Renal Cell Carcinoma Carcinogenesis Research Articles

ITIH1 suppresses carcinogenesis in renal cell carcinoma through regulation of the NF‑κB signaling pathway.

Renal cell carcinoma (RCC) is a common malignancy of the urinary system. Although traditional therapies, such as surgery assisted with chemotherapy have improved the quality of life and survival time of patients with RCC, patients with metastasis or recurrence benefit little from such therapies. At present, little is known about the underlying mechanisms of RCC, rendering treatment selection and implementation challenging. Therefore, investigating the cause and underlying mechanisms of RCC remain of importance to explore potential new avenues for its treatment. Inter-α-trypsin inhibitor heavy chain 1 (ITIH1) is an inflammation-associated gene reported to suppress the progression of liver cancer. However, its role in RCC remains poorly understood. Therefore, the present study aimed to investigate the role and mechanism of ITIH1 in RCC. Based on data obtained from The Cancer Genome Atlas database, ITIH1 expression was demonstrated to be significantly higher in tumor tissues compared with normal tissues, which was in turn negatively associated with the survival of patients with RCC. However, in RCC cells, ITIH1 was shown to be expressed at significantly lower levels compared with those in HK-2 cells. The discrepancy between tissues and cell lines might be due to the different environment of cell growth. ITIH1 knockdown in RCC cells significantly increased cell proliferation and invasion whilst significantly decreasing the apoptosis rate, compared with those in control cells (without ITIH1 knockdown). By contrast, overexpression of ITIH1 significantly inhibited cell proliferation and invasion in RCC cells. In terms of western blotting results, the phosphorylation levels of NF-κB were significantly increased following ITIH1 knockdown. The protein expression level of IκB significantly decreased whereas that of IKK, Cyclin D1, proliferating cell nuclear antigen and α-smooth muscle actin were significantly increased in ITIH1-knockdown cells, compared with those in the control cells (without ITIH1 knockdown). This suggests that the NF-κB pathway may be activated after ITIH1 knockdown. Following treatment with the NF-κB pathway inhibitor JSH-23 in combination with ITIH1 knockdown, RCC cell proliferation and invasion were significantly reduced compared with those after ITIH1 knockdown alone. In summary, results from the present study suggest that ITIH1 can serve an inhibitory role in the progression of RCC, which could potentially be inhibited through the NF-κB signaling pathway.

Molecular insight into renal cancer and latest therapeutic approaches to tackle it: anupdatedreview.

Renal cell carcinoma (RCC) is one of the most lethal genitourinary cancers, with the highest mortality rate, and may remain undetected throughout its development. RCC can be sporadic or hereditary. Exploring the underlying genetic abnormalities in RCC will have important implications for understanding the origins of nonhereditary renal cancers. The treatment of RCC has evolved over centuries from the era of cytokines to targeted therapy to immunotherapy. A surgical cure is the primary treatment modality, especially for organ-confined diseases. Furthermore, the urologic oncology community focuses on nephron-sparing surgical approaches and ablative procedures when small renal masses are detected incidentally in conjunction with interventional radiologists. In addition to new combination therapies approved for RCC treatment, several trials have been conducted to investigate the potential benefits of certain drugs. This may lead to durable responses and more extended survival benefits for patients with metastatic RCC (mRCC). Several approved drugs have reduced the mortality rate of patients with RCC by targeting VEGF signaling and mTOR. This review better explains the signaling pathways involved in the RCC progression, oncometabolites, and essential biomarkers in RCC that can be used for its diagnosis. Further, it provides an overview of the characteristics of RCC carcinogenesis to assist in combating treatment resistance, as well as details about the current management and future therapeutic options. In the future, multimodal and integrated care will be available, with new treatment options emerging as we learn more about the disease.

The Prognostic Role of ACO2 in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) continues to pose a challenge due to our limited understanding of its underlying pathophysiology. Aconitase 2 (ACO2) is a mitochondrial Fe-S cluster enzyme that catalyzes the stereospecific isomerization of citrate to isocitrate in the second step of the Krebs cycle. We investigated the relationship between ACO2 protein expression and the clinical course of RCC. Tumor samples were evaluated in a commercial tissue microarray for ACO2 expression using the H-score. The tissue microarrays contained a total of 96 cores from primary tumors, matched metastases, and matched adjacent tissues derived from 32 patients with RCC. The mean follow-up was 82.74 months. Correlation analysis of clinicopathological data and survival was performed. Expression levels of ACO2 mRNA were compared using publicly available data. All the tissue samples showed cytoplasmic ACO2 expression, with median H-scores of 139.7, 130.3 and 166.7 in primary tumor, metastatic tissue, and matched control tissue, respectively. A significantly higher ACO2 expression was found in normal tissues compared to primary and metastatic RCC. The analysis demonstrated a significantly positive correlation between ACO2 expression in primary tumors and their metastases. The results also showed a significant correlation between the expression of ACO2 and worse overall survival among patients with RCC. ACO2 may be used as a prognostic factor in RCC. Significant alterations in ACO2 expression are thought to occur in the early stages of RCC carcinogenesis. Considering the physiological role of ACO2, its dysregulation may constitute an adaptive trait of RCC for escaping the equilibrium phase of immunoediting.

Circ_0000069 contributes to the growth, metastasis and glutamine metabolism in renal cell carcinoma (RCC) via regulating miR-125a-5p-dependent SLC1A5 expression

BackgroundCircular RNAs (circRNAs) have emerged as critical mediators in various cancers, including renal cell carcinoma (RCC). In the present research, the functions of circ_0000069 in RCC were explored. MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) assay, western blot assay and immunohistochemistry (IHC) assay were performed for the expression of circ_0000069, microRNA-125a-5p (miR-125a-5p) and solute carrier family 1 member 5 (SLC1A5). Cell Counting Kit-8 (CCK-8) assay and 5′-ethynyl-2′-deoxyuridine (EdU) assay were performed for cell proliferation. Flow cytometry assay was manipulated for cell apoptosis. Transwell assay and wound-healing assay were utilized for cell invasion and migration. Glutamine metabolism level was evaluated by examining glutamine consumption, α-ketoglutarate production and glutamate production. Dual-luciferase reporter assay was used to analyze the relationships of circ_0000069, miR-125a-5p and SLC1A5. Murine xenograft model assay was conducted to analyze the function of circ_0000069 in vivo. ResultsCirc_0000069 level was abnormally upregulated in RCC tissues and cells. Knockdown of circ_0000069 inhibited the proliferation, invasion, migration and glutamine metabolism and promoted the apoptosis in RCC cells in vitro and restrained tumor growth in vivo. Circ_0000069 served as the sponge for miR-125a-5p. MiR-125a-5p inhibition ameliorated the effects of circ_0000069 knockdown on RCC cell malignant behaviors. SLC1A5 was identified as the target gene of miR-125a-5p. Moreover, miR-125a-5p overexpression repressed the progression of RCC cells, while SLC1A5 elevation abrogated the effect. ConclusionCirc_0000069 knockdown inhibited the carcinogenesis of RCC by regulating miR-125a-5p/SLC1A5 axis.

Novel Expression of Thymine Dimers in Renal Cell Carcinoma, Demonstrated through Immunohistochemistry.

Despite significant developments in renal cell carcinoma (RCC) detection and molecular pathology, mortality has been steadily rising. Advanced RCC remains an incurable disease. Better clinical management tools, i.e., RCC biomarkers, have yet to emerge. Thymine-dimers (TDs) were traditionally considered photo-dependent pre-mutagenic lesions, occurring exclusively during ultra-violet light exposure. Non-oxidative, direct, and preferential byproducts of DNA photochemical reactions, TDs, have recently shown evidence regarding UVR-independent formation. In this study, we investigate, for the first time, TD expression within RCC tumor tissue and tumor-adjacent healthy renal parenchyma using a TD-targeted IHC monoclonal antibody, clone KTM53. Remarkably, out of the 54 RCCs evaluated, 77.8% showed nuclear TD-expression in RCC tumor tissue and 37% in the tumor-adjacent healthy renal parenchyma. A comprehensive report regarding quantitative/qualitative TD-targeted immunostaining was elaborated. Two main distribution models for TD expression within RCC tumor tissue were identified. Statistical analysis showed significant yet moderate correlations regarding TD-positivity in RCC tissue/tumor-adjacent healthy renal parenchyma and TNM stage at diagnosis/lymphatic dissemination, respectively, indicating possible prognostic relevance. We review possible explanations for UVR-independent TD formation and molecular implications regarding RCC carcinogenesis. Further rigorous molecular analysis is required in order to fully comprehend/validate the biological significance of this newly documented TD expression in RCC.

Immunohistochemical Expression of CD44, MMP-2, MMP-9, and Ki-67 as the Prognostic Markers in Non-Clear Cell Renal Cell Carcinomas-A Prospective Cohort Study.

CD44 is the most frequently reported marker of the cancer stem cells in renal cell carcinoma (RCC). Matrix metalloproteinases MMP-2 and MMP-9 are key regulators of tumor invasion and metastasis. The aim of this study was to investigate the clinicopathologic and prognostic values of the immunohistochemical expression of CD44, MMP2, MMP9, and Ki-67 in papillary and chromophobe RCCs. In the case of papillary RCC, MMP-2 expression was positively correlated with patient age (p < 0.05), while CD44 expression was positively correlated with tumor stage (τ = 0.26, p < 0.05). Moreover, CD44 expression positively correlated with MMP-9 (τ = 0.39, p < 0.05). In the case of chromophobe RCC, only Ki-67 expression was negatively correlated with tumor stage (τ = −0.44, p < 0.05). During follow-up, a death was documented in 6 patients with papillary RCC. In these patients, CD44 expression was not a significant factor affecting the overall survival of patients (p > 0.05), whereas there was a positive correlation between increased MMP-9 expression and shorter overall survival (p < 0.05). Taken together, carcinogenesis in papillary RCC is probably dependent on both cancer stem cells and metalloproteinases activity. Expression of CD44 and MMP-9 can significantly improve the prediction of papillary RCC prognosis in the future.

Iron accumulation typifies renal cell carcinoma tumorigenesis but abates with pathological progression, sarcomatoid dedifferentiation, and metastasis.

Iron is a potent catalyst of oxidative stress and cellular proliferation implicated in renal cell carcinoma (RCC) tumorigenesis, yet it also drives ferroptosis that suppresses cancer progression and represents a novel therapeutic target for advanced RCC. The von Hippel Lindau (VHL)/hypoxia-inducible factor-α (HIF-α) axis is a major regulator of cellular iron, and its inactivation underlying most clear cell (cc) RCC tumors introduces both iron dependency and ferroptosis susceptibility. Despite the central role for iron in VHL/HIF-α signaling and ferroptosis, RCC iron levels and their dynamics during RCC initiation/progression are poorly defined. Here, we conducted a large-scale investigation into the incidence and prognostic significance of total tissue iron in ccRCC and non-ccRCC patient primary tumor cancer cells, tumor microenvironment (TME), metastases and non-neoplastic kidneys. Prussian Blue staining was performed to detect non-heme iron accumulation in over 1600 needle-core sections across multiple tissue microarrays. We found that RCC had significantly higher iron staining scores compared with other solid cancers and, on average, >40 times higher than adjacent renal epithelium. RCC cell iron levels correlated positively with TME iron levels and inversely with RCC levels of the main iron uptake protein, transferrin receptor 1 (TfR1/TFRC/CD71). Intriguingly, RCC iron levels, including in the TME, decreased significantly with pathologic (size/stage/grade) progression, sarcomatoid dedifferentiation, and metastasis, particularly among patients with ccRCC, despite increasing TfR1 levels, consistent with an increasingly iron-deficient tumor state. Opposite to tumor iron changes, adjacent renal epithelial iron increased significantly with RCC/ccRCC progression, sarcomatoid dedifferentiation, and metastasis. Lower tumor iron and higher renal epithelial iron each predicted significantly shorter ccRCC patient metastasis-free survival. In conclusion, iron accumulation typifies RCC tumors but declines toward a relative iron-deficient tumor state during progression to metastasis, despite precisely opposite dynamics in adjacent renal epithelium. These findings raise questions regarding the historically presumed selective advantage for high iron during all phases of cancer evolution, suggesting instead distinct tissue-specific roles during RCC carcinogenesis and early tumorigenesis versus later progression. Future study is warranted to determine how the relative iron deficiency of advanced RCC contributes to ferroptosis resistance and/or introduces a heightened susceptibility to iron deprivation that might be therapeutically exploitable.

Causal Association between Chronic Kidney Disease and Risk of 19 Site-Specific Cancers: A Mendelian Randomization Study.

Results of previous observational studies examining the risk of cancer among patients with chronic kidney disease (CKD) are conflicting. We here explore the causal relationship between estimated glomerular filtration rate (eGFR) and albuminuria, two principal measurements of CKD, and 19 site-specific cancers using Mendelian randomization (MR) analysis. Single-nucleotide polymorphisms reported to be strongly correlated with eGFR and albuminuria in recent large genome-wide association studies were used as instrumental variables to investigate the causal relationship with cancer using summary-level statistics from several cancer-specific consortia, as well as data of 347,408 participants in the UK Biobank and 260,405 participants in the FinnGen. Our data showed that impaired kidney function was associated with higher odds of leukemia [OR = 1.23; 95% confidence interval (CI), 1.06-1.43; P = 0.007], cervical cancer (OR = 1.22; 95% CI, 1.04-1.43; P = 0.017), and female renal cell carcinoma (OR = 1.4; 95% CI, 1.12-1.77; P = 0.004), per 10% decrease in eGFR. The ORs were 1.21 (95% CI, 1.07-1.36; P = 0.002) for colorectal cancer and 0.76 (95% CI, 0.62-0.92; P = 0.006) for non-Hodgkin lymphoma, per doubling odds of albuminuria. In multivariable MR, effect sizes of eGFR-cervical cancer remained strong after adjusting for confounders. The current study indicates that progression of CKD contributes to carcinogenesis of renal cell carcinoma, leukemia, cervical, and colorectal cancer. The potential association of kidney function and albuminuria with certain cancers warrants further investigation in order to provide appropriate recommendations regarding cancer screening among patients with CKD.

CircRNAs as Novel Biomarkers and Therapeutic Targets in Renal Cell Carcinoma.

Circular RNAs (circRNAs) are a type of long non-coding RNA with covalently closed loops that are naturally resistant to exoribonuclease. With the rapid development of high-throughput sequencing technologies and bioinformatics, increasing data suggest that circRNAs are abnormally expressed in renal cell carcinoma (RCC) and act as important regulators of RCC carcinogenesis and progression. CircRNAs play important biological roles in modulating cell proliferation, migration, invasion, apoptosis, and gemcitabine chemoresistance in RCC. Most of the circRNAs studied in RCC have been reported to be significantly associated with many clinicopathologic characteristics and survival parameters of RCC. The stability and specificity of circRNAs enable them potential molecular markers for RCC diagnosis and prognosis. Moreover, circRNAs have emerged as targets for developing new therapies, because they can regulate various signaling pathways associated with RCC initiation and progression. In this review, we briefly summarize the biogenesis, degradation, and biological functions of circRNAs as well as the potential clinical applications of these molecules for RCC diagnosis, prognosis, and targeted therapy.

Circ_0037866 Contributes to the Tumorigenesis of Renal Cell Carcinoma by Sequestering miR-384 to Elevate Chromobox 5 Expression

Background: Circular RNAs (circRNAs) were demonstrated to have roles in the carcinogenesis of renal cell carcinoma (RCC). Hence, this work aimed to determine the functions and molecular mechanism of circ_0037866 in regulating the progression of RCC. Methods: Quantitative real-time polymerase chain reaction and Western blotting were used to detect the levels of genes and proteins. In vitro assays, including colony formation, 5-ethynyl-2′-deoxyuridine, flow cytometry, transwell assays, and in vivo tumor formation, were conducted to investigate the effects of circ_0037866 on RCC tumorigenesis. Dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation assay were used to confirm the interaction between miR-384 and circ_0037866 or Chromobox 5 (CBX5). Results: Circ_0037866 is a stable circRNA and was found to be increased in RCC tissues and cells. Functionally, circ_0037866 silencing suppressed RCC cell survival, invasion, and migration in vitro, and impeded RCC cell tumorigenesis in the subcutaneous xenograft model. Mechanistically, circ_0037866 could function as a sponge for miR-384 to elevate the expression of its target CBX5. Furthermore, a series of rescue experiments showed that miR-384 inhibition reversed the anticancer effects of circ_0037866 knockdown on RCC cells; besides that, miR-384 restoration suppressed RCC cell growth and mobility, which were attenuated by CBX5 overexpression. Conclusion: Circ_0037866 knockdown restrains the tumorigenesis of RCC by miR-384/CBX5, revealing a promising molecular target for RCC therapy.

LDLR promotes growth and invasion in renal cell carcinoma and activates the EGFR pathway.

Previous studies identified an association of low-density lipoprotein (LDL) levels and LDL receptor (LDLR) with renal cell carcinoma (RCC) development. This study investigated the expression and roles of LDLR in RCC. LDLR expression was examined in clear cell RCC (ccRCC) and adjacent normal kidney tissues, and its clinicopathological significance was analyzed. The role of LDLR in RCC cell proliferation, cell cycle, and invasion were assessed in RCC cells with LDLR stable knockdown. LDLR expression was higher in ccRCC tissues than in normal kidney tissues and increased with RCC progression. LDLR knockdown in RCC cells inhibited cell growth, migration and invasion, and induced G1/S cell cycle arrest. We identified an interaction between LDLR and EGFR, and EGFR signaling protein expression was reduced after LDLR knockdown. Our findings reveal that LDLR plays an important role in RCC carcinogenesis, suggesting that LDL and LDLR might be potential targets for therapeutic intervention in RCC.

Lipid metabolism reprogramming in renal cell carcinoma.

Metabolic reprogramming is recognized as a hallmark of cancer. Lipids are the essential biomolecules required for membrane biosynthesis, energy storage, and cell signaling. Altered lipid metabolism allows tumor cells to survive in the nutrient-deprived environment. However, lipid metabolism remodeling in renal cell carcinoma (RCC) has not received the same attention as in other cancers. RCC, the most common type of kidney cancer, is associated with almost 15,000 death in the USA annually. Being refractory to conventional chemotherapy agents and limited available targeted therapy options has made the treatment of metastatic RCC very challenging. In this article, we review recent findings that support the importance of synthesis and metabolism of cholesterol, free fatty acids (FFAs), and polyunsaturated fatty acids (PUFAs) in the carcinogenesis and biology of RCC. Delineating the detailed mechanisms underlying lipid reprogramming can help to better understand the pathophysiology of RCC and to design novel therapeutic strategies targeting this malignancy.

Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus

SummaryOur study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.

Modeling Neoplastic Growth in Renal Cell Carcinoma and Polycystic Kidney Disease.

Renal cell carcinoma (RCC) and autosomal dominant polycystic kidney disease (ADPKD) share several characteristics, including neoplastic cell growth, kidney cysts, and limited therapeutics. As well, both exhibit impaired vasculature and compensatory VEGF activation of angiogenesis. The PI3K/AKT/mTOR and Ras/Raf/ERK pathways play important roles in regulating cystic and tumor cell proliferation and growth. Both RCC and ADPKD result in hypoxia, where HIF-α signaling is activated in response to oxygen deprivation. Primary cilia and altered cell metabolism may play a role in disease progression. Non-coding RNAs may regulate RCC carcinogenesis and ADPKD through their varied effects. Drosophila exhibits remarkable conservation of the pathways involved in RCC and ADPKD. Here, we review the progress towards understanding disease mechanisms, partially overlapping cellular and molecular dysfunctions in RCC and ADPKD and reflect on the potential for the agile Drosophila genetic model to accelerate discovery science, address unresolved mechanistic aspects of these diseases, and perform rapid pharmacological screens.

Comparative Assessment of the WNT/β-Catenin Pathway, CacyBP/SIP, and the Immunoproteasome Subunit LMP7 in Various Histological Types of Renal Cell Carcinoma

ObjectiveThe Wnt/ß-catenin pathway plays an important role in pathogenesis of variety cancers. Most studies on changes in WNT/β-catenin pathway in renal cell carcinoma (RCC) apply only to clear cell RCC, while there are no comparative assessments of this signaling pathway in various histological types of renal tumors in the available literature. Additionally, considering the close relationship between WNT/β-catenin signaling, CacyBP/SIP and proteasomal activity, it seemed worth comparing WNT/β-catenin pathway, CacyBP/SIP and LMP7 immunoproteasome subunit in human samples of clear cell, papillary, and chromophobe RCC.MethodsTests were performed on sections of three types of kidney tumors together with surrounding unchanged tissue fragments collected from 50 patients. Samples were divided into three groups depending on the histological type of cancer: clear cell, papillary and chromophobe RCC. Immunohistochemistry and PCR methods were used to identify WNT10A, Fzd5, β-catenin, GSK-3ß, CacyBP/SIP, LMP7, and gene expression.ResultsImmunoreactivity and expression of WNT10A, Fzd5, β-catenin, GSK-3ß, CacyBP/SIP, LMP7 in clear cell RCC was markedly increased compared to non-cancerous kidney tissue. In papillary RCC, immunoreactivity and expression of WNT/β-catenin pathway, CacyBP/SIP, LMP7 was also increased compared to non-malignant kidneys, but it was less pronounced than in clear cell RCC. The least substantial increase in immunoreactivity and expression of WNT/β-catenin pathway, CacyBP/SIP, LMP7 was found in chromophobe RCC, compared to other RCC histological subtypes studied.ConclusionsStudy results suggest an important role of WNT/β-catenin pathway, CacyBP/SIP and LMP7 in RCC carcinogenesis, and may indicate new aspects of pathomechanisms leading to differences in the biology of clear cell, papillary and chromophobe RCC.

MicroRNA‑218 inhibits tumor angiogenesis of human renal cell carcinoma by targeting GAB2.

Renal cell carcinoma (RCC) is one of the most common malignant cancers in the adult urinary system worldwide. Tumor angiogenesis is a critical process during cancer progression, as it modulates carcinogenesis and metastasis. In recent years, microRNA-218 (miR-218) has been confirmed to play a crucial role in tumor suppression. However, the role of miR-218 in RCC angiogenesis remains unclear. In the present study, it was found that the expression of miR-218 was decreased in RCC tumor tissues and cell lines as detected by real-time PCR analysis. Tube formation assays and migration assays also confirmed that miR-218 inhibited the interaction between RCC cells and vascular endothelial cells by suppressing proangiogenic factor vascular endothelial growth factor A (VEGFA) in RCC cells. miR-218 also repressed the subcutaneous tumorigenesis of RCC cells in nude mice, and the corneal angiogenesis in rabbit eyes. The underlying molecular mechanism was elucidated; miR-218 targets GRB2-associated binding protein 2 (GAB2), thereby inhibiting the PI3K/AKT/mTOR/VEGFA pathway. These results provide new insights into the mechanism of RCC carcinogenesis and progression, suggesting that miRNA-218 may be a therapeutic target for the treatment of RCC.

The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy.

Renal cell carcinoma (RCC) is one of the most common tumours of the urinary system, andis insidious and not susceptible to chemoradiotherapy. As the most common subtype of RCC (70-80% of cases), clear cell renal cell carcinoma (ccRCC) is characterized by the loss of von Hippel-Lindau and the accumulation of robust lipid and glycogen. For advanced RCC, molecular-targeted drugs, tyrosine kinase inhibitors (TKIs) and the immune checkpoint inhibitors (ICIs) have been increasingly recommended and investigated. Due to the existence of a highly dynamic, adaptive and heterogeneous tumour microenvironment (TME), and due to the glucose and lipid metabolism in RCC, this cancer may be accompanied by various types of resistance to TKIs and ICIs. With the increased production of lactate, nitric oxide, and other new by-products of metabolism, novel findings of the TME and key metabolic enzymes drived by HIF and other factors have been increasingly clarified in RCC carcinogenesis and therapy. However, there are few summaries of the TME and tumour metabolism for RCC progression and therapy. Here, we summarize and discuss the relationship of the important implicated characteristics of the TME as well as metabolic molecules and RCC carcinogenesis to provide prospects for future treatment strategies to overcome TME-related resistance in RCC.

Telomere Length in Renal Cell Carcinoma: The Jekyll and Hyde Biomarker of Ageing of the Kidney.

Renal cell carcinoma (RCC) is a heterogeneous group of cancers where the clear cell (ccRCC) is the most common and the most lethal. The absence of accurate diagnostic and follow-up biomarkers along with the time-limited response to therapies may explain the lethality and shows the necessity of new sensitive and specific biomarkers. One of the most studied molecules are the telomeres: specialized ribonucleoprotein structures that keep the structural integrity of the genome. Among other features, telomere length (TL) has been widely studied in several tumor models regarding its biomarker potential, due to the easy detection and quantification. The scope of this review was to analyze all the information about this parameter in RCC. There was some disparity in the results of the studies, since some pointed to an association between short TL and risk or poor outcome of RCC; others between long TL and RCC outcome and some did not find any association. We propose some epidemiological and biological explanations to these differences. The telomeres may play a dual role during RCC carcinogenesis in the early stages, short telomeres may increase RCC risk and in late carcinogenesis, long telomeres seem to be associated with tumor prognosis. However, the controversy of the results along with the lack of specificity are some problems that need to be clarified for the usage of TL as a prognostic biomarker.

Cancer-Specific Loss of Urocortin3 in Human Renal Cancer.

The corticotropin-releasing hormone (CRH) system, its receptors corticotropin-releasing hormone receptor 1 (CRHR1) and 2 (CRHR2), and its corresponding binding protein corticotropin-releasing hormone-binding protein (CRHBP) as well as the urocortin proteins-structural homologues to CRH, which are included in this peptide family-have become interesting oncological targets recently. Carcinogenesis of various human tumors has been reported with an altered presence of members of this system. The aim of the present study was to examine the role of urocortin3 (UCN3) in renal cell carcinoma (RCC). Therefore, tumoral tissues of 106 patients with RCC and available corresponding normal tissues were analyzed using qPCR for quantitative mRNA expression analysis. Tissue localization and protein signals of UCN3 in normal and tumoral renal specimens were evaluated using western blot and immunohistochemistry. In addition, correlation studies of UCN3 mRNA expression with clinicopathological parameters of patients with RCC and different histological subtypes were evaluated. UCN3 mRNA was significantly downregulated in nearly all tumoral tissues (p = 7.92 × 10-13). The same effect was observed at protein level using immunohistochemistry. Level of UCN3 mRNA expression was not directly correlated with clinicopathological parameters. We report for the first time the significant downregulation of UCN3 in RCC. These results demonstrate a possible involvement of the CRH system and its significance in carcinogenesis of RCC.

RBM10-TFE3 renal cell carcinoma characterised by paracentric inversion with consistent closely split signals in break-apart fluorescence in-situ hybridisation: study of 10 cases and a literature review.

Xp11 rearrangement in renal cell carcinoma (RCC) typically involves gene fusion to the gene encoding transcription factor E3 (TFE3), a member of the microphthalmia-associated transcription factor family on chromosome Xp11.2. Dual-colour break-apart fluorescence in-situ hybridisation (FISH) is recommended to confirm histological diagnoses. Recently, RNA-binding motif protein 10 (RBM10), encoded by a gene on chromosome Xp11.3, was identified as a chimeric partner of TFE3; thus, RBM10-TFE3 fusion results from paracentric inversion. RBM10-TFE3 RCC may yield a false-negative result in FISH analysis of TFE3 expression. The aim of the present study was to investigate the clinicopathological features of RBM10-TFE3 RCC. Ten patients with RBM10-TFE3 RCC aged 31-71years were investigated. Histological analysis, immunostaining, dual-colour break-apart FISH for TFE3, reverse transcription polymerase chain reaction and sequencing analysis were performed. No patient had a history of exposure to chemotherapy. Two of these patients died of RCC, and three were alive but developed metastases. Microscopically, the tumours were composed of a mixed architecture of tubulocystic and papillary patterns with scattered psammoma bodies. The tumours showed strong nuclear immunoreactivity for TFE3. FISH showed consistent closely spaced split signals in the RCCs of four patients, and polysomic signals with occasional closely spaced split signals in the RCCs of six patients. Of the latter six patients, five had renal failure, and four developed tumours in kidneys subjected to haemodialysis. The present study suggests that the carcinogenesis of RBM10-TFE3 RCC in some, but not all, patients may be associated with chronic kidney disease. The aggressive nature of RBM10-TFE3 RCC should be considered, as five patients experienced metastases.