Integration of Lipidomics and Transcriptomics Reveals Reprogramming of the Lipid Metabolism and Composition in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase (SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

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The Significance of INHBE Expression in the Cancer Cells of Clear-Cell Renal Cell Carcinoma

Urologia Internationalis ◽

10.1159/000518161 ◽

2021 ◽

pp. 1-11

Author(s):

Zi-Bin Xu ◽

Mei-Fu Gan ◽

Hong-Yuan Yu ◽

Li-Cai Mo ◽

Yu-Hui Xia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cell ◽

Tumor Tissue ◽

Transforming Growth Factor ◽

Clear Cell ◽

Tumor Promoter ◽

Sequencing Data ◽

Cell Renal Cell Carcinoma

Background: Activins and inhibins are structurally related dimeric glycoprotein hormones belonging to the transforming growth factor-β superfamily but whether they are also involved in malignancy is far from clear. No study has reported the expression of INHBE in kidney cancer. The purpose of this study was to examine the expressions of INHBE in the tumor tissue of patients with clear-cell renal cell carcinoma (ccRCC) and to explore the pathologic significance. Methods: The INHBE mRNA expression in the tumor tissue of ccRCC patients was analyzed by using RNA sequencing data from the TCGA database. To examine the expression of inhibin βE protein, 241 ccRCC patients were recruited and immunohistochemistry was performed on the tumor tissue of these patients along with 39 normal renal samples. The association between the inhibin βE expression level and patient’s clinicopathological indices was evaluated. Results: In the normal renal tissue, inhibin βE was found to be expressed mainly by renal tubular epithelial cells. In the tumor tissue, inhibin βE was expressed mainly in cancer cells. The expressions of INHBE mRNA and protein in the tumor tissue of ccRCC patients increased significantly compared with those in normal renal samples. There was a significant correlation between the level of inhibin βE in the tumor tissue and tumor grade. Patients with a lower inhibin βE expression in the tumor tissue were found to have a longer overall survival and disease-specific survival. Conclusions: INHBE might be involved in the pathogenesis of ccRCC and function as a tumor promoter.

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Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma

Translational Oncology ◽

10.1016/j.tranon.2019.10.015 ◽

2020 ◽

Vol 13 (2) ◽

pp. 177-185 ◽

Cited By ~ 6

Author(s):

Johannes C. van der Mijn ◽

Leiping Fu ◽

Francesca Khani ◽

Tuo Zhang ◽

Ana M. Molina ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Lipid Metabolism ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Early Stage ◽

Cell Renal Cell Carcinoma ◽

Genome Wide ◽

Induced Changes

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Single-cell genetic analysis validates cytopathological identification of circulating cancer cells in patients with clear cell renal cell carcinoma

Oncotarget ◽

10.18632/oncotarget.25102 ◽

2018 ◽

Vol 9 (28) ◽

pp. 20058-20074 ◽

Cited By ~ 8

Author(s):

Lucile Broncy ◽

Basma Ben Njima ◽

Arnaud Méjean ◽

Christophe Béroud ◽

Khaled Ben Romdhane ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Genetic Analysis ◽

Cell Carcinoma ◽

Single Cell ◽

Cancer Cells ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Circulating Cancer Cells

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CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p

Molecular Cancer ◽

10.1186/s12943-019-0997-z ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 27

Author(s):

Lu Wang ◽

Guang Yang ◽

Danfeng Zhao ◽

Jiaqi Wang ◽

Yang Bai ◽

...

Keyword(s):

Stem Cells ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Lung Metastasis ◽

Renal Cell ◽

Clear Cell ◽

Epithelial Mesenchymal Transition ◽

Cell Renal Cell Carcinoma ◽

Mesenchymal Transition

Abstract Background Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells. Methods The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined. Results CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis. Conclusions CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. Graphical abstract ᅟ

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The Uniqueness of Clear Cell Renal Cell Carcinoma: Summary of the Process and Abnormality of Glucose Metabolism and Lipid Metabolism in ccRCC

Frontiers in Oncology ◽

10.3389/fonc.2021.727778 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaochen Qi ◽

Quanlin Li ◽

Xiangyu Che ◽

Qifei Wang ◽

Guangzhen Wu

Keyword(s):

Renal Cell Carcinoma ◽

Lipid Metabolism ◽

Glucose Metabolism ◽

Cell Carcinoma ◽

Kidney Cancer ◽

Renal Cell ◽

Cancer Metabolism ◽

Clear Cell ◽

Future Research ◽

Cell Renal Cell Carcinoma

Kidney cancer is a cancer with an increasing incidence in recent years. Clear cell renal cell carcinoma (ccRCC) accounts for up to 80% of all kidney cancers. The understanding of the pathogenesis, tumor progression, and metastasis of renal carcinoma is not yet perfect. Kidney cancer has some characteristics that distinguish it from other cancers, and the metabolic aspect is the most obvious. The specificity of glucose and lipid metabolism in kidney cancer cells has also led to its being studied as a metabolic disease. As the most common type of kidney cancer, ccRCC has many characteristics that represent the specificity of kidney cancer. There are features that we are very concerned about, including the presence of lipid droplets in cells and the obesity paradox. These two points are closely related to glucose metabolism and lipid metabolism. Therefore, we hope to explore whether metabolic changes affect the occurrence and development of kidney cancer by looking for evidence of changes on expression at the genomic and protein levels in glucose metabolism and lipid metabolism in ccRCC. We begin with the representative phenomenon of abnormal cancer metabolism: the Warburg effect, through the collection of popular metabolic pathways and related genes in the last decade, as well as some research hotspots, including the role of ferroptosis and glutamine in cancer, systematically elaborated the factors affecting the incidence and metastasis of kidney cancer. This review also identifies the similarities and differences between kidney cancer and other cancers in order to lay a theoretical foundation and provide a valid hypothesis for future research.

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Metabolic features of clear-cell renal cell carcinoma: mechanisms and clinical implications

Canadian Urological Association Journal ◽

10.5489/cuaj.665 ◽

2013 ◽

Vol 5 (4) ◽

pp. 274

Author(s):

Jehonathan H. Pinthus H. Pinthus ◽

Kaitlyn F. Whelan ◽

Daniel Gallino ◽

Jian-Ping Lu ◽

Nathan Rothschild

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cell ◽

Clear Cell ◽

Response To Therapy ◽

Clinical Implications ◽

Cell Renal Cell Carcinoma ◽

Normal Cells ◽

Dietary Nutrients

Central to the malignant behaviour that endows cancer cells withgrowth advantage is their unique metabolism. Cancer cells canprocess nutrient molecules differently from normal cells and useit to overcome stress imposed on them by various therapies. Thismetabolic conversion is controlled by specific genetic mutationsthat are associated with activation of oncogenes and loss of tumoursuppressor proteins. Understanding these processes is importantas it can lead to the discovery of biomarkers that can predict theaggressiveness of the disease and its response to therapy, and evenmore importantly, to the development of novel therapeutics. A classictumour in this respect is clear-cell renal cell carcinoma (RCC). Inthis review, we will begin with a brief summary of normal cellularbioenergetic pathways, which will be followed by a descriptionof the characteristic metabolism of glucose and lipids in clear-cellRCC cells and its clinical implications. Data relating to the potentialeffect of dietary nutrients on RCC will also be reviewed alongwith potential therapies targeted at interrupting specific metabolicpathways in clear-cell RCC.Le métabolisme unique des cellules cancéreuses est au coeur ducomportement malin qui leur confère un avantage sur le plan de lacroissance. Les cellules cancéreuses peuvent traiter les moléculesde nutriment différemment des cellules normales et utilisent cesmolécules pour surmonter le stress imposé par les différents traitements.La conversion métabolique est contrôlée par des mutationsgénétiques précises associées à l’activation d’oncogènes et à laperte de protéines de suppression tumorale. Il est important debien saisir ces processus, car leur élucidation peut mener à ladécouverte de biomarqueurs permettant de prédire l’agressivité dela maladie et la réponse au traitement et, fait encore plus important,elle peut mener à la mise au point de nouveaux médicaments. À cetégard, l’hypernéphrome à cellules claires représente une tumeurclassique. Dans cet article, nous commençons par résumer brièvementles voies bioénergétiques cellulaires normales, puis nouspoursuivons avec une description du métabolisme caractéristiquedu glucose et des lipides dans les cellules de l’hypernéphrome àcellules claires et ses répercussions cliniques. Les données associéesà l’effet potentiel des nutriments sur l’hypernéphrome à cellulesclaires seront aussi passées en revue, ainsi que les thérapiesciblées potentielles visant l’interruption de voies métaboliquesparticulières dans l’hypernéphrome à cellules claires.

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Potential Links Between YB-1 and Fatty Acid Synthesis in Clear Cell Renal Carcinoma

Medical Research Archives ◽

10.18103/mra.v8i10.2273 ◽

2020 ◽

Vol 8 (10) ◽

Author(s):

Carter MCauley ◽

Vasthy Anang ◽

Breanna Cole ◽

Glenn Simmons

Keyword(s):

Fatty Acids ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Patient Outcomes ◽

Renal Cell ◽

Cancer Biology ◽

Renal Carcinoma ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Novel Approaches

According to the National Institutes of Health, clear cell renal cell carcinoma (ccRCC) is the most common type of Renal Cell Carcinoma (RCC), making up approximately 75% of total renal carcinoma cases. Clear cell Renal Cell Carcinoma is characterized by a significant accumulation of lipids in the cytoplasm, which allows light from microscopes to pass through giving them a “clear” phenotype. Many of these lipids are in the form of fatty acids, both free and incorporated into lipid droplets. RCC is typically associated with a poor prognosis due to the lack of specific symptoms. Some symptoms include blood in urine, fever, lump on the side, weight loss, fatigue, to name a few; all of which can be associated with non-specific, non-cancerous, health conditions that contribute to difficult diagnosis. Treatment of RCC has typically been centered around radical nephrectomy as the standard of care, but due to the potentially small size of lesions and the possibility of causing surgically induced chronic kidney disease, treatments have shifted to more cautious, less invasive approaches. These approaches include active surveillance, nephron-sparing surgery, and other minimally invasive techniques like cryotherapy and renal ablation. Although these techniques have had the desired effect of reducing the number of surgeries, there is still considerable potential for renal impairment and the chance that tumors can grow out of control without surgery. With the difficulty that surrounds the treatment of ccRCC and its considerably high mortality rate amongst urological cancers, it is important to look for novel approaches to improve patient outcomes. This review looks at available literature and our data that suggests the lipogenic enzyme stearoyl-CoA desaturase may be more beneficial to patient survival than once thought. As our understanding of the importance of lipids in cell metabolism and longevity matures, it is important to present new perspectives that present a new understanding of ccRCC and the role of lipids in survival mechanisms engaged by transformed cells during cancer progression. In this review, we provide evidence that pharmacological inhibition of lipid desaturation in renal cancer patients is not without risk, and that the presence of unsaturated fatty acids may be a beneficial factor in patient outcomes. Although more direct experimental evidence is needed to make definitive conclusions, it is clear that the work reviewed herein should challenge our current understanding of cancer biology and may inform novel approaches to the diagnosis and treatment of ccRCC.

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Prognostic significance of two lipid metabolism enzymes, HADHA and ACAT2, in clear cell renal cell carcinoma

Tumor Biology ◽

10.1007/s13277-015-4720-4 ◽

2015 ◽

Vol 37 (6) ◽

pp. 8121-8130 ◽

Cited By ~ 15

Author(s):

Zuohui Zhao ◽

Jiaju Lu ◽

Liping Han ◽

Xiaoqing Wang ◽

Quanzhan Man ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Lipid Metabolism ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Prognostic Significance ◽

Cell Renal Cell Carcinoma ◽

Metabolism Enzymes

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GATA3 suppresses human fibroblasts-induced metastasis of clear cell renal cell carcinoma via an anti-IL6/STAT3 mechanism

Cancer Gene Therapy ◽

10.1038/s41417-019-0146-2 ◽

2019 ◽

Vol 27 (9) ◽

pp. 726-738 ◽

Cited By ~ 2

Author(s):

Qianqian Shi ◽

Renfang Xu ◽

Guanglai Song ◽

Hao Lu ◽

Dong Xue ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Conditioned Medium ◽

Renal Cancer ◽

Renal Cell ◽

Clear Cell ◽

Normal Fibroblast ◽

Cell Renal Cell Carcinoma ◽

Renal Cancer Cell

AbstractTumorigenesis and metastasis depend on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. It is, however, unclear regarding the molecular mechanisms underlying the progress and metastasis of human clear-cell renal cell carcinoma in the microenvironment with fibroblasts. In this work, we investigated the effect of normal fibroblasts on the metastasis of renal cancer and the relevant signaling pathways. We isolated normal fibroblasts from normal renal tissues and used normal fibroblast-conditioned medium culture renal cancer cells. The CCK-8 and transwell assays showed that normal fibroblasts conditioned medium significantly enhanced ccRCC cell migration. IL6 mediated the cross talk between normal fibroblasts and the cancer cells, and promoted tumor cell migration through the STAT3 pathway. In contrast, GATA3 was downregulated at both mRNA and protein levels in the normal fibroblast-conditioned medium treated with renal cancer cells, but upregulated in adjacent normal tissues. GATA3 overexpression significantly reduced STAT3 phosphorylation and attenuated the migration in both renal cancer cell and IL6-stimulated renal cancer cell. Taken together, our findings suggest that the IL6/STAT3 pathway plays a crucial role in the normal fibroblast-enhanced clear-cell renal cell carcinoma metastasis, while GATA3 may mitigate this effect by inhibiting IL6/STAT3 signaling.

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