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V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2), belonging to the ETS family of transcription factors, is implicated in a broad range of cellular functions. Recently, ETS2 has been found playing an important role in the progression of some types of cancers. However, it remains unclear whether ETS2 has any effects on renal cell carcinoma (RCC). In this study, we investigated the biological functions of ETS2 in RCC. The results showed that ETS2 was highly expressed in RCC tissues and cell lines and its expression had an association with clinicopathological characteristics of RCC patients. In addition, down-regulation of ETS2 significantly inhibited RCC cell invasion in vitro and metastasis in vivo as well as suppressed the epithelial-mesenchymal transition (EMT) process. We also found that ETS2 down-regulation significantly reduced the levels of PI3K and Akt phosphorylation in RCC cells. Taken together, we suggest that ETS2 is of potential value as a molecular target for RCC treatment. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) accounts for approximately 2%-3% of human malignancies and is the most aggressive among urologic tumors. Biological heterogeneity, drug resistance, and chemotherapy side effects are the biggest obstacles to the effective treatment of RCC. The NF-kB transcription factor is one of several molecules identified to be responsible for the aggressive phenotype of this tumor. In the past decade, several studies have demonstrated the activation of NF-kB in RCC, and many have implicated NF-kB1 (p50) as an important molecule in tumor progression and metastasis. In the present study, a lentivirus was used to deliver shRNA targeting NF-kB1 into mouse RCC (Renca) cells. It was determined that the knockdown of the NF-kB1 gene led to a reduction in cell proliferation and late apoptosis/necrosis in vitro. Flow cytometry analysis demonstrated G2/M arrest in the cells. In addition, immunoblotting analysis revealed a significant increase in cyclin B1 and Bax. In vivo experiments showed that Renca-shRNA-NF-kB1 cells have significantly diminished tumori genicity. Moreover, immunohistochemical analysis revealed an increase in necrotic areas of Renca-shRNA-NF-kB1 tumors. Thus, this study indicates that downregulation of NF-kB1 can suppress RCC tumorigenesis by inducing late apoptosis/necrosis. Therefore, NF-kB1 may be a potential therapeutic target for RCC. [ABSTRACT FROM AUTHOR]

Twist1 is a key transcription factor, which confers tumor cells with cancer stem cell (CSC)-like characteristics and enhances epithelial-mesenchymal transition in pathological conditions including tumor malignancy and metastasis. This study aimed to evaluate the expression patterns and clinical significance of Twist1 in renal cell carcinoma (RCC). The cytoplasmic and nuclear expression of Twist1 were examined in 252 well-defined renal tumor tissues, including 173 (68.7%) clear cell renal cell carcinomas (ccRCC), 45 (17.9%) papillary renal cell carcinomas (pRCC) and 34 (13.5%) chromophobe renal cell carcinoma, by immunohistochemistry on a tissue microarray. The association between expression of this marker and clinicopathologic parameters and survival outcomes were then analyzed. Twist1 was mainly localized to the cytoplasm of tumor cells (98.8%). Increased cytoplasmic expression of Twist1 was associated with higher grade tumors (P = 0.045), renal vein invasion (P = 0.031) and microvascular invasion (P = 0.044) in RCC. It was positively correlated with higher grade tumors (P = 0.026), shorter progression-free survival time (P = 0.027) in patients with ccRCC, and also with higher stage in pRCC patients (P = 0.036). Significantly higher cytoplasmic expression levels of Twist1 were found in ccRCC and pRCC subtypes, due to their more aggressive tumor behavior. Increased cytoplasmic expression of Twist1 had a critical role in worse prognosis in ccRCC. These findings suggest that cytoplasmic, rather than nuclear expression of Twist1 can be considered as a prognostic and therapeutic marker for targeted therapy of RCC, especially for ccRCC patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: CD105 is recently described as a cancer stem cell (CSC) marker. OBJECTIVE: The present study was aimed to investigate the expression and prognostic significance of the CSC marker CD105 in different histological subtypes of renal cell carcinoma (RCC). METHODS: Expression of CD105 was evaluated using immunohistochemistry in RCC samples on tissue microarrays including clear cell RCCs (ccRCCs), papillary, and chromophobe RCCs. The association between CD105 expression and clinicopathological features as well as survival outcomes was determined. RESULTS: In ccRCC, increased tumoral cytoplasmic and endothelial expression of CD105 were significantly associated with advanced stage, renal vein invasion, and microvascular invasion (MVI). In addition, MVI was associated with a worse overall survival (OS). Moreover, in multivariate analysis tumor stage and nuclear grade were independent prognostic factors for OS both in case of tumoral cytoplasmic and endothelial CD105 expression. Additionally, CD105 expression was found to be a predictor of worse OS in univariate analysis. However, in papillary and chromophobe RCC, no significant association was found between CD105 expression and clinicopathological parameters or prognosis. CONCLUSIONS: We showed that CD105 expression was associated with more aggressive tumor behavior, more advanced disease, and worse prognosis in ccRCC but not in the other RCC subtypes. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are emerging as pivotal regulators in the development and progression of various cancers, including renal cell carcinoma (RCC). MicroRNA-384 (miR-384) has been found to be an important cancer-related miRNA in several types of cancers. However, the role of miR-384 in RCC remains unclear. In this study, we aimed to investigate the potential function of miR-384 in regulating tumorigenesis in RCC. Here we found that miR-384 was significantly downregulated in RCC tissues and cell lines. Overexpression of miR-384 significantly inhibited the growth and invasion of RCC cells, whereas inhibition of miR-384 had the opposite effects. Bioinformatic analysis and luciferase reporter assay showed that miR-384 directly targeted the 3'-untranslated region of astrocyte elevated gene 1 (AEG-1). Further data showed that miR-384 could negatively regulate the expression of AEG-1 in RCC cells. Importantly, miR-384 expression was inversely correlated with AEG-1 expression in clinical RCC specimens. Moreover, miR-384 regulates the activation of Wnt signaling. Overexpression of AEG-1 significantly reversed the antitumor effects of miR-384. Overall, these findings suggest that miR-384 suppresses the growth and invasion of RCC cells via downregulation of AEG-1, providing a potential therapeutic target for the treatment of RCC. [ABSTRACT FROM AUTHOR]

Background: Stereotactic ablative radiotherapy (SABR) is an emerging therapy for primary renal cell carcinoma. The authors assessed safety, efficacy, and survival in a multi-institutional setting. Outcomes between single-fraction and multifraction SABR were compared.Methods: Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 4.0. Patient, tumor, and treatment characteristics were stratified according to the number of radiotherapy fractions (single vs multiple). Survival outcomes were examined using Kaplan-Meier estimates and Cox proportional-hazards regression.Results: Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control, cancer-specific survival, and progression-free survival were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years. On multivariable analysis, tumors with a larger maximum dimension and the receipt of multifraction SABR were associated with poorer progression-free survival (hazard ratio, 1.16 [P < .01] and 1.13 [P = .02], respectively) and poorer cancer-specific survival (hazard ratio, 1.28 [P < .01] and 1.33 [P = .01], respectively). There were no differences in local failure between the single-fraction cohort (n = 1) and the multifraction cohort (n = 2; P = .60). The mean ( ± standard deviation) estimated glomerular filtration rate at baseline was 59.9 ± 21.9 mL per minute, and it decreased by 5.5 ± 13.3 mL per minute (P < .01).Conclusions: SABR is well tolerated and locally effective for treating patients who have primary renal cell carcinoma and has an acceptable impact on renal function. An interesting observation is that patients who receive single-fraction SABR appear to be less likely to progress distantly or to die of cancer. Cancer 2018;124:934-42. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that dysregulation of microRNAs is associated with the development of multiple malignancies. miR-186 has been reported as a critical cancer regulator in several types of cancers. However, its functional significance and molecular mechanism underlying renal cell carcinoma (RCC) remain unknown. In this study, our results showed that miR-186 expression was dramatically downregulated in RCC tissues and cell lines compared to that in adjacent normal tissues and cell lines. Overexpression of miR-186 significantly inhibited cell growth, colony formation, and cell invasion; caused cell cycle arrest at the G0/G1 phase; and induced cell apoptosis as detected by MTT, colony formation, Transwell assay, and flow cytometry assays in RCC cells. In addition, inhibition of miR-186 expression promoted RCC cell proliferation, invasion, and cell cycle progression and reduced apoptosis. Bioinformatics analysis and luciferase reporter assay confirmed that the 3¢-UTR of sentrin-specific protease 1 (SENP1) was a direct target of miR-186. A remarkably reverse correlation was observed between miR-186 and SENP1 mRNA in RCC tissues. Furthermore, immunohistochemical staining revealed that SENP1 was positively expressed in RCC specimens. Restoration of SENP1 expression could partially abrogate the inhibitory effect of miR-186 overexpression on RCC cell proliferation through activating NF-ĀB signaling and its downstream proteins. These data demonstrated that miR-186 acted as a novel tumor suppressor and potential therapeutic biomarker in the progression of RCC by directly targeting SENP1. [ABSTRACT FROM AUTHOR]

Transforming acidic coiled-coil protein 3 (TACC3) is a member of the TACC family and plays an important role in regulating cell mitosis, transcription, and tumorigenesis. However, the expression pattern and roles of TACC3 in renal cell carcinoma (RCC) remain unclear. The aim of this study was to investigate the role of TACC3 in RCC. We demonstrated overexpression of TACC3 in human RCC cell lines at both RNA and protein levels. Moreover, knockdown of TACC3 repressed RCC cell proliferation, migration, and invasion in vitro. In addition, knockdown of TACC3 inactivated PI3K/Akt signaling in RCC cells. Furthermore, knockdown of TACC3 significantly reduced tumor growth in xenograft tumor-bearing mice. Taken together, our findings showed that TACC3 was increased in human RCC cell lines, and knockdown of TACC3 inhibited the ability of cell proliferation, migration, invasion, and tumorigenesis in vivo. Therefore, TACC3 may act as a therapeutic target for the treatment of human RCC. [ABSTRACT FROM AUTHOR]

Increased abdominal imaging has led to an increase in the detection of the incidental small renal mass (SRM). With increasing recognition that the malignant potential of SRMs is heterogeneous, ranging from benign (15%-20%) to aggressive (20%), enthusiasm for more conservative management strategies in the elderly and infirmed, such as active surveillance (AS), have grown considerably. As the management of the SRM evolves to incorporate ablative techniques and AS for low risk disease, the role of renal mass biopsy (RMB) to help guide individualized therapy is evolving. Historically, the role of RMB was limited to the evaluation of suspected metastatic disease, renal abscess, or lymphoma. However, in the contemporary era, the role of biopsy has grown, most notably to identify patients who harbor benign lesions and for whom treatment, particularly the elderly or frail, may be avoided. When performing a RMB to guide initial clinical decision making for small, localized tumors, the most relevant questions are often relegated to proof of malignancy and documentation (if possible) of grade. However, significant intratumoral heterogeneity has been identified in clear cell renal cell carcinoma (ccRCC) that may lead to an underestimation of the genetic complexity of a tumor when single-biopsy procedures are used. Heterogeneous genomic landscapes and branched parallel evolution of ccRCCs with spatially separated subclones creates an illusion of clonal dominance when assessed by single biopsies and raises important questions regarding how tumors can be optimally sampled and whether future evolutionary tumor branches might be predictable and ultimately targetable. This work raises profound questions concerning the genetic landscape of cancer and how tumor heterogeneity may affect, and possibly confound, targeted diagnostic and therapeutic interventions. In this review, we discuss the current role of RMB, the implications of tumor heterogeneity on diagnostic accuracy, and highlight promising future directions.

BACKGROUND: Renal cell carcinoma (RCC) represents the seventh malignant neoplasm in patients under 75 years old and affects both sexes equally; however, its presence associated with Urothelial Carcinoma (UC) is not registered. Therefore the diagnosis of synchronous ipsilateral primary RCC y UC is considered extraordinary rare, with only 50 cases reported in the literature. CASE: The present study reports the case of a 76-year-old male with an initial clinical diagnosis of renal cell carcinoma, whose postoperative pathology showed synchronous ipsilateral urothelial carcinoma in the renal pelvis. CONCLUSIONS: Synchronous ipsilateral RCC and UC is extraordinarily rare, with only a few cases reported in the literature until now and causes many challenges for research; in the first place, the necessity to do a correct preoperatory diagnosis in order to achieve a better surgical management for the patient; the lack of consensus about the prognosis and survival; and finally, the possible risk factors involved in the simultaneous cancer development. [ABSTRACT FROM AUTHOR]

Metastases to the breast are very uncommon as compared to primary tumours. Breast is an unusual site for metastasis from renal cell carcinoma. Only occasional cases are reported in the literature. These metastases must be clearly diagnosed as the treatment of primary breast cancer and metastases differs markedly. Treatment of isolated metastases from renal cell carcinoma is usually surgical resection. We report two cases of isolated metachronous metastases to breast from renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC) is a newly introduced histological type of RCC, which is caused by loss of subunit genes of SDH. It is known to frequently demonstrate familial occurrence and be frequently associated with gastrointestinal stromal tumors and paraganglioma. To date, only 53 cases have been reported. Here, we present an additional case of SDH-deficient RCC occurring in a 40-year-old female. The tumor was histologically biphasic, consisting of tubular and solid architectures. The tumor cells possessed oval nuclei with small nucleoli, and an eosinophilic granular cytoplasm with occasional vacuoles. These cells completely lost the immunohistochemical expression of B subunit of SDH (SDHB). Consequently, the tumor was diagnosed as SDHB-deficient RCC. We identified a novel germ line mutation of the SDHB gene, and also confirmed a hemizygous deletion of the wild-type allele in the tumor cells. To define the pathological characteristics of SDH-deficient RCC, precise diagnosis and accumulation of more cases are required. [ABSTRACT FROM AUTHOR]

Prominin-1 (CD133) is one of the most commonly used markers for cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CSCs in renal cell carcinoma (RCC) remains unclear. The aim of this study was to investigate the expression patterns and prognostic significance of the cancer stem cell marker CD133 in different histological subtypes of RCC. CD133 expression was evaluated using immunohistochemistry in 193 well-defined renal tumor samples on tissue microarrays, including 136 (70.5%) clear cell renal cell carcinomas (CCRCCs), 26 (13.5%) papillary RCCs, and 31 (16.1%) chromophobe RCCs. The association between CD133 expression and clinicopathological features as well as the survival outcomes was determined. There was a statistically significant difference between CD133 expression among the different RCC subtypes. In CCRCC, higher cytoplasmic expression of CD133 was significantly associated with increase in grade, stage, microvascular invasion (MVI) and lymph node invasion (LNI), while no association was found with the membranous expression. Moreover, on multivariate analysis, TNM stage and nuclear grade were independent prognostic factors for overall survival (OS) in cytoplasmic expression. We showed that higher cytoplasmic CD133 expression was associated with more aggressive tumor behavior and more advanced disease in CCRCC but not in the other examined subtypes. Our results demonstrated that higher cytoplasmic CD133 expression is clinically significant in CCRCC and is associated with increased tumor aggressiveness and is useful for predicting cancer progression. [ABSTRACT FROM AUTHOR]

This study was to investigate the involvement of long non-coding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) in renal cell carcinoma (RCC) and to further uncover its underlying mechanism. In this study, the expression of CCAT1 and Livin of RCC tissues or cells was determined using qRT-PCR (quantitative real-time PCR) and western blot, respectively. RNA pulldown and RIP (RNA-Binding Protein Immunoprecipitation) assays were performed to examine the sequence interaction between CCAT1 and Livin. The viability and apoptosis of RCC cells was assessed by MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and TUNEL (TdT-mediated dUTP nick end labeling) assays, respectively. Mice of tumor animal models were established to observe the effect of CCAT1 on RCC tumor growth. The relative expression of CCAT1 in RCC tissues and cell lines was obviously higher than that of the control. CCAT1 knockdown could reduce cell viability and increase the apoptosis of RCC cells in vitro. Furthermore, Livin was significantly inhibited by CCAT1 silencing; RNA pulldown and RIP assays showed that CCAT1 was physically associated with Livin protein. Moreover, Livin overexpression not only significantly inhibited RCC cell apoptosis and increased cell viability, but completely reversed the si-CCAT1-mediated repression of cell viability. More importantly, CCAT1 silencing could inhibit the growth of RCC in vivo that was accompanied by the reduction of Livin in RCC tissues. CCAT1 inhibits RCC cell apoptosis and increases cell viability through up-regulation of Livin. [ABSTRACT FROM AUTHOR]

Tumor protein D52 (TPD52) is a member of the TPD52-like protein family and plays different roles in various types of malignancies. However, its role in renal cell carcinoma (RCC) is still unclear. In this study, we investigated the role of TPD52 in RCC. The mechanism of TPD52 in RCC was also investigated. Our data demonstrated that the expression levels of TPD52 in both mRNA and protein were significantly decreased in RCC cells. Overexpression of TPD52 inhibited proliferation, migration, and invasion with decreased epithelial-mesenchymal transition (EMT) phenotype in RCC cells, as well as attenuated tumor growth in renal cancer xenografts. Mechanistically, overexpression of TPD52 significantly inhibited downregulated phosphorylation levels of PI3K and Akt in RCC cells. In conclusion, the present study demonstrated that TPD52 inhibited growth and metastasis of RCC, at least in part, by suppressing the PI3K/Akt signaling pathway. Therefore, these findings suggest that TPD52 may be a promising therapeutic target for the treatment of human RCC. [ABSTRACT FROM AUTHOR]

Increasing evidence has demonstrated that aberrant microRNAs (miRNAs) play important roles in the pathogenesis of most human malignancies. The purpose of this study was to explore the role of miR-30b-5p in human RCC. In the current study, we firstly found that the expression levels of miR-30b-5p were lower in both RCC tissues and cell lines. Then, we found that enforced miR-30b-5p expression and knockdown of GNA13 significantly suppressed the proliferation, invasion, migration and EMT of RCC cell lines. In addition, miR-30b-5p directly targeted GNA13 and repressed its expression. Furthermore, re-expression of GNA13 (without the 3′-UTR) could partially abrogate the miR-30b-5p-induced cell proliferation and metastasis inhibition. Taken together, these findings indicated that miR-30b-5p acts as a novel tumor suppressor to regulate RCC cell proliferation, metastasis and EMT through downregulation of GNA13 expression. Therefore, miR-30b-5p may be considered a potential biomarker for the diagnosis of RCC. [ABSTRACT FROM AUTHOR]

The 58-kDa microspherule protein (MSP58) has been reported to play an important role in the tumorigenesis and progression of cancers. However, little is known about the role of MSP58 in human renal cell carcinoma (RCC). In this study, we investigated the expression and biological roles of MSP58 in RCC. The results indicated that the expressions of MSP58 at both mRNA and protein levels were greatly up-regulated in human RCC tissues and cell lines. Down-regulation of MSP58 significantly suppressed the proliferation, migration/invasion of RCC cells, as well as attenuated tumor growth in a 786-O xenograft model in vivo . Mechanistically, knockdown of MSP58 expression sharply down-regulated the protein expression levels of β-catenin, c-myc and cyclin D1 in 786-O cells. Taken together, these findings showed that MSP58 downregulation suppressed the proliferation and invasion of RCC cells, at least in part, through regulating the Wnt/β-catenin signaling pathway. Thus, MSP58 may act as a novel therapeutic target for the treatment of RCC. [ABSTRACT FROM AUTHOR]

Background: In recent years, there have been increasing indications for percutaneous renal biopsy. Fine-needle aspiration (FNA), with or without core needle biopsy (CB), has been used increasingly in the management of renal tumors at the study institution.Methods: A computerized search of laboratory records was conducted to retrieve FNA cases of renal masses as well as the correlating CB and/or nephrectomy specimens. The cases spanned a period of 10 years (2006-2015). The diagnoses were classified into 5 categories: malignant, suspicious for malignancy, neoplastic, atypical, and negative/nondiagnostic. Based on the results of the nephrectomy specimens, the diagnostic rate, sensitivity, and diagnostic accuracy were calculated among 3 groups of specimens: FNA only, CB only, and combined FNA and CB.Results: A total of 247 cases of FNA with 123 correlating CB and 101 follow-up nephrectomy specimens were identified. The diagnostic rate, sensitivity, and diagnostic accuracy were 72%, 78%, and 96%, respectively, for FNA; 87%, 92%, and 94%, respectively, for CB; and 92%, 92%, and 94%, respectively, for the combined FNA and CB group. Renal cell carcinoma and its variants were the most common histologic diagnoses (112 of 174 cases; 64%). Significant diagnostic discrepancy was noted in one case: a malignant melanoma that was misdiagnosed as renal cell carcinoma in both the preoperative FNA specimen and in the CB specimen.Conclusions: In the current study, both FNA and CB demonstrated excellent diagnostic accuracy (96% and 94%, respectively). The combination of FNA and CB was found to significantly improve the diagnostic rate when compared with either FNA alone (92% vs 72%; P<.05) or CB alone (92% vs 87%). Cancer Cytopathol 2017;125:407-15. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Small renal masses (SRMs; ≤4 cm) represent a challenging issue. Computed tomography (CT) is widely used for investigating renal tumors even if its ability to differentiate among the different subtypes has not yet been definitively established. Purpose To assess the potential role of the morphological features and angiodynamic behavior on multiphasic CT in the preoperative evaluation of SRMs. Material and Methods The CT images of 80 patients with SRMs who underwent surgical resection at our institution were retrospectively reviewed. The morphological features, the pattern, and the quantitative analysis of enhancement were assessed for each lesion and were correlated with the histological subtypes. Results Overall, 81 SRMs were evaluated. Final pathological examination showed 30 (37%) oncocytomas, 22 (27.2%) clear cell renal cell carcinomas (ccRCCs), 16 (19.8%) papillary RCCs (pRCCs), and 13 (16%) chromophobe RCCs (chRCCs). Of the morphological features, only necrosis was significantly associated with ccRCC ( P = 0.047). The analysis of enhancement allowed the identification of two groups of lesions, based on arterial behavior: hypervascular (oncocytomas/ccRCC) and hypovascular (chRCC/pRCC) lesions. A significant difference between the two groups in terms of degree of enhancement on CT phases was found ( P < 0.05); this was also confirmed by the receiver operating characteristic (ROC) analysis. Conclusion Except for necrosis, the morphological features are not useful in making a correct diagnosis in the case of SRMs. The angiodynamic behavior on multiphasic CT showed high accuracy in differentiating between hypovascular and hypervascular tumors; this differentiation could be useful for deciding on the most appropriate clinical management of SRMs. [ABSTRACT FROM AUTHOR]

Background: Renal cell carcinomas (RCCs) display broad resistance against conventional radio-and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). Methods: Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. Results: Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan-and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC knockdown cells. Conclusion: Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic and intrinsic pathways of apoptosis in RCCs. In this context, ARC cooperates with anti-apoptotic Bcl-2 family members to exert its strong anti-apoptotic effects and is therefore an important factor not only in the therapeutic resistance but also in future therapy strategies (i.e., Bcl-2 inhibitors) in RCC. In sum, targeting of ARC may enhance the therapeutic response in combination therapy protocols. [ABSTRACT FROM AUTHOR]

The pre-mRNA splicing regulator serine-arginine protein kinase 1 (SRPK1), a member of the SR kinase family, plays an essential role in cancer development and various pathophysiological processes. However, its expression pattern and functions in renal cell carcinoma (RCC) remain unknown. Therefore, the aim of this study was to assess the role of SRPK1 in RCC. Our data showed that SRPK1 was significantly upregulated in human RCC tissues and cell lines. SRPK1 interference significantly inhibited the proliferation of RCC cells and inhibited tumor growth in vivo. In addition, SRPK1 interference also suppressed migration and invasion in RCC cells. A mechanistic study showed that SRPK1 interference inhibited the phosphorylation of PI3K and Akt in RCC cells. In conclusion, our findings suggest that SRPK1 interference inhibits the growth and invasion of RCC cells through suppressing the PI3K/Akt signaling pathway. Thus, SRPK1 might be a therapeutic target for the treatment of RCC. [ABSTRACT FROM AUTHOR]

Accurate nuclear classification (e.g., grading of renal cell carcinoma (RCC) biopsy images) is important to better understand fundamental phenomena such as tumor growth. In this paper, an automated pipeline is proposed to quantitatively analyze RCC data. A novel segmentation methodology is firstly used to delineate cell nuclei based on minimum description length (MDL) constrained B-spline curve fitting. From the obtained segmentations, thirteen features are then extracted based on five types of characteristics. These features are used to classify cell nuclei in biopsy images. Associations among nuclei are computed and represented by graphical networks to enable further analysis. Finally, a support vector machine (SVM) based decision-graph classifier is introduced to classify the biopsy images with the purpose of grading. Experimental results on real RCC data show that our SVM-based decision-graph classifier achieves 95.20% of classification accuracy while the SVM classifiers achieve 93.33% of classification accuracy. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) represents one of the most resistant tumors to radiation and chemotherapy. Current therapies for RCC patients are inefficient due to the lack of diagnostic and therapeutic markers. The expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. In the present study, we investigated the receptor tyrosine kinase-like orphan receptor 2 (Ror2), a new tumor-associated kinase, in RCC primary tumors and cell lines. Knockdown of Ror2 expression in RCC cells with specific shRNA significantly reduced cell proliferation and induced apoptosis. Using in vitro migration and Matrigel invasion assays, we found that cell migration and invasive ability were also significantly inhibited. In RCC, Ror2 expression correlated with expression of genes involved at the cell cycle and migration, including PCNA, CDK1, TWIST, and MMP-2. Furthermore, in vivo xenograft studies in nude mice revealed that administration of a Ror2 shRNA plasmid significantly inhibited tumor growth. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is one of the most common kidney cancers worldwide. Although great progressions have been made in the past decades, its morbidity and lethality remain increasing. Long noncoding RNAs (lncRNAs) are demonstrated to play significant roles in the tumorigenesis. This study aimed to investigate the detailed roles of lncRNA FTX in RCC cell proliferation and metastasis. Our results showed that the transcript levels of FTX in both clinical RCC tissues and the cultured RCC cells were significantly upregulated and associated with multiple clinical parameters of RCC patients, including familial status, tumor sizes, lymphatic metastasis, and TNM stages. With cell proliferation assays, colony formation assays, and cell cycle assays, we testified that knockdown of FTX in A498 and ACHIN cells with specific shRNAs inhibited cell proliferation rate, colony formation ability, and arrested cell cycle in the G0/G1 phase. FTX depletion also suppressed cell migration and invasion with Transwell assays and wound-healing assays. These data indicated the prooncogenic potential of FTX in RCC, which makes it a latent therapeutic target of RCC diagnosis and treatment in the clinic. [ABSTRACT FROM AUTHOR]

Metastatic neoplasms occurring in the nasal and paranasal sinuses are infrequent occurrences. In this study, we present one such case of a 61-year-old male patient with a known clear cell renal carcinoma presenting to us with signs and symptoms of acute sinusitis. The patient subsequently underwent CT and MRI examinations, which revealed a neoplastic mass in the right frontal sinus, which was surgically resected and was later confirmed histologically as a metastatic deposit from clear cell renal carcinoma. The patient is currently being treated with chemotherapy and radiotherapy and is doing well., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Qureshi et al.)

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant genetic disorder resulting from mutations in the fumarate hydratase (FH) gene. It is characterised by a predisposition to cutaneous and uterine leiomyomas (fibroids) and an aggressive form of renal cell carcinoma (RCC). We report the case of a 53-year-old female who presented with an unusual rash in the context of a personal and family history of uterine leiomyomas requiring hysterectomy. A skin biopsy confirmed cutaneous leiomyomas and subsequent genetic testing demonstrated a pathogenic heterozygous mutation on exon 7 of the FH gene, confirming a diagnosis of HLRCC. Due to the recognised association with renal cell carcinoma in this syndrome, abdominal imaging was performed, which excluded RCC, and the patient was commenced on lifelong surveillance with annual abdominal magnetic resonance imaging., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Audet et al.)

Metastatic lesions to the paranasal sinuses and skull base, while rare, carry a poor prognosis. Renal cell carcinoma has been reported in multiple case reports to be one of the most common distant malignancies to spread to the paranasal sinuses; however, it is often unrecognized by physicians, and thus treatment is delayed. To increase awareness of this disease process, we describe three cases of metastatic renal cell carcinoma to the sinonasal cavity, which is the largest case series in the literature to date., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Hess et al.)

Renal cell carcinoma (RCC) is an aggressive tumour, with 25% of the cases presenting with distant metastases at the time of diagnosis. Approximately 33% of the patients with RCC eventually develop metastatic spread. RCC can metastasize to various sites including the lung, liver, bone, brain, adrenal gland, and more. Cardiac metastasis is rare in RCC, but even rarer in the absence of inferior vena cava (IVC) involvement. This case report presents a 60-year-old male patient who was referred by his general practitioner due to breathing difficulties. An initial echocardiogram revealed a right ventricular outflow tract obstruction caused by a mass. A subsequent cardiac MRI showed a right ventricular mass with features suggestive of a metastatic spread. A CT scan of the thorax, abdomen and pelvis was done to ascertain the primary tumour which revealed RCC, without involving the IVC. Due to the presence of metastases, advanced disease, and heavy tumour burden, the multidisciplinary team concluded that there were almost negligible treatment options available at that stage and recommended the best supportive care and community hospice support. The patient was discharged once his symptoms improved, as per his request, and he passed away peacefully at home within a month. This case highlights the very rare occurrence of cardiac metastasis of RCC without IVC involvement. It also illustrates the approach and investigations involved in the evaluation of complex cardiac masses., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Joshi et al.)

Background: Renal cell carcinoma is the most lethal urological cancer and contributes significantly to morbidity and mortality due to cancers of the urogenital tract. In routine diagnostic surgical pathology practice of renal tumours, immunohistochemistry is a helpful ancillary technique after routine H & E. The role of renal immunohistochemistry is explored in this study., Materials and Methods: The paraffin-embedded tissue blocks of all the confirmed cases of renal cell carcinoma seen at the University College Hospital (UCH), Ibadan, during the 10-year study period of 2007 to 2016 were retrieved, sectioned and immunohistochemistry done using monoclonal antibodies for EMA, Vimentin and CD117 following standard protocols. Frequency statistics and chi-square were applied to data to determine proportions and associations using the Statistical Package for the Social Sciences (SPSS) version 23., Results: A total of 48 cases of renal cell carcinoma were seen within the study period that met the inclusion criteria for the study. The age range of the patients was between 3 to 76 years with an average age of 44.17 years. The male-to-female ratio was 1:1.3. Fuhrman Grade 2 nuclei were predominant (43.75%) while Fuhrman Grade 4 nuclei had the lowest frequency (6.25%). EMAstaining patterns for the different histological patterns of RCC showed no statistically significant difference while Vimentin and CD117 staining patterns showed a statistically significant difference. There was no statistically significant difference observed between the staining patterns of all three markers and the nuclear grades of the cases of RCC., Conclusion: This study demonstrated the usefulness of Vimentin and CD117 in differentiating chromophobe variant of renal cell carcinoma from other subtypes while EMA showed variable expression across the various subtypes., Competing Interests: The Authors declare that no competing interest exists, (Copyright © 2023 by West African Journal of Medicine.)

Distant renal cell carcinoma (RCC) metastatic disease is mostly seen in the lungs, bones, and lymph nodes. The incidence of local recurrences within the ipsilateral retroperitoneum (RFR) is very low. We report a case of a 79-year-old male with recurrent left renal fossa RCC with pancreatic tail invasion who presented with large bowel obstruction. To the best of our knowledge, no cases have been reported of recurrent left renal fossa RCC initially presenting as extrinsic large bowel obstruction., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Wasifuddin et al.)

Background: Renal cancer is one of the most common malignant tumors of the urinary system, with distant metastasis occurring 30% of patients. Therefore, early detection and monitoring of tumor progression are of great significance in the diagnosis and treatment of renal cancer. However, current biomarkers used to diagnose, monitor recurrence and assess prognosis of renal cancer are still uncertain. Circulating tumor cells (CTCs) are tumor cells detached from the primary tumor or metastasis, invaded and existing in the peripheral blood, and are one of the most promising liquid biopsy targets because they can provide complete cell biological information. Microfluidic chip has advantages of miniaturization, high integration, and fast analysis, which has advantages in CTC separation and enrichment., Methods: In this study, 1 mL peripheral blood of each 30 patients with early localized renal cancer was collected before and 1 day after surgery. CTC enrichment was performed by microfluidic chip and CTCs were identified by immunofluorescence staining. All patients were followed up for a median of 17 months., Results: The number of CTCs before surgery was higher than that after surgery (P<0.001), and the number was positively correlated with tumor-node-metastasis (TNM) stage and International Society of Urological Pathology (ISUP) grade. Patients in group CTC ≤2 had a longer progression-free survival (PFS) than those in group CTC ≥3 (P<0.05)., Conclusions: Surgical treatment can remarkably reduce the number of CTCs in patients, and CTC counts can also play a role in monitoring tumor load and predicting prognosis in renal cancer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2920/coif). The authors have no conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

Rationale and Objectives: This study investigated the utility of histogram parameters derived from diffusion-weighted imaging (DWI) for evaluating renal cell carcinoma (RCC) grading prior to surgery., Materials and Methods: This retrospective study included 88 patients who were histopathologically diagnosed with RCC and underwent magnetic resonance imaging (MRI) examinations. The patients were divided into two groups as well-differentiated (Group 1) and poorly differentiated (Group 2). Demographic data, preoperative MRI findings, MRI apparent diffusion coefficient (ADC) histogram analyzes, operation types, postoperative histopathological data and cancer stages of the patients were recorded. The histogram parameters of ADC values, comprising the mean, minimum, maximum, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles, as well as skewness, kurtosis, and variance, were calculated., Results: The study included 59 males and 29 women with an average age of 56.21 ± 1.33 years. There were 52 patients in Group 1 and 36 patients in Group 2. The ADCmin, ADCmean, ADCmax, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of ADC values of the poorly differentiated group were all lower than those of the well-differentiated group. ADCmin and the 5th percentile of ADC values, as well as ADCmean and the 10th, 25th, 50th, and 75th percentiles of ADC values, showed a statistically significant difference (p < 0.05). The AUC, sensitivity, and specificity of the ADCmin value were 0.703, 56.3%, and 75.7%, respectively., Conclusion: The present study indicated that histogram parameters generated from DWI were capable of differentiating between high-grade and low-grade RCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Unlike for most other malignancies, application of FDG PET/CT is limited for renal cell carcinoma (RCC), mainly due to physiological excretion of FDG from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys. Published clinical observations were discordant regarding the role of FDG PET/CT in diagnosing and staging RCC, and FDG PET/CT is not recommended for this purpose based on current national and international guidelines. However, quantitative FDG PET/CT imaging may facilitate the prediction of the degree of tumor differentiation and allow for prognosis of the disease. FDG PET/CT has potency as an imaging biomarker to provide useful information about patient’s survival. FDG PET/CT can be effectively used for postoperative surveillance and restaging with high sensitivity, specificity and accuracy, as early diagnosis of recurrent/metastatic disease can drastically affect therapeutic decision and alter outcome of patients. FDG uptake is helpful for differentiating benign or bland emboli from tumor thrombosis in RCC patients. FDG PET/CT also has both higher sensitivity and accuracy when compared to bone scan to detect RCC metastasis to the bone. FDG PET/CT can play a strong clinical role in the management of recurrent and metastatic RCC. In monitoring the efficacy of new target therapy such as tyrosine kinase inhibitors (TKI) treatment for advanced RCC, FDG PET/CT has been increasingly used to assess the therapeutic efficacy, and change in FDG uptake is a strong indicator of biological response to TKI.

Transglutaminase 2 (TG2) is a multifunctional crosslinking enzyme that displays transamidation, protein disulfide isomerase, protein kinase, as well as GTPase and ATPase activities. TG2 can also act as an adhesion molecule involved in the syndecan and integrin receptor signaling. In recent years, TG2 was implicated in cancer progression, survival, invasion, migration, and stemness of many cancer types, including renal cell carcinoma (RCC). Von Hippel-Lindau mutations leading to the subsequent activation of Hypoxia Inducible Factor (HIF)-1-mediated signaling pathways, survival signaling via the PI3K/Akt pathway resulting in Epithelial Mesenchymal Transition (EMT) metastasis and angiogenesis are the main factors in RCC progression. A number of studies have shown that TG2 was important in HIF-1- and PI3K-mediated signaling, VHL and p53 stabilization, glycolytic metabolism and migratory phenotype in RCC. This review focuses on the role of TG2 in the regulation of molecular pathways nurturing not only the development and propagation of RCC, but also drug-resistance and metastatic potential.

Background: Although current guidelines recommend administering adjuvant immunotherapy following resection of advanced primary renal cell carcinoma (RCC), the clinical benefit of presurgical immunotherapy for patients with RCC remains uncertain., Case Description: We conducted a retrospective analysis of five patients diagnosed with RCC who developed inferior vena cava (IVC) tumor thrombus and were treated with radical nephrectomy following combined immunotherapy with a tyrosine kinase inhibitor. The median follow-up after nephrectomy was 23 months (range, 19-30 months). In all cases, the size of the IVC tumor thrombus decreased, and three of the cases demonstrated a decrease in the tumor thrombus level. Surgical margins were negative in all cases, and none of the patients experienced any major intraoperative complications. However, adhesions were encountered at the operative sites during surgery in all cases. One patient required a lymphatic intervention due to abdominal lymphatic leakage (Clavien IIIa) within 90 days after operation. Our case series demonstrated a median progression-free survival (PFS) of 11 months [95% confidence interval (CI)]: 5.5-22.5 months). No patient died during the follow-up period., Conclusions: Presurgical therapy combined with immunotherapy and tyrosine kinase inhibitors warrants consideration. Nevertheless, surgeons should be mindful of the difficulties that may arise beyond the clinical stage., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-203/coif). The authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Background: Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), is insensitive to radiotherapy and chemotherapy after surgery. Deoxyribonuclease 1-like 3 (DNASE1L3), an endonuclease that cleaves both membrane-encapsulated single- and double-stranded DNA, suppresses cell cycle progression, proliferation and metabolism in hepatocellular carcinoma cells. There is currently no established link between DNASE1L3 and RCC inhibition. We are gonging to explored the mechanism underlying the relationship between DNASEL1L3 and RCC., Methods: RNA sequencing data for RCC tissue and peritumoral tissue were downloaded from The Cancer Genome Atlas database and analyzed. The expression levels of DNASE1L3 in RCC and normal samples were verified using the Gene Expression Omnibus (GEO) database, Human Protein Atlas database and western blotting. The role and potential mechanism of DNASE1L3 were investigated by analysis of immune-related databases and wound healing, invasion, cell counting kit 8 and immunofluorescence assays., Results: We revealed that DNASE1L3 expression was downregulated in RCC group compared with control group [The Cancer Genome Atlas (TCGA): 7.98 vs. 10.87, P<0.001]. Meanwhile, DNASE1L3 expression correlated with the clinical characteristics of patients. Patients with low DNASE1L3 expression had worse survival (P<0.001) and larger (r=-0.32, P<0.001) and heavier tumors (r=-0.17, P<0.001). DNASE1L3 overexpression inhibited the proliferation (786-O: 0.135±0.014 vs. 0.322±0.027, P<0.001) and invasion (786-O: 1,479±134 vs. 832±67, P<0.05) of RCC cells. The expression of DNASE1L3 was significantly correlated with the tumor immune microenvironment and drug sensitivity in ccRCC. Moreover, the level of the key phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway protein P-AKT was decreased in the group of cells transfected with DNASE1L3., Conclusions: This study strongly suggest that DNASE1L3 may be a promising potential biomarker for the diagnosis and treatment of ccRCC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-355/coif). The authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Background: Na + /H + exchanger (NHE) maintains the alkaline pH of epithelial cells working at the cellular membrane and exchanging H + /Na + ions. In renal tubular epithelial cells, the reabsorption of NaCl is implemented by NHE3 isoform, which is regulated by NHE regulatory factor-1 (NHERF1). Normally situated at the apical zones of proximal tubular cells, NHERF1 participates in cytoskeletal reorganization and signal transduction facilitating structural stability and ion exchange. Based on an extensive search in English literature, NHERF1/EBP50 immunoexpression has been studied in breast, colon, and other tumors with only one study on 21 cases of renal cell carcinomas (RCC)., Methods: Using NHERF1/EBP50 immunohistochemistry (IHC) on 64 (82%) RCCs (34 clear cells, 21 papillary and 9 chromophobe types) and 14 (18%) oncocytomas, we evaluated and scored NHERF1/EBP50 immunoexpression depending on the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading system followed by ultrastructural identification of microlumen-like structures (MLS) in clear cell renal cell carcinomas (ccRCC)., Results: Staining patterns varied throughout the tumors and within individual tumors. Only ccRCC showed unique MLS within the cytoplasm of tumor cells. All neoplasia-transformed tubular cells, regardless of the tumor grade and stage, had altered immunoexpression of NHERF1/EBP50 ranging from complete absence to aberrant expression in the luminal cell membrane, nuclear or cytoplasmic localizations., Conclusions: Only ccRCC showed unique dot-like condensations of immunostaining/MLS at membranous, submembranous, and paranuclear localizations. The latter two localizations were mainly observed in the combined WHO/ISUP grade 1 and 2 group compared to the combined group of grade 3 and 4 tumor samples (P=0.0146 and P<0.0001, respectively). Ultrastructurally, the MLS were identified as thick microvilli trapped by a single-layer membrane, displaced into the cytoplasm and ranging from 400 nm to 3.5 µm. These significant ultrastructural reorganizations may contribute to tumor progression, metastasis, and drug resistance., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-101/coif). The authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic approach to diverse malignancies, leading to substantial enhancements in patient prognosis. However, along with their benefits, ICIs also increase the incidence of immune-related adverse events (irAEs). In the present paper, we highlight four cases of carpal tunnel syndrome (CTS) as an uncommon manifestation of toxicity induced by ICIs. Although diagnosed with different malignancies, the patients were undergoing ICI therapy when they developed CTS-consistent side effects accompanied by severe neuropathy. Prompt treatment with corticosteroids, intravenous immunoglobulins, or methotrexate resulted in complete symptomatic relief for all patients. This article therefore emphasizes the importance of recognizing and managing rare adverse events associated with ICI use to ensure optimal patient care.