Pathogenesis Of Renal Cell Carcinoma Research Articles

Abstract 5090: Prognosis of renal cell carcinoma patients with VHL mutations to immune checkpoint inhibitors

Abstract Background: The von Hippel-Lindau (VHL) gene is a tumor suppressor gene. Although VHL gene alterations play a key role in the pathogenesis of renal cell carcinoma (RCC), and several therapies targeting this molecular pathway have been studied, such as sunitinib, pazopanib and axitinib. However, it is not clear whether VHL mutation is a prognostic factor for immunotherapy in renal cell carcinoma. Methods: The impact of VHL mutations on survival outcomes in RCC patients received immunotherapy or non-immunotherapy were verified in the Memorial Sloan Kettering Cancer Center (MSKCC) trials and The Cancer Genome Atlas (TCGA) RCC cohort, respectively. An in-house Chinese RCC cohort (n=950) was used for the analysis of immune-related markers. The relationship between clinical pathologic features and VHL were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: In the MSKCC cohort, a total of 143 RCC patients receiving immunotherapy were enrolled, of which 117 (81.8%) were clear cell RCC and 143 (100%) microsatellite-stable RCC. VHL mutation was significantly associated with high TMB score (P =0.017). Kaplan-Meier survival analysis showed that patients with VHL mutation obtained better OS compared to VHL wild-type (50 months vs. 23 months, HR, 0.36; 95% CI 0.21-0.64; P<0.001). In the TCGA cohort, all RCC patients received non- immunotherapy. No association was observed between VHL and OS (HR, 1.00; 95% CI 0.73-1.38; P=0.981). VHL mutations were significantly associated with higher TMB levels (P=0.006) and MSI-H (P=0.004) in the in-house Chinese RCC cohorts. Conclusions: Our results suggest that VHL mutation may be associated with better OS in RCC patients receiving immunotherapy. The exact mechanisms underlying VHL are needed to be further evaluated. Citation Format: Dong Shen, Yufeng Huang, Zhiwei Wu, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. Prognosis of renal cell carcinoma patients with VHL mutations to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5090.

No Time to Die: How Kidney Cancer Evades Cell Death.

The understanding of the pathogenesis of renal cell carcinoma led to the development of targeted therapies, which dramatically changed the overall survival rate. Nonetheless, despite innovative lines of therapy accessible to patients, the prognosis remains severe in most cases. Kidney cancer rarely shows mutations in the genes coding for proteins involved in programmed cell death, including p53. In this paper, we show that the molecular machinery responsible for different forms of cell death, such as apoptosis, ferroptosis, pyroptosis, and necroptosis, which are somehow impaired in kidney cancer to allow cancer cell growth and development, was reactivated by targeted pharmacological intervention. The aim of the present review was to summarize the modality of programmed cell death in the pathogenesis of renal cell carcinoma, showing in vitro and in vivo evidence of their potential role in controlling kidney cancer growth, and highlighting their possible therapeutic value.

Extracellular Vesicles-A New Potential Player in the Immunology of Renal Cell Carcinoma.

The incidence of renal cell carcinoma (RCC) has doubled in the developed world within the last fifty years, and now it is responsible for 2–3% of diagnosed cancers. The delay in diagnosis and the not fully understood pathogenesis are the main challenges that have to be overcome. It seems that extracellular vesicles (EVs) are one of the key players in tumor development since they ensure a proper microenvironment for the tumor cells. The stimulation of angiogenesis and immunosuppression is mediated by molecules contained in EVs. It was shown that EVs derived from cancer cells can inhibit T cell proliferation, natural killer lymphocyte activation, and dendritic cell maturation by this mechanism. Moreover, EVs may be a biomarker for the response to anti-cancer treatment. In this review, we sum up the knowledge about the role of EVs in RCC pathogenesis and show their future perspectives in this field.

Современные молекулярно-генетические аспекты гистологических вариантов почечно-клеточной карциномы

The article presents the main molecular mechanisms of the pathogenesis of renal cell carcinoma. The molecular pathways that determine the development of histological variants of renal cell carcinoma and the role of stem cells markers in the carcinogenesis of these tumors are considered.

Carbonic anhydrase 10 functions as a tumor suppressor in renal cell carcinoma and its methylation is a risk factor for survival outcome.

Carbonic anhydrase 10 (CA10), one of the carbonic anhydrase isozymes, is explored to be downregulated in several tumor types, which indicates its critical role in tumorigenesis. However, its biologic and pathological function remains elusive in the pathogenesis of renal cell carcinoma (RCC). We examined expressions and functions of CA10 in RCC primary tumors and cell lines, assessed its tumor suppressive functions and further explored its impact on survival outcome of RCC patients. We found that CA10 was down-expressed in RCC primary tumors compared with adjacent non-malignant renal tissues. Promoter CpG methylation seemed to directly suppress the transcription of CA10 in RCC cells, which could be reversed by demethylation treatment. Restoration of CA10 in 786-O and Caki-2 cell lines inhibited their cell proliferation and promoted their apoptosis by regulating relevant apoptosis factors. Kaplan-Meier curve identified that CA10 methylation status was associated with progression-free survival in RCC (P = 0.021). Multivariate Cox regression analyses indicated the CA10 methylation status [HR, 4.724; 95% CI, 1.056-21.136; P = 0.042] was an independent predictor of disease progression. Collectively, our study demonstrates that CA10 as a tumor suppressor is frequently inactivated by promoter CpG methylation in RCC and its methylation is a risk factor for the prognosis of RCC.

The Role of Ferric Nitrilotriacetate in Renal Carcinogenesis and Cell Death: From Animal Models to Clinical Implications.

Simple SummaryIron is essential for cellular growth and survival. As a consequence, iron deficiency causes pleiotropic effects on the organism, while iron overload is also deleterious by means of oxidative tissue injury, which causes hepatic cirrhosis, diabetes mellitus, and cardiomyopathy in humans. Non-heme iron comprises ferric ion (Fe(III)), which is much more prominent in the transferrin, ferritin, or labile iron pool than the ferrous ion (Fe(II)); in contrast, ferrous ion yields more reactive oxygen species (ROS) than ferric ion does. In rodents, ferric nitrilotriacetate (Fe-NTA) elicits hepatic and renal oxidized lipids via a glutathione-cycle-dependent iron reduction that eventually causes renal cell carcinoma (RCC). In addition to iron-mediated carcinogenesis, ferroptosis is triggered by the iron-dependent accumulation of lipid peroxidation to lethal levels. Here, the mechanisms of iron- and ROS-mediated RCC and the therapeutic possibility of ferroptosis are discussed.Iron is essential for cellular growth, and various ferroproteins and heme-containing proteins are involved in a myriad of cellular functions, such as DNA synthesis, oxygen transport, and catalytic reactions. As a consequence, iron deficiency causes pleiotropic effects, such as hypochromic microcytic anemia and growth disturbance, while iron overload is also deleterious by oxidative injury. To prevent the generation of iron-mediated reactive oxygen species (ROS), ferritin is synthesized to store excess iron in cells that are consistent with the clinical utility of the serum ferritin concentration to monitor the therapeutic effect of iron-chelation. Among the animal models exploring iron-induced oxidative stress, ferric nitrilotriacetate (Fe-NTA) was shown to initiate hepatic and renal lipid peroxidation and the development of renal cell carcinoma (RCC) after repeated intraperitoneal injections of Fe-NTA. Here, current understanding of Fe-NTA-induced oxidative stress mediated by glutathione-cycle-dependent iron reduction and the molecular mechanisms of renal carcinogenesis are summarized in combination with a summary of the relationship between the pathogenesis of human RCC and iron metabolism. In addition to iron-mediated carcinogenesis, the ferroptosis that is triggered by the iron-dependent accumulation of lipid peroxidation and is implicated in the carcinogenesis is discussed.

Epstein\u2013Barr virus infection is associated with the nuclear factor-kappa B p65 signaling pathway in renal cell carcinoma

BackgroundThere have been few studies regarding viral involvement in the pathogenesis of renal cell carcinoma (RCC). The aim of this study was to examine the possible association of Epstein–Barr virus (EBV) infection with clinicopathological features and cellular biomarkers including p53, p16INK4a, Ki-67 and nuclear factor-kappa B (NF-κB) in RCC tumors.MethodsIn this prospective study, 122 histologically confirmed Formalin-fixed Paraffin-embedded RCC tissue specimens along with 96 specimens of their corresponding peritumoral tissues and 23 samples of blunt renal injuries were subjected to nested polymerase chain reaction (nPCR) in order to amplify EBV DNA sequences. The expression of p53, p16INK4a, Ki-67 and NF-κB was investigated by immunohistochemistry (IHC) assay. Statistical analysis was employed to demonstrate the possible associations.ResultsInfection with EBV was found to be significantly associated with RCC. Our results indicate that p65 NF-κB signaling pathway is probably involved in EBV-mediated RCC pathogenesis. Moreover, we found p53, Ki-67 and cytoplasmic NF-κB expression to be associated with tumor nuclear grade in RCC patients. The expression of p53 and Ki-67 was associated with primary tumor category as well. In addition, p53 overexpression was significantly more frequent among nonconventional RCC tumors than the conventional histologic type.ConclusionsInfection with EBV is likely to play an important role in the development of RCC through the constitutive and permanent activation of NF-κB p65 signaling pathway. However, more experiments and supporting data are required to reach a decisive conclusion.

LncRNA LINC00460 facilitates the proliferation and metastasis of renal cell carcinoma via PI3K/AKT signaling pathway.

Renal cell carcinoma (RCC) is one of the most prevalent cancers diseases in the worldwide. Long noncoding RNAs (LncRNAs) have been indicated as a mediator acted in tumorigenesis of RCC. LINC00460 has been reported to participate in many kinds of malignancies and promotes cancer progressions. However, the mechanism of LINC00460 on RCC is yet to be investigated. This study aimed to explore the potential function and regulation mechanism of LINC00460 in RCC. We analysed the LINC00460 expression and the prognosis in RCC patients using Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) databases. LINC00460 level in normal renal cell line and RCC cell lines were examined by qRT-PCR. We study the effects of LINC00460 on proliferation, migration, invasion, apoptosis in RCC cells lines using a series of in vivo and in vitro experiments. RNA sequencing (RNA-seq) analysis was applied to searching potential LINC00460 related signal pathway in RCC. We identified the significant up-regulated expression of LINC00460 both in RCC tissues and cell. RCC patients with elevated LINC00460 expression have shorter survival. Up-expression of LINC00460 promoted cell proliferation, invasion and migration, meanwhile down-regulation of LINC00460 exerted inhibitory effect on these activities. We crucially identified that LNC00460 promotes development of RCC by influencing the PI3K/AKT pathway. Knockdown of LNC00460 decreased the phosphorylation of AKT and mTOR. The key finding of our study showed that LINC00460 functions as an oncogene in RCC pathogenesis by mediating the PI3K/AKT.

Cytokines in Renal Cell Carcinoma: A Step Towards Earlier Detection and Targeted Therapy.

Symptoms of renal cell carcinoma (RCC) have typically late onset and correlate with its advanced stage. No biomarkers of RCC are currently available. The present study analyzed the immuno-biochemical profile of RCC by measuring the levels of cytokines engaged in RCC pathophysiology. Cytokines were examined by capture sandwich immunoassays in tumor tissue and urine. Specimens of cancer and nearby healthy kidney tissues were obtained during nephrectomy from 60 RCC patients. The urine was obtained from both patients and healthy subjects. The findings in RCC tumor tissue compared to healthy renal tissues were following: (i) increases in interleukin-15 (IL-15), vascular endothelial growth factor (VEGF), interferon gamma-induced protein-10 (IP-10), macrophage inflammatory protein-1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), and eotaxin, with VEGF, IP-10, and MIP-1β significantly associated with the histologic tumor nuclear grading (NG); (ii) increases in platelet-derived growth factor (PDGF), IL-15, MIP-1ß, eotaxin, and MCP-1 in urine, with significant associations noticed between cytokines and disease stages for eotaxin and MCP-1; and (iii) decreases in PDGF, IL-15, MCP-1, VEGF, MIP-1β, and eotaxin in urine from six patients on the third day after nephrectomy. We conclude that cytokines may play a critical role in the local pathogenesis of RCC, which opens the way for potential targeting of these molecules in novel therapies and their use as biomarkers for early noninvasive detection of RCC.

LncRNAs in the Regulation of Genes and Signaling Pathways through miRNA-Mediated and Other Mechanisms in Clear Cell Renal Cell Carcinoma.

The fundamental novelty in the pathogenesis of renal cell carcinoma (RCC) was discovered as a result of the recent identification of the role of long non-coding RNAs (lncRNAs). Here, we discuss several mechanisms for the dysregulation of the expression of protein-coding genes initiated by lncRNAs in the most common and aggressive type of kidney cancer—clear cell RCC (ccRCC). A model of competitive endogenous RNA (ceRNA) is considered, in which lncRNA acts on genes through the lncRNA/miRNA/mRNA axis. For the most studied oncogenic lncRNAs, such as HOTAIR, MALAT1, and TUG1, several regulatory axes were identified in ccRCC, demonstrating a number of sites for various miRNAs. Interestingly, the LINC00973/miR-7109/Siglec-15 axis represents a novel agent that can suppress the immune response in patients with ccRCC, serving as a valuable target in addition to the PD1/PD-L1 pathway. Other mechanisms of action of lncRNAs in ccRCC, involving direct binding with proteins, mRNAs, and genes/DNA, are also considered. Our review briefly highlights methods by which various mechanisms of action of lncRNAs were verified. We pay special attention to protein targets and signaling pathways with which lncRNAs are associated in ccRCC. Thus, these new data on the different mechanisms of lncRNA functioning provide a novel basis for understanding the pathogenesis of ccRCC and the identification of new prognostic markers and targets for therapy.

Chinese Medicine Leptochloa chinensis Inhibits the Malignant Behaviors of Renal Cell Carcinoma 786-O Cells by Regulating the mTOR Pathway.

Background Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system that seriously threatens human life and health. This study aims to explore the role of the traditional Chinese medicine Leptochloa chinensis in the pathogenesis of RCC. Meanwhile, this study also revealed the molecular biological mechanism of its antitumor activity. Methods Human RCC 786-O cells were cultured in the RPMI-1640 medium, which contains different concentrations of Leptochloa chinensis (1,000, 3,000, and 9,000 μg/ml). MTT and flow cytometry assays were used to detect the viability of 786-O cells. Transwell and wound healing assays were used to detect cell metastasis. The protein expression was observed by western blot analysis. Results Leptochloa can inhibit cell proliferation and induce apoptosis in RCC 786-O cells. In addition, Leptochloa can weaken the migration and invasion of 786-O cells. More importantly, Leptochloa can block the mTOR pathway by inhibiting the protein expression of p-mTOR. Moreover, the high concentration of Leptochloa chinensis has a better inhibitory effect on 786-O cells. Conclusion The traditional Chinese medicine Leptochloa chinensis inhibits the viability and metastasis of 786-O cells by blocking the mTOR pathway.

Genetic Analysis Reveals the Important Role of the APC Gene in Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. The aim of this study was to elucidate the molecular pathogenesis of sporadic RCC in Taiwan. Fifteen patients with RCC were screened for mutations in the von Hippel-Lindau (VHL) gene by PCR and Sanger sequencing. The methylation status of promoters of 24 tumor suppressor genes by methylation sensitive multiplex ligation-dependent probe amplification analysis was also determined. Inactivation of the VHL gene was observed in 5 cases: three missense somatic mutations, one promoter methylation, and one small deletion. In RCCs, methylation was most frequently observed in APC (100%), CDKN2B (92.9%), CASP8, MLH1_167, and KLLN (85.7.4%), but not in FHIT, MLH1_463, DAPK1, or HIC1 (0%). In addition to VHL inactivation, promoter methylation of APC may be a universal pathognomonic event in the tumorigenesis of RCC and a candidate diagnostic and therapeutic biomarker.

The Effect Of Beclin 1, P53 Mutation, Ki-67 Proliferation İndex, Tumor Necrosis and Microvascular İnvasion On Prognosis İn Renal Cell Carcinomas and Their Relationship With Known Prognostic Parameters

Aim: The aim of this study was to help identify new prognostic markers in renal cell carcinomas (RCC), to show the role of autophagy in the pathogenesis of RCC and to shed light on new treatment modalities in RCC. Material and Methods: Clinicopathological stages, tumor necrosis and microvascular invasion (MVI) were determined retrospectively and Beclin-1, Ki-67, and p53 were studied immunohistochemically. Results: Tumor necrosis, MVI, Ki-67, and p53 in RCCs were positively correlated with Fuhrman nuclear grade and pathologic tumor stage, while Beclin-1 was only associated with nuclear grade. MVI and Ki-67 were associated with distant organ and lymph node metastasis. Ki-67 and necrosis correlated positively with p53 and Beclin-1 expression, but not with MVI. Beclin-1 were positively correlated necrosis, but not with p53 and MVI. p53, Ki-67 and MVI were negatively correlated with survival, while the effect of Beclin -1 and necrosis on survival couldn’t be demonstrated. Conclusion: Ki-67, p53, and MVI in RCCs are prognostic parameters with effects on survival. Although Beclin-1 was not a prognostic parameter associated with survival, its expression in tumor tissue was found to be increased. At the same time, there is less staining in non-tumor renal parenchyma. Beclin-1 is a marker of autophagy and is thought to be involved in RCC pathogenesis rather than its prognostic significance.

The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features

BackgroundRenal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy. MethodsExpression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay. ResultsExpression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro. ConclusionInactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.

Erratum to: Analysis of miRNA-Mediated ceRNAs In The Pathogenesis of Renal Cell Carcinoma: An In Silico Approach

The author recognized that some references are excluded and positioned in incorrect places due to the reference manager software after the manuscript [E1] is published. Immediately, the author requested from the journal for the corrections of the errors as follows.

Epigenetic silencing of ZBTB28 promotes renal cell carcinogenesis.

Zinc finger and BTB domain-containing protein 28 (ZBTB28) is a potential tumor suppressor for some cancers. However, its epigenetic regulation and functions in renal cell carcinoma (RCC) remain to be elucidated. The expression of ZBTB28 mRNA was analyzed by semi-quantitative reverse transcription polymerase chain reaction (PCR) in nine RCC cell lines and normal kidney tissues. Methylation status of ZBTB28 promoter was assessed by methylation-specific PCR in RCC cell lines, primary RCC, tumors and adjacent tissues. The involvement of ZBTB28 in cell proliferation and migration was investigated. ZBTB28 promoter was hypermethylated in 88.9% (8/9) of RCC cell lines with reduced ZBTB28 mRNA expression, and could be reversed by DNA methyltransferase inhibitors. The methylation of ZBTB28 promoter was detected in 73.5% (36/49) of primary RCC tissues, compared with 7.1% (1/14) in normal tissues. Overexpression of ZBTB28 significantly inhibited RCC cell proliferation and migration, and induced apoptosis. Further analyses revealed that ZBTB28 upregulation could inhibit multiple oncogenic signaling transduction pathways. ZBTB28 is frequently silenced by promoter methylation in RCC pathogenesis and functions as a novel tumor suppressive gene. ZBTB28 may be a potential target for the development of RCC therapeutic strategies.

Role of SIRT1/AMPK signaling in the proliferation, migration and invasion of renal cell carcinoma cells.

Renal cell carcinoma (RCC) is a lethal urologic tumor commonly seen in men that best responds to partial nephrectomy. An enhanced understanding of the molecular pathogenesis of RCC can broaden treatment options and tumor prevention strategies. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates several bioactive substances, and the present study aimed to identify the role of SIRT1/AMP-activated protein kinase (AMPK) signaling in RCC progression. SIRT1 expression was detected in 100 patients with RCC using tissue microarray immunohistochemistry. SIRT1-knockdown and overexpression were performed via RNA interference and plasmid transfection. Inhibition of AMPK was used for the phenotypic rescue assays to verify whether AMPK was a downstream target of SIRT1. Reverse transcription-quantitative PCR was performed to verify transfection efficiency. Transwell, MTT and flow cytometry apoptosis assays were performed to evaluate the migration, invasion, proliferation and early apoptosis level of RCC cells. SIRT1 and AMPK protein expression in human RCC tissues and cell lines (786-O and ACHN) was detected using western blotting and immunofluorescence staining. The current results, combined with data from The Cancer Genome Atlas database, revealed that SIRT1 expression in RCC tissues was downregulated compared with in adjacent normal tissues. Additionally, high SIRT1 expression was associated with an improved prognosis in patients with RCC. Overexpression of SIRT1 inhibited the proliferation, migration and invasion of RCC cell lines and induced apoptosis, while inhibition of SIRT1 expression had the opposite effects. Further experiments indicated that SIRT1 may serve an anticancer role by upregulating the expression levels of downstream AMPK, thus revealing a potential therapeutic target for RCC.

PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review).

Renal cell carcinoma (RCC) accounts for over 90% of all renal malignancies, and mainly affects the male population. Obesity and smoking are involved in the pathogenesis of several systemic cancers including RCC. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway regulates cell growth, differentiation, migration, survival, angiogenesis, and metabolism. Growth factors, hormones, cytokine and many extracellular cues activate PI3K/AKT/mTOR. Dysregulation of this molecular pathway is frequently reported in human cancers including RCC and is associated with aggressive development and poor survival rate. mTOR is the master regulator of cell metabolism and growth, and is activated in many pathological processes such as tumour formation, insulin resistance and angiogenesis. mTOR inhibitors are used at present as drug therapy for RCC to inhibit cell proliferation, growth, survival, and the cell cycle. Temsirolimus and everolimus are two mTOR inhibitors that are currently used for the treatment of RCC. Drugs targeting the PI3K/AKT/mTOR signalling pathway may be one of the best therapeutic options for RCC.

Immunohistochemical analysis of beta-catenin expression: a probable prognostic marker and potential therapeutic target in renal cell carcinoma

Background and aimsRenal cell carcinoma (RCC) seems to be the most aggressive type of genitourinary neoplasm. Down regulation of normal beta-catenin expression contributes to development of RCC, reflecting the role of beta-catenin/Wnt signaling pathway in pathogenesis. This study aims to evaluate the significance of beta-catenin expression and its correlation with the prognostic parameters.MethodsA cross-sectional observational study was carried out in a tertiary care center on 58 RCC cases using variables like histological grade and type, tumor stage, necrosis. Formalin fixed, paraffin-embedded blocks were evaluated for beta-catenin expression by immunohistochemistry using scoring system. Data were analyzed by mean ± SD, χ2 test, Pearson’s correlation test.ResultsMembranous score (MS) had a strong negative correlation with tumor stage (r=−0.407, p=0.044) and grade (r=−0.787, p=<0.001). Mean membranous score difference between low (Stage 1 and 2) vs. high stage (Stage 3 and 4) and low (Grade 1 and 2) vs. high grade (Grade 3 and 4) was statistically significant (p<0.001). Cytoplasmic score (CS) had positive correlation with tumor stage (r=0.586; p=0.002). No significant correlation was evident between cytoplasmic scores and tumor grade, however the mean cytoplasmic score difference between low grade vs. high grade was statistically significant (p < 0.001).ConclusionBeta-catenin may play a crucial role in the pathogenesis of RCC and has a positive correlation with the biological behavior of this tumor. The important role of beta-catenin as a prognostic parameter and probably a critical evaluator of targeted chemotherapy cannot be overemphasized.

Circulating Th22 cells, as well as Th17 cells, are elevated in patients with renal cell carcinoma

T-helper (Th) 22 cells serve an essential role in different types of tumors and autoimmune diseases. No research has been conducted to study the role of Th22 cells in the pathogenesis of renal cell carcinoma (RCC). We aimed to evaluate the prognostic value of circulating Th22, Th17, and Th1 cells in RCC patients. Thirty-two newly diagnosed RCC patients and thirty healthy controls were enlisted in the research. Their peripheral blood was collected, and the frequencies of circulating Th22, Th17, and Th1 cells were detected by flow cytometry. Plasma IL-22 concentrations were examined by an enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to identify the mRNA expression levels of aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) in peripheral blood mononuclear cells (PBMC). Compared with the healthy control group, the frequency of circulating Th22 and Th17 cells and concentrations of plasma IL-22 were significantly increased in RCC patients. However, there was no significant difference in the frequency of Th1 cells. A positive correlation between Th22 cells and plasma IL-22 levels was found in RCC patients. Also, there was a significant positive correlation between Th22 and Th17 cells in RCC patients. An up-regulated expression of AHR and RORC transcription factors were also observed in RCC patients. As tumor stage and grade progressed, the frequencies of Th22 and Th17 cells and the level of plasma IL-22 significantly increased. Meanwhile, there was a positive correlation between Th22 and Th17 cells and RCC tumor stage or grade. Furthermore, patients with high Th22 or Th17 cells frequency displayed a decreased trend in survival rate. Our research indicated that the increased circulating Th22 and Th17 cells and plasma IL-22 may be involved in the pathogenesis of RCC and may be involved in the occurrence and development of tumors. Th22 cells, plasma IL-22, and Th17 cells may be promising new clinical biomarkers and may be used as cellular targets for RCC therapeutic intervention.