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Molecular Insights in Kidney Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 July 2023) | Viewed by 5511

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Special Issue Editors

Dr. Lily Wu

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Guest Editor

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
Interests: renal cell carcinoma; metastatic progression; VHL in oncogenesis; new PDXs

Prof. Dr. Brian Shuch

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Guest Editor

Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
Interests: renal cell carcinoma; molecular genetics; clinical trials

Dr. Huihui Ye

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Guest Editor

Department of Pathology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
Interests: renal cell carcinoma; tumor microenvironment; cancer genetics and pathology

Special Issue Information

Dear colleagues,

Kidney cancer (renal cell carcinoma, RCC) encompasses multiples subtypes with disparate pathological and molecular characteristics and clinical outcomes. Several genetic lesions are known to be pathogenic for subtypes of RCC. For instance, the inactivation or dysfunction of VHL (von Hippel Landau) tumor suppressor gene is oncogenic for clear cell RCC (ccRCC), while the dysfunction of fumarate hydratase (FH) is associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). Importantly, the interplay between genetic and metabolic alterations in tumor cells, and their influences on immune cells and microenvironmental components clearly modulate cancer progression and therapeutic response. A greater understanding of the molecular communication super highway in the tumor microenvironment of RCC will be instrumental to devise more effective targeted therapies in order to improve the outcome of this cancer. This Special Issue will focus on these molecular translational researches in RCC

Dr. Lily Wu
Prof. Dr. Brian Shuch
Dr. Huihui Ye
Guest Editors

Manuscript Submission Information

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Keywords

kidney cancer
renal cell carcinoma
clear cell RCC
genetic lesions
subtypes of RCC
molecular translational researches

Published Papers (4 papers)

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Research

10 pages, 14466 KiB

Open AccessArticle

VHL L169P Variant Does Not Alter Cellular Hypoxia Tension in Clear Cell Renal Cell Carcinoma

by Junhui Hu, Desmond J. Smith and Lily Wu

Int. J. Mol. Sci. 2023, 24(18), 14075; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241814075 - 14 Sep 2023

Cited by 1 | Viewed by 1034

Abstract

In the current era of tumor genome sequencing, single amino acid missense variants in the von Hippel–Lindau (VHL) tumor suppressor gene are frequently identified in clear cell renal carcinoma (ccRCC). Due to the incomplete knowledge of the structural architecture of VHL protein, the functional significance of many missense mutations cannot be assigned. L169P is one such missense mutation identified in the case of aggressive, metastatic ccRCC. Here, we characterized the biochemical activity, transcriptomic hypoxia signature and biological functions of the L169P variant. Lentiviral vector expressing either wildtype (WT) or L169P VHL were used to transduce two VHL-deficient human ccRCC cell lines, 786-O and RCC4. The stability of the VHL protein and the expression level of VHL, HIF1α and HIF2α were analyzed. The impact of restoring L169P or WT VHL on the hypoxia gene expression program in 786-O cells was assessed by mRNA sequencing (RNAseq) and computed hypoxic scores. The impact of restoring VHL expression on the growth of ccRCC models was assessed in cell cultures and in chorioallantoic membrane (CAM) xenografts. In the 786-O cells, the protein stability of L169P VHL was comparable to WT VHL. No obvious difference in the capability of degrading HIF1α and HIF2α was observed between WT and L169P VHL in the 786-O or RCC4 cells. The hypoxic scores were not significantly different in the 786-O cells expressing either wildtype or L169P VHL. From the cellular function perspective, both WT and L169P VHL slowed cell proliferation in vitro and in vivo. The L169P VHL variant is comparable to WT VHL in terms of protein stability, ability to degrade HIF1α factors and ability to regulate hypoxia gene expression, as well as in the suppression of ccRCC tumor cell growth. Taken together, our data indicate that the L169P VHL variant alone is unlikely to drive the oncogenesis of sporadic ccRCC. Full article

(This article belongs to the Special Issue Molecular Insights in Kidney Cancer)

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15 pages, 8008 KiB

Open AccessArticle

TROAP Promotes the Proliferation, Migration, and Metastasis of Kidney Renal Clear Cell Carcinoma with the Help of STAT3

by Jun Wang, Hongyuan Wan, Yuanyuan Mi, Sheng Wu, Jie Li and Lijie Zhu

Int. J. Mol. Sci. 2023, 24(11), 9658; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119658 - 02 Jun 2023

Cited by 2 | Viewed by 1339

Abstract

Kidney renal clear cell carcinoma (KIRC) is a subtype of renal cell carcinoma that threatens human health. The mechanism by which the trophinin-associated protein (TROAP)–an important oncogenic factor–functions in KIRC has not been studied. This study investigated the specific mechanism by which TROAP functions in KIRC. TROAP expression in KIRC was analyzed using the RNAseq dataset from the Cancer Genome Atlas (TCGA) online database. The Mann–Whitney U test was used to analyze the expression of this gene from clinical data. The Kaplan–Meier method was used for the survival analysis of KIRC. The expression level of TROAP mRNA in the cells was detected using qRT-PCR. The proliferation, migration, apoptosis, and cell cycle of KIRC were detected using Celigo, MTT, wound healing, cell invasion assay, and flow cytometry. A mouse subcutaneous xenograft experiment was designed to demonstrate the effect of TROAP expression on KIRC growth in vivo. To further investigate the regulatory mechanism of TROAP, we performed co-immunoprecipitation (CO-IP) and shotgun liquid chromatography–tandem mass spectrometry (LC-MS). TCGA-related bioinformatics analysis showed that TROAP was significantly overexpressed in KIRC tissues and was related to higher T and pathological stages, and a poor prognosis. The inhibition of TROAP expression significantly reduced the proliferation of KIRC, affected the cell cycle, promoted cell apoptosis, and reduced cell migration and invasion. The subcutaneous xenograft experiments showed that the size and weight of the tumors in mice were significantly reduced after TROAP-knockdown. CO-IP and post-mass spectrometry bioinformatics analyses revealed that TROAP may combine with signal transducer and activator of transcription 3 (STAT3) to achieve tumor progression in KIRC; this was verified by functional recovery experiments. TROAP may regulate KIRC proliferation, migration, and metastasis by binding to STAT3. Full article

(This article belongs to the Special Issue Molecular Insights in Kidney Cancer)

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14 pages, 2283 KiB

Open AccessArticle

MicroRNA-155-5p Targets JADE-1, Promoting Proliferation, Migration, and Invasion in Clear Cell Renal Cell Carcinoma Cells

by Thomas Kalantzakos, Kailey Hooper, Sanjna Das, Travis Sullivan, David Canes, Alireza Moinzadeh and Kimberly Rieger-Christ

Int. J. Mol. Sci. 2023, 24(9), 7825; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097825 - 25 Apr 2023

Cited by 1 | Viewed by 1457

Abstract

Clear cell renal cell carcinoma (ccRCC) incidence has been rising in recent years, with strong association between differential microRNA (miRNA) expression and neoplastic progression. Specifically, overexpression of miR-155-5p has been associated with promoting aggressive cancer in ccRCC and other cancers. In this study, we further investigate the role of this miRNA and one of its protein targets, Jade-1, to better understand the mechanism behind aggressive forms of ccRCC. Jade-1, a tumor suppressor, is stabilized by Von-Hippel Lindau (VHL), which is frequently mutated in ccRCC. Experiments featuring downregulation of miR-155-5p in two ccRCC cell lines (786-O and Caki-1) attenuated their oncogenic potential and led to increased levels of Jade-1. Conversely, knockdown experiments with an anti-Jade-1 shRNA in 786-O and Caki-1 cells showed increased metastatic potential through elevated proliferation, migration, and invasion rates. In a mouse xenograft model, downregulation of miR-155 decreased the rate of tumor implantation and proliferation. Direct interaction between miR-155-5p and Jade-1 was confirmed through a 3′UTR luciferase reporter assay. These findings further elucidate the mechanism of action of miR-155-5p in driving an aggressive phenotype in ccRCC through its role in regulating Jade-1. Full article

(This article belongs to the Special Issue Molecular Insights in Kidney Cancer)

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17 pages, 3074 KiB

Open AccessArticle

Differential Expression and Clinical Relevance of C-X-C Motif Chemokine Receptor 4 (CXCR4) in Renal Cell Carcinomas, Benign Renal Tumors, and Metastases

by Moritz Maas, Aymone Kurcz, Jörg Hennenlotter, Marcus Scharpf, Falko Fend, Simon Walz, Viktoria Stühler, Tilman Todenhöfer, Arnulf Stenzl, Jens Bedke and Steffen Rausch

Int. J. Mol. Sci. 2023, 24(6), 5227; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065227 - 09 Mar 2023

Cited by 1 | Viewed by 1234

Abstract

C-X-C Motif Chemokine Receptor 4 (CXCR4) is part of the human chemokine system and involved in progression and metastasis in renal cell carcinoma (RCC). However, the role of CXCR4 protein expression in RCC remains controversial. In particular, data regarding the subcellular distribution of CXCR4 in RCC and RCC metastasis as well as CXCR4 expression in renal tumors of variant histology are limited. The aim of the present study was the evaluation of the differential CXCR4 expression in RCC primary tumor and metastatic tissue as well as in variant renal histologies. In addition, the prognostic capacity of CXCR4 expression in organ-confined clear cell RCC (ccRCC) was evaluated. Three independent renal tumor cohorts (primary ccRCC cohort n₁ = 64; cohort of various histological entities n₂ = 146; metastatic RCC tissue cohort n₃ = 92) were evaluated using tissue microarrays (TMA). After immunohistochemical staining for CXCR4, nuclear and cytoplasmic expression patterns were evaluated. CXCR4 expression was correlated with validated pathologic prognosticators, clinical data, and overall and cancer-specific survival. Positive cytoplasmic staining was observed in 98% of the benign and 38.9% of the malignant samples. Nuclear staining was positive for 94.1% of the benign samples and 83% of the malignant samples. The median cytoplasmic expression score was found to be higher in benign tissue than in ccRCC (130.00 vs. 0.00); median nuclear expression score analysis indicated the opposite (56.0 vs. 71.0). Within malignant subtypes, the highest expression score was seen in papillary renal cell carcinomas (cytoplasmic: 117.50, nuclear: 41.50). Within benign renal tumors, high cytoplasmic and nuclear CXCR4 expression scores were seen for oncocytomas (cytoplasmic: 100.00, nuclear: 31.00). Expression scores in RCC metastasis ranked between benign renal tissue and ccRCC in cytoplasmic and nuclear expression. Cytoplasmic CXCR4 expression was identified as a prognostic factor for OS and CSS (p = 0.042; p = 0.019). Multivariate analysis including clinicopathological parameters did not reveal an independent prognostic character of CXCR4 expression. CXCR4 expression differs significantly within benign lesions and renal neoplasms. Cytoplasmic and nuclear expression of CXCR4 could be detected across all RCC subtypes. The prognostic value of CXCR4 in ccRCC was confirmed in univariate analysis. Full article

(This article belongs to the Special Issue Molecular Insights in Kidney Cancer)

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