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.

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Role of Wnt Signaling Pathways in Clear Cell Renal Cell Carcinoma Pathogenesis in Relation to VHL and HIF Status

Clinical Oncology and Research ◽

10.31487/j.cor.2020.03.09 ◽

2020 ◽

pp. 1-7

Author(s):

Raviprakash T. Sitaram ◽

Börje Ljungberg ◽

Göran Roos ◽

Marene Landström ◽

Raviprakash T. Sitaram

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Genetic Changes ◽

Genetic Abnormalities ◽

Tumor Types

Renal cell carcinoma (RCC) encompasses various tumor types characterized by a variety of genetic abnormalities. The genetic changes, like mutations, deletions, and epigenetic alterations, can affect the signaling components and signaling networks, causing the modification of tumor pathogenesis and prognosis of RCC. The most prevalent RCC, clear cell RCC (ccRCC), is asymptomatic in the early stages, refractory to chemotherapy and radiation therapy, and has a poorer prognosis compared with the papillary and chromophobe ccRCC types. Loss of the VHL gene and upregulation of oxygen sensors, hypoxiainducible factor alphas (HIF-α), which promote different growth factors, is a signature of sporadic ccRCC. The VHL-HIF-α and Wnt/β-catenin pathways are closely connected and contribute to the ontogeny of ccRCC. This review confines to ccRCC and the role of the Wnt/β-catenin signaling pathways and its crosstalk with VHL/HIF.

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Signaling pathway-based stratification of clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.434 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 434-434

Author(s):

Italia Bongarzone ◽

Mattia Cremona ◽

Virginia A. Espina ◽

Francesca Miccichè ◽

Silvia Veneroni ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Transcription Factors ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Renal Cell ◽

Clear Cell ◽

Loss Of Function ◽

Cell Renal Cell Carcinoma ◽

Group A ◽

Group B

434 Background: There are marked differences in responses to therapy among patients with clear cell renal cell carcinoma (ccRCC), which makes the outcome difficult to predict. This study is aimed to define a new classification system that would elucidate distinctions between carcinomas in order to facilitate selection of the appropriate treatment. We mapped cell signaling pathways in individual renal cell carcinomas and identified different classes based on commonly shared phosphorylation-driven signaling networks. Methods: Laser capture microdissection and reverse-phase protein arrays were used to profile 75 key nodes in 16 primary clear cell renal cancers. These nodes represent many signaling pathways known to be important in tumorigenesis and progression. Results: Statistical analysis revealed significant differences (p <0.05) in signaling levels between two groups of samples, group A (4 samples) and group B (12 samples), for 27 of the 75 endpoints tested. In group A, high activation levels of EGFR, RET, and RASGFR1 converged to activate AKT/mTOR. Group B, showed high phosphorylation levels of ERK1/2 and STAT transcription factors and samples significantly partitioned in two clusters of 7 and 5 cases designated C and D. Group C showed elevated expression of a regulator of autophagy, LC3B; group D showed activation of Src and STAT transcription factors, suggesting the presence of cytokine-mediated cell survival pathways. A DNA copy number analysis was performed on the same samples and the results showed that group B represents some paradigmatic cases of ccRCC, with VHL loss-of-function mutations. Conclusions: The proteins identified appeared to be linked to pathways that are targeted by drugs typically used to treat clear cell renal cell carcinoma. Thus, this type of analysis could be useful for stratifying patients and selecting the best therapeutic approaches.

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Comparison of stem cell signaling pathways in long-term responders (LR) versus primary refractory (PR) patients with metastatic clear-cell renal cell carcinoma (ccRCC) under sunitinib (SU) treatment (SULONG study).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.4578 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 4578-4578

Author(s):

Javier Puente ◽

Nuria Laínez ◽

María José Méndez-Vidal ◽

Emilio Esteban ◽

Daniel E. Castellano ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Stem Cell ◽

Cell Signaling ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Cell Signaling Pathways

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The Notch and TGF-β Signaling Pathways Contribute to the Aggressiveness of Clear Cell Renal Cell Carcinoma

PLoS ONE ◽

10.1371/journal.pone.0023057 ◽

2011 ◽

Vol 6 (8) ◽

pp. e23057 ◽

Cited By ~ 45

Author(s):

Jonas Sjölund ◽

Anna-Karin Boström ◽

David Lindgren ◽

Sugata Manna ◽

Aristidis Moustakas ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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Validation of CT radiomics for prediction of distant metastasis after surgical resection in patients with clear cell renal cell carcinoma: exploring the underlying signaling pathways

European Radiology ◽

10.1007/s00330-020-07590-2 ◽

2021 ◽

Author(s):

Yuanshen Zhao ◽

Guiqin Liu ◽

Qiuchang Sun ◽

Guangtao Zhai ◽

Guangyu Wu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Surgical Resection ◽

Distant Metastasis ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma

Cancers ◽

10.3390/cancers13071554 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1554

Author(s):

Lisa Kinget ◽

Eduard Roussel ◽

Diether Lambrechts ◽

Bram Boeckx ◽

Loïc Vanginderhuysen ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Bone Metastasis ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Protein Coding ◽

Rna Molecules ◽

Regulatory Functions ◽

Substantial Morbidity

Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC.

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Integrative analysis of protein-coding and non-coding RNAs identifies clinically relevant subtypes of clear cell renal cell carcinoma

Oncotarget ◽

10.18632/oncotarget.12340 ◽

2016 ◽

Vol 7 (50) ◽

pp. 82671-82685 ◽

Cited By ~ 7

Author(s):

Zongcheng Li ◽

Yaowen Chen ◽

Shuofeng Hu ◽

Jian Zhang ◽

Jiaqi Wu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Integrative Analysis ◽

Cell Renal Cell Carcinoma ◽

Protein Coding ◽

Non Coding Rnas

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AURKB: a promising biomarker in clear cell renal cell carcinoma

PeerJ ◽

10.7717/peerj.7718 ◽

2019 ◽

Vol 7 ◽

pp. e7718 ◽

Cited By ~ 4

Author(s):

Bangbei Wan ◽

Yuan Huang ◽

Bo Liu ◽

Likui Lu ◽

Cai Lv

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Renal Cell ◽

Clear Cell ◽

Cytokine Receptor ◽

Receptor Interaction ◽

Immune Network ◽

Cell Renal Cell Carcinoma ◽

Iga Production

BackgroundAurora kinase B (AURKB) is an important carcinogenic factor in various tumors, while its role in clear cell renal cell carcinoma (ccRCC) still remains unclear. This study aimed to investigate its prognostic value and mechanism of action in ccRCC.MethodsGene expression profiles and clinical data of ccRCC patients were downloaded from The Cancer Genome Atlas database. R software was utilized to analyze the expression and prognostic role ofAURKBin ccRCC. Gene set enrichment analysis (GSEA) was used to analyzeAURKBrelated signaling pathways in ccRCC.ResultsAURKBwas expressed at higher levels in ccRCC tissues than normal kidney tissues. IncreasedAURKBexpression in ccRCC correlated with high histological grade, pathological stage, T stage, N stage and distant metastasis (M stage). Kaplan-Meier survival analysis suggested that highAURKBexpression patients had a worse prognosis than patients with lowAURKBexpression levels. Multivariate Cox analysis showed thatAURKBexpression is a prognostic factor of ccRCC. GSEA indicated that genes involved in autoimmune thyroid disease, intestinal immune network for IgA production, antigen processing and presentation, cytokine-cytokine receptor interaction, asthma, etc., were differentially enriched in theAURKBhigh expression phenotype.ConclusionsAURKBis a promising biomarker for predicting prognosis of ccRCC patients and a potential therapeutic target. In addition,AURKBmight regulate progression of ccRCC through modulating intestinal immune network for IgA production and cytokine-cytokine receptor interaction, etc. signaling pathways. However, more research is necessary to validate the findings.

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