Clear Cell Renal Carcinoma: MicroRNAs With Efficacy in Preclinical<i>In Vivo</i>Models

Weidle, Ulrich H.; Nopora, Adam

doi:10.21873/cgp.20265

Cited by 4 publications

(5 citation statements)

References 189 publications

(319 reference statements)

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“…Some transcription factors are accumulated due to VHL inactivation, which induces the expression of vascular endothelial growth factor (VEGF). Therefore, ccRCCs are often highly vascularized and respondent to anti-angiogenic therapy (3). Subsequent mutations commonly arise in BAP1/PBRM1/SET2/KDM5C, giving rise to DNA repair defects.…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic Role of miR-217 During Clear Cell Renal Carcinoma Progression

2022

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Clear cell renal carcinoma (ccRC) comprises a set of heterogeneous, fast-progressing pathologies with poor prognosis. Analyzing ccRC progression in terms of modifications at the molecular level may provide us with a broader understanding of the disease, paving the way for improved diagnostics and therapeutics. The role of micro-RNAs (miRs) in cancer by targeting both oncogenes and tumor suppressor genes is widely known. Despite this knowledge, the role of specific miRs and their targets in the progression of ccRC is still unknown. To evaluate the action of miRs and their target genes during ccRC progression, here we implemented a three-step method for constructing miR–gene co-expression networks for each progression stage of ccRC as well as for adjacent-normal renal tissue (NT). In the first step, we inferred all miR–gene co-expression interactions for each progression stage of ccRC and for NT. Afterwards, we filtered the whole miR–gene networks by differential gene and miR expression between successive stages: stage I with non-tumor, stage II with stage I, and so on. Finally, all miR–gene interactions whose relationships were inversely proportional (overexpressed miR and underexpressed genes and vice versa) were kept and removed otherwise. We found that miR-217 is differentially expressed in all contrasts; however, its targets were different depending on the ccRC stage. Furthermore, the target genes of miR-217 have a known role in cancer progression—for instance, in stage II network, GALNTL6 is overexpressed, and it is related to cell signaling, survival, and proliferation. In the stage III network, WNK2, a widely known tumor suppressor, is underexpressed. For the stage IV network, IGF2BP2, a post-transcriptional regulator of MYC and PTEN, is overexpressed. This data-driven network approach has allowed us to discover miRs that have different targets through ccRC progression, thus providing a method for searching possible stage-dependent therapeutic targets in this and other types of cancer.

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Section: Introductionmentioning

confidence: 99%

“…Alternatively, miRNAs can be associated to the development of tumor-suppressive and oncogenic functions, and their ability to modulate different genes may be also context dependent (3). Specifically, miR-gene regulation may repress or promote transcription (non-canonical) or translation (canonical) (15).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Role of miR-217 During Clear Cell Renal Carcinoma Progression

2022

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“…Additionally, recent research has identified targeting the ACE2/Ang-(1-7) axis is a promising therapeutic strategy [ 42 ]. Other studies have discovered new markers, like SPOP (targeted by miR-520,372/373) and CBP (targeted by miR-200a-3p), as a tractable target for the treatment of ccRCC [ 43 ]. ccRCC tumors harbor mutations in the VHL gene, resulting in the loss of oxygen-sensing ability, increasing the stability of hypoxia-inducible factors (HIFs), and thus inducing metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

Yang

Zhou

et al. 2022

Bioengineered

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas, with high mortality and poor prognoses worldwide. Succinate dehydrogenase (SDH) consists of four nuclear-encoded subunits and it is the only complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Previous studies have shown decreased SDH activity in ccRCC. However, the role and underlying molecular mechanisms of SDH in ccRCC initiation and development remain unclear. In the present study, pan-cancer analysis of SDH gene expression was analyzed and the relationship between SDH gene expression and clinicopathological parameters was assessed using different databases. cBioPortal, UACLAN, and Tumor Immune Estimation Resource (TIMER) were subsequently utilized to analyze genetic alterations, methylation, and immune cell infiltration of SDH genes in ccRCC patients. We found SDHs were significantly downregulated in ccRCC tissues and correlated with ccRCC progression. Increased methylation and high SDH promoter mutation rates may be the cause of reduced expression of SDHs in ccRCC. Moreover, the interaction network showed that SDH genes were correlated with ferroptosis-related genes. We further demonstrated that SDH inhibition dampened oxidative phosphorylation, reduced ferroptotic events, and restored ferroptotic cell death, characterized by eliminated mitochondrial ROS levels, decreased cellular ROS and diminished peroxide accumulation. Collectively, this study provides new insights into the regulatory role of SDH in the carcinogenesis and progression of ccRCC, introducing a potential target for advanced antitumor therapy through ferroptosis.

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“…One group of molecules that could be considered as clinical targets in ccRCC are microRNAs (miRNAs) ( 5 , 6 ). These non-coding small RNAs elicit tumor suppressive and oncogenic characteristics by targeting multiple expressed genes in order to alter multiple biological events including cellular proliferation, migration, invasion, epithelial-mesenchymal transition, and cell death events ( 5 , 6 ). Interestingly, in contrast to eukaryotic mRNAs, the clustering and unified transcription of miRNAs is common ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Deregulated expression of the 14q32 miRNA cluster in clear cell renal cancer cells

et al. 2023

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Clear cell renal cell carcinomas (ccRCC) are characterized by arm-wide chromosomal alterations. Loss at 14q is associated with disease aggressiveness in ccRCC, which responds poorly to chemotherapeutics. The 14q locus contains one of the largest miRNA clusters in the human genome; however, little is known about the contribution of these miRNAs to ccRCC pathogenesis. In this regard, we investigated the expression pattern of selected miRNAs at the 14q32 locus in TCGA kidney tumors and in ccRCC cell lines. We demonstrated that the miRNA cluster is downregulated in ccRCC (and cell lines) as well as in papillary kidney tumors relative to normal kidney tissues (and primary renal proximal tubule epithelial (RPTEC) cells). We demonstrated that agents modulating expression of DNMT1 (e.g., 5-Aza-deoxycytidine) could modulate 14q32 miRNA expression in ccRCC cell lines. Lysophosphatidic acid (LPA, a lysophospholipid mediator elevated in ccRCC) not only increased labile iron content but also modulated expression of a 14q32 miRNA. Through an overexpression approach targeting a subset of 14q32 miRNAs (specifically at subcluster A: miR-431-5p, miR-432-5p, miR-127-3p, and miR-433-3p) in 769-P cells, we uncovered changes in cellular viability and claudin-1, a tight junction marker. A global proteomic approach was implemented using these miRNA overexpressing cell lines which uncovered ATXN2 as a highly downregulated target. Collectively, these findings support a contribution of miRNAs at 14q32 in ccRCC pathogenesis.

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Clear Cell Renal Carcinoma: MicroRNAs With Efficacy in PreclinicalIn VivoModels

Cited by 4 publications

References 189 publications

Oncogenic Role of miR-217 During Clear Cell Renal Carcinoma Progression

Oncogenic Role of miR-217 During Clear Cell Renal Carcinoma Progression

Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

Deregulated expression of the 14q32 miRNA cluster in clear cell renal cancer cells

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