scholarly journals Characterization of the expression of LAT1 as a prognostic indicator and a therapeutic target in renal cell carcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kosuke Higuchi ◽  
Shinichi Sakamoto ◽  
Keisuke Ando ◽  
Maihulan Maimaiti ◽  
Nobushige Takeshita ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Migration And Invasion ◽  
Large Neutral Amino Acid ◽  
Dependent Manner ◽  
Expression Levels

AbstractLarge neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.

scholarly journals HCRP-1 regulates cell migration and invasion via EGFR-ERK mediated up-regulation of MMP-2 with prognostic significance in human renal cell carcinoma

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Feifei Chen ◽  
Junpeng Deng ◽  
Xin Liu ◽  
Wang Li ◽  
Junnian Zheng
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Migration ◽  
Cell Carcinoma ◽  
Cancer Progression ◽  
Renal Cell ◽  
Prognostic Significance ◽  
Migration And Invasion ◽  
Human Renal Cell Carcinoma ◽  
Cell Migration And Invasion ◽  
Erk Phosphorylation

Abstract Previous studies indicated a role of hepatocellular carcinoma-related protein-1(HCRP-1) in human cancers, however, its expression pattern in renal cell carcinoma (RCC) and the molecular mechanism of HCRP-1 on cancer progression have not been characterized. In the present study, HCRP-1 expression was examined in a RCC tissue microarray. The negative expression of HCRP-1 was significantly correlated with tumor grade (P = 0.002), TNM stage (P = 0.001) and pT status (P = 0.003). Furthermore, we showed a strong correlation between negative HCRP-1 expression and worse overall and disease-specific survival (P = 0.0003 and P = 0.0012, respectively). Knockdown of HCRP-1 promoted cell migration and invasion in 786-O and OS-RC-2 cell lines. HCRP-1 depletion increased matrix metalloproteinase (MMP)-2 protein level, with increased extracellular signal-regulatedkinase (ERK) phosphorylation, which could be reversed by ERK siRNA or ERK inhibitor, PD98059. Further analysis showed that HCRP-1 knockdown induced epidermal growth factor receptor (EGFR) phosphorylation. Treatment with EGFR inhibitor or EGFR siRNA blocked HCRP-1-mediated up-regulation of EGFR, ERK phosphorylation and MMP-2 expression. In summary, our results showed that negative HCRP-1 expression is an independent prognostic factor for RCC patients and promotes migration and invasion by EGFR-ERK-mediated up-regulation of MMP-2. HCRP-1 may serve as a therapeutic target for RCC.

Multicenter Phase II Trial of S-1 in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma

2010 ◽  
Vol 28 (34) ◽  
pp. 5022-5029 ◽  
Author(s):  
Seiji Naito ◽  
Masatoshi Eto ◽  
Nobuo Shinohara ◽  
Yoshihiko Tomita ◽  
Masato Fujisawa ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
Phase Ii ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Free Survival ◽  
Expression Levels ◽  
Mrna Expression Levels

Purpose This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU). Methods Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse-transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy. Results A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S-1, and 28 (62.2%) had stable disease. Median progression-free survival was 9.2 months. The severity of most adverse events was mild to moderate. The most common grade 3/4 drug-related adverse events were neutropenia (8.9%) and anorexia (8.9%). The expression level of thymidylate synthase (TS) mRNA was significantly lower in patients who responded to treatment (t-test, P = .048), and progression-free survival was significantly longer in patients whose TS mRNA expression levels were below the median value, as compared with those with higher levels (log-rank test, P = .006). Conclusion S-1 is active against cytokine-refractory mRCC. Quantification of TS mRNA levels in tumors before treatment may facilitate prediction of the response of mRCC to S-1.

scholarly journals Low Expression Levels of SLC22A12 Indicates a Poor Prognosis and Progresses Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiaju Xu ◽  
Yuenan Liu ◽  
Jingchong Liu ◽  
Yi Shou ◽  
Zhiyong Xiong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Survival Data ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Set Enrichment Analysis ◽  
Migration And Invasion ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Low Expression

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 4/5 of all kidney cancers. Accumulation of minor changes in the cellular homeostasis may be one cause of ccRCC. Therefore, we downloaded the RNA sequencing and survival data of the kidney renal cell carcinoma (KIRC) cohort from the Cancer Genome Atlas (TCGA) database. After the univariate and multivariate Cox regression analyses, 19 kidney-specific differentially expressed genes (DEGs) were found. Solute Carrier Family 22 Member 12 (SLC22A12) resulted in an independent prognostic predictor for both overall survival (OS) and disease-free survival (DFS). SLC22A12 expression was lower in tumoral tissue compared to normal tissue. Moreover, patients in the SLC22A12 low expression group had a higher pathological stage and worse survival than the high expression group. Additionally, qRT-PCR assay, immunoblotting test (IBT), and immunohistochemical (IHC) analyses of cancer tissues/cells and the corresponding normal controls verified that SLC22A12 is downregulated in ccRCC. Receiver operator characteristic (ROC) curves showed that the low expression level of SLC22A12 could be a good diagnostic marker for ccRCC (AUC=0.7258; p <0.0001). Gene set enrichment analysis (GSEA) showed that SLC22A12 expression levels are related to metabolism, cell cycle, and tumor-related signaling pathways. GO and KEGG analyses revealed that SLC22A12 transports multiple organic compounds, ions, and hormones and participates in the extracellular structure organization. Furthermore, SLC22A12 over-expression in vitro inhibited the proliferation, migration, and invasion of renal cancer cells by regulating PI3K/Akt pathways. Such effects were reversed when knocking out SLC22A12. In summary, as a transporter for many vital metabolites, SLC22A12 may affect tumor cell survival through its impacts on the mentioned metabolites. In conclusion, this study uncovered that SLC22A12 is a promising prognostic and diagnostic biomarker for ccRCC.

Supression of tumor progression and metastasis in renal cell carcinoma by miR-192, miR-194, and miR-215.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 385-385 ◽  
Author(s):  
Heba W. Z. Khella ◽  
Marize Bakhet ◽  
Ghassan Allo ◽  
Michael A. S. Jewett ◽  
Andrew Girgis ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Migration ◽  
Tumor Progression ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Target Prediction ◽  
Migration And Invasion ◽  
Expression Levels ◽  
Cell Migration And Invasion

385 Background: miRNAs play a crucial rule in tumor progression and metastasis. We previously identified miR-192, miR-194 and miR-215 to be down-regulated in metastatic compared to primary clear cell renal cell carcinoma (ccRCC). In this work, we examine the role of miR-192, miR-194, and miR-215 in RCC progression and aggressiveness. Methods: We examined the role of these three miRNAs on tumor cell migration and invasion abilities using RCC cell line models. We performed target prediction analysis and experimentally validated the targets using independent approaches. In addition, we examined the clinical utility of miR-215 as a potential prognostic marker in RCC by measuring miR-215 expression using qRT-PCR in 61 formalin-fixed paraffin-embedded tissues from primary ccRCC and correlated the expression levels with clinical outcome. Results: Restoration of miR-192, miR-194, and miR-215 expression decreased cell migration and invasion in RCC cell lines. Target prediction analysis identified three potential targets of these miRNAs; MDM2, TYMS, and SIP1/ZEB2. We validated the miRNA-target interaction experimentally using three approaches. First by measuring the effect of miRNA overexpression on mRNA and protein levels of the predicted target, then by measuring the effect of miRNA overexpression on a luciferase signal of a vector containing the 3’UTR of the predicted target, and finally, by validating these interactions in vivoby examining the presence of an inverse correlation between miRNA changes and the expression levels of their targets on clinical specimens. In 61 patients with resected ccRCC tumors, we found that low miR-215 expression in the primary was associated with a significantly reduced recurrence-free survival. (26.4 vs. 49.2 months, respectively, p = 0.0320). Conclusions: Our analysis showed that miR-192, miR-194, and miR-215 are involved in RCC metastasis and that miR-215 predicts for recurrence in patients with resected RCC. Our findings pave the way to the clinical use of miRNAs as prognostic markers and potential therapeutic targets.

scholarly journals DDX3X is Epigenetically Repressed in Renal Cell Carcinoma and Serves as a Prognostic Indicator and Therapeutic Target in Cancer Progression

2020 ◽  
Vol 21 (8) ◽  
pp. 2881
Author(s):  
Tsung-Chieh Lin
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Progression ◽  
Renal Cell ◽  
Biological Effects ◽  
The Cancer Genome Atlas ◽  
Prognostic Indicators ◽  
Rna Helicases ◽  
Poor Overall Survival ◽  
Expression Levels

DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked (DDX3X) is a member of the DEAD-box family of RNA helicases whose function has been revealed to be involved in RNA metabolism. Recent studies further indicate the abnormal expression in pan-cancers and the relevant biological effects on modulating cancer progression. However, DDX3X’s role in renal cell carcinoma (RCC) progression remains largely unknown. In this study, a medical informatics-based analysis using The Cancer Genome Atlas (TCGA) dataset was performed to evaluate clinical prognoses related to DDX3X. The results suggest that DDX3X is epigenetically repressed in tumor tissue and that lower DDX3X is correlated with the poor overall survival of RCC patients and high tumor size, lymph node metastasis, and distant metastasis (TNM staging system). Furthermore, knowledge-based transcriptomic analysis by Ingenuity Pathway Analysis (IPA) revealed that the SPINK1-metallothionein pathway is a top 1-repressed canonical signaling pathway by DDX3X. Furthermore, SPINK1 and the metallothionein gene family all serve as poor prognostic indicators, and the expression levels of those genes are inversely correlated with DDX3X in RCC. Furthermore, digoxin was identified via Connectivity Map analysis (L1000) for its capability to reverse gene signatures in patients with low DDX3X. Importantly, cancer cell proliferation and migration were decreased upon digoxin treatment in RCC cells. The results of this study indicate the significance of the DDX3Xlow/SPINK1high/metallothioneinhigh axis for predicting poor survival outcome in RCC patients and suggest digoxin as a precise and personalized compound for curing those patients with low DDX3X expression levels.

Progression-free survival as a clinical trial endpoint in advanced renal cell carcinoma

2011 ◽  
Vol 18 (0) ◽  
Author(s):  
Sebastien J. Hotte ◽  
G.A. Bjarnason ◽  
D.Y.C. Heng ◽  
M.A.S. Jewett ◽  
A. Kapoor ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Advanced Renal Cell Carcinoma ◽  
Free Survival ◽  
Clinical Trial Endpoint ◽  
Trial Endpoint

scholarly journals Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis

Oncogene ◽  
2021 ◽  
Author(s):  
Ming-xiao Zhang ◽  
Li-zhen Zhang ◽  
Liang-min Fu ◽  
Hao-hua Yao ◽  
Lei Tan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Positive Feedback ◽  
Renal Cell ◽  
Clear Cell ◽  
Biological Significance ◽  
Specific Inhibitor ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Cell Renal Cell Carcinoma

AbstractLong noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

scholarly journals Prognostic value of DCE-CT-derived blood volume and flow compared to core biopsy microvessel density in patients with metastatic renal cell carcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Aska Drljevic-Nielsen ◽  
Finn Rasmussen ◽  
Patricia Switten Nielsen ◽  
Christina Stilling ◽  
Kennet Thorup ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Blood Volume ◽  
Metastatic Renal Cell Carcinoma ◽  
Microvessel Density ◽  
Renal Cell ◽  
Core Biopsy ◽  
Progression Free Survival ◽  
Prognostic Impact ◽  
Tumour Metastasis

Abstract Background Angiogenesis is prominent in metastatic renal cell carcinoma (mRCC). We compared two angiogenesis assessment methods: dynamic contrast-enhanced computed tomography (DCE-CT)-derived blood volume (BV) and blood flow (BF) and core biopsy microvessel density (MVD). Methods As planned in DaRenCa Study-1 study, DCE-CT and core biopsy were performed from the same tumour/metastasis at baseline. MVD was assessed by CD34 immunostaining in tumour (CD34-indexT) or tumour including necrosis (CD34-indexTN). BV and BF were assessed using the DCE-CT software. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier analysis. Spearman coefficient (rho) tested the correlation between MVD and BV, BF, or CT density (HU). Results At baseline, 25 patients had analysable scans and tissue. BVdeconv, BVPatlak, and BFdeconv > median were associated with favourable OS (43.2 versus 14.6 months, p = 0.002; 31.6 versus 20.2 months, p = 0.015; and 31.6 versus 24.5 months, p = 0.019). CD34-indexT and CD34-indexTN did not correlate with age (p = 0.543), sex (p = 0.225), treatment (p = 0.848), International mRCC Database Consortium category (p = 0.152), synchronous versus metachronous metastatic disease (p = 0.378), or tumour volume (p = 0.848). CD34-indexT or CD34-indexTN > median was not associated with PFS (p = 0.441 and p = 0.854, respectively) or OS (p = 0.987 and p =0.528, respectively). CD34-indexT or CD34-indexTN was not correlated with BV, BF, or HU (rho 0.20–0.26). Conclusions Differently from MVD, DCE-CT-derived BV and BF had prognostic impact and may better reflect angiogenesis in mRCC. Trial registration NCT01274273

scholarly journals Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2

2021 ◽  
Vol 69 (4) ◽  
pp. 888-892
Author(s):  
Joseph I Clark ◽  
Brendan Curti ◽  
Elizabeth J Davis ◽  
Howard Kaufman ◽  
Asim Amin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Melanoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

scholarly journals Efficacy and Safety of Nivolumab and Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study

2021 ◽  
Vol 28 (2) ◽  
pp. 1402-1411
Author(s):  
Koji Iinuma ◽  
Koji Kameyama ◽  
Kei Kawada ◽  
Shota Fujimoto ◽  
Kimiaki Takagi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Efficacy And Safety ◽  
Lymphocyte Ratio

We conducted a multicenter, retrospective study to evaluate the efficacy and safety of combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, we focused on patients who received NIVO+IPI and were stratified into intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium model at five institutions in Japan. The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS). In addition, we evaluated the role of inflammatory cell ratios, namely neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as predictive biomarkers in patients with mRCC. The median follow-up period was 1 year, and the 1-year OS rate was 95.8%. The ORR and DCR were 34.3% and 80.0%, respectively. According to BOR, four patients (11.4%) achieved complete response. According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033). Although 71.4% of the patients experienced treatment-related adverse events (TRAEs) with NIVO+IPI, only four patients discontinued NIVO+IPI due to grade 3/4 TRAEs. Patients treated with NIVO+IPI as a first-line therapy for advanced or mRCC achieved relatively better oncological outcomes. Therefore, NIVO+IPI may have potential advantages and may lead to a treatment effect compared to those receiving targeted therapies. In addition, PLR >188.1 may be a useful predictive marker for mRCC patients who received NIVO+IPI.

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