and 2 patients died at 12 and 48 months respectively. CONCLUSIONS: Bilateral PLG and lymph node aspiration for examination of the mRNA expressions of PSA and PSMA in the lymph fluid help to confirm PLNM preoperatively. Radical retropubic prostatectomy with adjuvant androgen deprivation or external radiotherapy is safe and effective for the treatment of PCa with PLNM, but it should be chosen cautiously for those with Gleason 5+5.

Right-Crossed, Fused Renal Ectopia L-Shaped Kidney Type with Urinary Chyluria.

Crossed fused renal ectopia combined with chyluria is extremely rare. Here we report the case of a patient who was admitted to our institution since milky urine and was finally found to have an L-shaped fused kidney and renal pelvis fistula. The patient was cured by renal pelvic instillation sclerotherapy.

The advantages of unilateral pedal lymphography in the diagnosis of chyluria.

OBJECTIVES: To evaluate the efficacy and safety of pedal lymphography (PLG) in the localization diagnosis of chyluria. METHODS: Cystoscopy was performed in 153 patients and PLG in 121 cases. Unilateral or staged bilateral ligation and stripping of renal lymphatic vessel were performed according to the results of cystoscopy and/or PLG. RESULTS: Unilateral and bilateral urinary excretion of chyle was detected in 123 and 1 case by cystoscopy, respectively. In 121 cases receiving PLG, 100 cases of unilateral fistulous connection between the renal pelvis and the lymphatic system, 18 cases of bilateral fistulas and 1 case of lymphatic bladder fistula were demonstrated. PLG has a higher diagnostic rate for the detection of bilateral lymphatic renal pelvis fistulas than cystoscopy (p<0.05). 28 cases received renal pedicle lymphatic disconnection only according to the results of cystoscopy, and 3 of them failed (10.1%). While 121 cases had the same operation according to the results of PLG, only 1 case failed the operation (0.8%). CONCLUSIONS: PLG was efficient and safe for the localization diagnosis of chyluria, with a higher detection rate of bilateral fistulas than cystoscopy. PLG might benefit the selection of appropriate therapy and improve the surgical effect.

Predicting CTLA4 expression and prognosis in clear cell renal cell carcinoma using a pathomics signature of histopathological images and machine learning.

Background: CTLA4, an immune checkpoint, plays an important role in tumor immunotherapy. The purpose of this study was to develop a pathomics signature to evaluate CTLA4 expression and predict clinical outcomes in clear cell renal cell carcinoma (ccRCC) patients. Methods: A total of 354 patients from the TCGA-KIRC dataset were enrolled in this study. The patients were stratified into two groups based on the level of CTLA4 expression, and overall survival rates were analyzed between groups. Pathological features were identified using machine learning algorithms, and a gradient boosting machine (GBM) was employed to construct the pathomics signatures for predicting prognosis and CTLA4 expression. The predictive performance of the model was subsequently assessed. Enrichment analysis was performed on diferentially expressed genes related to the pathomics score (PS). Additionally, correlations between PS and TMB, as well as immune infiltration profiles associated with different PS values, were explored. In vitro experiments, CTLA4 knockdown was performed to investigate its impact on cell proliferation, migration, invasion, TGF-ß signaling pathway, and macrophage polarization. Results: High expression of CTLA4 was associated with an unfavorable prognosis in ccRCC patients. The pathomics signature displayed good performance in the validation set (AUC = 0.737; P < 0.001 in the log-rank test). The PS was positively correlated with CTLA4 expression. We next explored the underlying mechanism and found the associations between the pathomics signature and TGF-ß signaling pathways, TMB, and Tregs. Further in vitro experiments demonstrated that CTLA4 knockdown inhibited cell proliferation, migration, invasion, TGF-ß expression, and macrophage M2 polarization. Conclusion: High expression of CTLA4 was found to correlate with poor prognosis in ccRCC patients. The pathomics signature established by our group using machine learning effectively predicted both patient prognosis and CTLA4 expression levels in ccRCC cases.

Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.

Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-ß) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-ß+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-ß+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.

Deubiquitinase UCHL1 stabilizes KDM4B to augment VEGF signaling and confer bevacizumab resistance in clear cell renal cell carcinoma.

BACKGROUND: Bevacizumab resistance poses barriers to targeted therapy in clear cell renal cell carcinoma (ccRCC). Whether there exist epigenetic targets that modulate bevacizumab sensitivity in ccRCC remains indefinite. The focus of this study is to explore the role of UCHL1 in ccRCC. METHODS: Both in vitro and in vivo experiments were utilized to investigate the roles of UCHL1 in ccRCC. In vivo ubiquitination assays were performed to validate the posttranslational modification of KDM4B by UCHL1. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were utilized to explore KDM4B/VEGFA epigenetic regulations. RESULTS: UCHL1 was increased in ccRCC and associated with unfavorable survival outcomes in patients. UCHL1 was required for ccRCC growth and migration. Mechanistically, the wild-type UCHL1, but not C90A mutant, mediated the deubiquitination of KDM4B and thereby stabilized its proteins. KDM4B was up-regulated in ccRCC and potentiated cell growth. UCHL1 depended on KDM4B to augment ccRCC malignancies. Targeting UCHL1 suppressed tumor growth, colony formation, and migration abilities, which could be rescued by KDM4B. Furthermore, KDM4B was directly bound to the promoter region of VEGFA, abolishing repressive H3K9me3 modifications. KDM4B coordinated with HIF2α to activate VEGFA transcriptional levels. UCHL1-KDM4B axis governs VEGFA levels to sustain the angiogenesis phenotypes. Finally, a specific small-molecule inhibitor (6RK73) targeting UCHL1 remarkably inhibited ccRCC progression and further sensitized ccRCC to bevacizumab treatment. CONCLUSION: Overall, this study defined an epigenetic mechanism of UCHL1/KDM4B in activating VEGF signaling. The UCHL1-KDM4B axis represents a novel target for treating ccRCC and improving the efficacy of anti-angiogenesis therapy.

Reduction of intercellular adhesion molecule 1 may play a role in anti-inflammatory effect of hyaluronic acid in a rat model of severe non-bacterial cystitis.

PURPOSE: To evaluate the impact of intercellular adhesion molecule 1 (ICAM-1) in hyaluronic acid (HA) therapy in rats model of severe non-bacterial cystitis. METHODS: Cystitis models in Sprague-Dawley female rats were produced by combination of intraperitoneal cyclophosphamide (CYP) with intravesical protamine/lipopolysaccharide (PS/LPS). HA or heparin (0.5 ml) was introduced intravesically to rats' bladders followed PS/LPS. Bladder tissue was prepared for histology including mast cell presence and measurement of ICAM-1, tumor necrosis factor (TNF)-α, and interleukin 6 (IL-6). RESULTS: Cystitis model using intraperitoneal CYP and intravesical SP/LPS showed serious inflammation, higher mast cell count with elevated ICAM-1, TNF-α, and IL-6 levels. After intravesical heparin or HA treatment, incidence of grades 3-4 bladder inflammation and tissue ICAM-1 level were only significantly lower in HA group (P = 0.017, P = 0.021, respectively), but not in heparin group (P = 0.12, P = 0.798, respectively). Remarkably lower level of TNF-α (P = 0.003) and ICAM-1 (P = 0.006) was detected in HA-treated rats compared with heparin-treated rats. Inflammation grade and ICAM-1 level had strong correlation (P < 0.001). IL-6 level after HA or heparin instillation had no difference. CONCLUSIONS: Intravesical administration of HA decreased the severity of bladder inflammation, mast cell presence, and levels of ICAM-1 and TNF-α in a rat model of severe non-bacterial cystitis; its effect was more obvious than that of heparin. Reduction of ICAM-1 may play a role in the anti-inflammatory effect of HA.

Computed tomography-based radiomics prediction of CTLA4 expression and prognosis in clear cell renal cell carcinoma.

OBJECTIVES: To predict CTLA4 expression levels and prognosis of clear cell renal cell carcinoma (ccRCC) by constructing a computed tomography-based radiomics model and establishing a nomogram using clinicopathologic factors. METHODS: The clinicopathologic parameters and genomic data were extracted from 493 ccRCC cases of the Cancer Genome Atlas (TCGA)-KIRC database. Univariate and multivariate Cox regression and Kaplan-Meier analysis were performed for prognosis analysis. Cibersortx was applied to evaluate the immune cell composition. Radiomic features were extracted from the TCGA/the Cancer Imaging Archive (TCIA) (n = 102) datasets. The support vector machine (SVM) was employed to establish the radiomics signature for predicting CTLA4 expression. Receiver operating characteristic curve (ROC), decision curve analysis (DCA), and precision-recall curve were utilized to assess the predictive performance of the radiomics signature. Correlations between radiomics score (RS) and selected features were also evaluated. An RS-based nomogram was constructed to predict prognosis. RESULTS: CTLA4 was significantly overexpressed in ccRCC tissues and was related to lower overall survival. A higher CTLA4 expression was independently linked to the poor prognosis (HR = 1.458, 95% CI 1.13-1.881, p = 0.004). The radiomics model for the prediction of CTLA4 expression levels (AUC = 0.769 in the training set, AUC = 0.724 in the validation set) was established using seven radiomic features. A significant elevation in infiltrating M2 macrophages was observed in the RS high group (p < 0.001). The predictive efficiencies of the RS-based nomogram measured by AUC were 0.826 at 12 months, 0.805 at 36 months, and 0.76 at 60 months. CONCLUSIONS: CTLA4 mRNA expression status in ccRCC could be predicted noninvasively using a radiomics model based on nephrographic phase contrast-enhanced CT images. The nomogram established by combining RS and clinicopathologic factors could predict overall survival for ccRCC patients. Our findings may help stratify prognosis of ccRCC patients and identify those who may respond best to ICI-based treatments.

The SIRT7-mediated deacetylation of CHD1L amplifies HIF-2α-dependent signal that drives renal cell carcinoma progression and sunitinib resistance.

BACKGROUND: Aberrant interplay between epigenetic reprogramming and hypoxia signaling contributes to renal cell carcinoma progression and drug resistance, which is an essential hallmark. How the chromatin remodelers enhance RCC malignancy remains to be poorly understood. We aimed to elucidate the roles of CHD1L in determining hypoxia signaling activation and sunitinib resistance. METHODS: The qRT-PCR, western blotting, and immunohistochemistry technologies were used to detect CHD1L expressions. Lentivirus transfection was used to generate stable CHD1L-KD cells. The roles of SIRT7/CHD1L were evaluated by CCK-8, wound healing, transwell assays, xenograft models, and tail-vein metastasis models. Co-immunoprecipitation, Chromatin Immunoprecipitation (ChIP), and luciferase reporter assays were conducted to explore epigenetic regulations. RESULTS: We screened and validated that CHD1L is up-regulated in RCC and correlates with poorer prognosis of patients. CHD1L overexpression notably enhances cell proliferation, migration, and self-renewal capacities in vitro and in vivo. Mechanistically, SIRT7 physically interacts with CHDL1 and mediates the deacetylation of CHD1L. Wild-type SIRT7, but not H187Y dead mutant, stabilizes CHD1L protein levels via attenuating its ubiquitination levels. SIRT7 is increased in RCC and correlates with hazardous RCC clinical characteristics. SIRT7 depends on CHD1L to exert its tumor-promoting functions. Accumulated CHD1L amplifies HIF-2α-driven transcriptional programs via interacting with HIF-2α. CHD1L recruits BRD4 and increases the RNA polymerase II S2P loading. CHD1L ablation notably abolishes HIF-2α binding and subsequent transcriptional activation. CHD1L overexpression mediates the sunitinib resistance via sustaining VEGFA and targeting CHD1L reverses this effect. Specific CHD1L inhibitor (CHD1Li) shows a synergistic effect with sunitinib and strengthens its pharmaceutical effect. CONCLUSIONS: These results uncover a CHD1L-mediated epigenetic mechanism of HIF-2α activation and downstream sunitinib resistance. The SIRT7-CHD1L-HIF-2α axis is highlighted to predict RCC prognosis and endows potential targets.

YAP-Activated SATB2 Is a Coactivator of NRF2 That Amplifies Antioxidative Capacity and Promotes Tumor Progression in Renal Cell Carcinoma.

Aberrant epigenetic reprogramming contributes to the progression of renal cell carcinoma (RCC). Elucidation of key regulators of epigenetic reprogramming in RCC could help identify therapeutic vulnerabilities to improve treatment. Here, we report upregulation of the nuclear matrix-associated protein, special AT-rich binding protein-2 (SATB2), in RCC samples, which correlated with poor prognosis. SATB2 inhibition suppressed RCC growth and self-renewal capacities. YAP/TEAD4 activated SATB2 expression and depended on SATB2 to enhance cell proliferation. Transcriptome analysis implicated that SATB2 regulates NRF2 downstream targets to suppress oxidative stress without altering NRF2 levels. Integrated chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin using sequencing analyses demonstrated that SATB2 coordinated with NRF2 to drive enhancer-promoter interactions, amplifying transcriptional activity. SATB2 recruited SWI/SNF complex subunits, including BRD7 or BRG1, to sustain DNA accessibility. Increased SATB2 triggered chromatin remodeling into configurations that rendered RCC more sensitive to SATB2 deficiency. Moreover, SATB2 ablation promoted the sensitivity of RCC to chemotherapy-induced apoptosis. Finally, targeting SATB2 or BRD7 effectively restricted the proliferation of YAP-high tumors in patient-derived xenografts and patient-derived organoids. Together, SATB2 is an oncogenic chromatin organizer in RCC, and targeting SATB2 is an effective strategy to suppress the YAP-high RCC. SIGNIFICANCE: A YAP-SATB2-NRF2 regulatory axis amplifies antioxidative stress signaling and provides potential therapeutic targets to enhance response to chemotherapy in renal cell carcinoma.

Retroperitoneal adrenal-sparing surgery for the treatment of Cushing's syndrome caused by adrenocortical adenoma: 8-year experience with 87 patients.

BACKGROUND: The objective of this study was to present our 8-year experience with partial adrenalectomy via the retroperitoneal approach for the treatment of Cushing's adenoma. METHODS: A total of 93 patients who underwent adrenal surgery for Cushing's adenoma from March 2003 to December 2010 were enrolled in this study. Preoperative, intraoperative, and postoperative variables were reviewed from the database. Student's t test was used to analyze the continuous data, and the χ(2) test was used to analyze the categoric data. A value of p < 0.05 was considered statistically significant. RESULTS: Adrenal-sparing surgery was performed in 87 cases (31 by open surgery, 56 by retroperitoneal laparoscopy). Six patients underwent open/laparoscopic total adrenalectomy because of recurrent disease or a large size. The cure rate in our series was 97.8%. Hypertension resolved in 34 of 64 patients (53.1%), diabetes in 7 of 27 patients (25.9%) and obesity in 28 of 48 patients (58.3%). One patient died during the postoperative period. The intraoperative complication rate for the open surgery group was significantly higher than that for the retroperitoneal laparoscopy group (9.1 vs. 1.7%). CONCLUSIONS: The retroperitoneal approach is reliable and safe for treating Cushing's syndrome. The laparoscopic technique can decrease the prevalence of intraoperative complications. Retroperitoneal laparoscopic partial adrenalectomy can be performed with extremely low morbidity and achieves an excellent outcome, although death may occur during the postoperative period in high-risk patients. Postoperative management plays an important role in the surgical treatment of Cushing's syndrome.

Tension-free vaginal tape retropubic sling for recurrent stress urinary incontinence after Burch colposuspension failure.

OBJECTIVES: To verify the efficacy and to clarify the mechanism of the tension-free vaginal tape retropubic sling for recurrent stress urinary incontinence after Burch colposuspension failure. METHODS: A total of 24 women having tension-free vaginal tape retropubic sling placement for recurrent stress urinary incontinence after a previous failed Burch urethropexy were enrolled in the present study. Median follow up was 57 months (range 12-96). Pre- and postoperative urethral mobility and urodynamics were evaluated. RESULTS: Preoperatively, all 24 patients had intrinsic sphincter deficiency and 14 had urethral hypermobility. Postoperatively, 15 patients were completely dry and two had a leakage of urine less than 5 g/h. The overall success rate was 70.8%. There was a significant postoperative increase of maximum urethral closure pressure (P < 0.001), and a decrease of average flow rate (P = 0.001) and urethral hypermobility (P < 0.001). When comparing successful with failure cases, only elevated maximum urethral closure pressure (P = 0.002) was significantly different. Multivariate logistic regression showed the change of maximum urethral closure pressure (P = 0.011) was the only independent parameter significantly correlated with the outcome of sling placement. CONCLUSIONS: Recurrent stress urinary incontinence with intrinsic sphincter deficiency after Burch colposuspension might be well treated with the tension-free vaginal tape retropubic sling by effectively elevating the maximum urethral closure pressure.

Primary malignant teratoma of the kidney: a rare case report and literature review.

Teratomas originate from pluripotent cells and can differentiate along one or more embryonic germ lines. Renal teratoma is infrequent and malignant renal teratoma is even rarer. Experience in the diagnosis and treatment of this uncommon malignancy is seriously limited. In this report, we described the case of a 64-year-old female who complained of right flank pain for 4 months. Computed tomography (CT) revealed a hypodense mass (50 mm in maximum diameter) with slow contrast enhancement and obscure boundary located in the lower pole of the right kidney. CT also showed multiple retroperitoneal lymphadenectasis. Retroperitoneal laparoscopic right radical nephrectomy along with regional lymphadenectomy was successfully performed, and postoperative pathological examination confirmed malignant teratoma of the kidney. After surgery, the patient received adjuvant chemotherapy with BEP (bleomycin, etoposide, and cisplatin) protocol. At the 6-month follow-up, pulmonary and liver metastases were discovered by CT and the patient refused any further treatment. Unfortunately, she died at 16 months postoperatively. Although primary renal malignant teratoma is extremely rare, this kind of tumor should be taken into consideration. Currently, there is no therapeutic standard consensus for this disease and the prognosis remains unclear. Early detection and surgical intervention is critical, and more research on postoperative adjuvant therapy should be performed.