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

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

Metabolites ◽

10.3390/metabo10120509 ◽

2020 ◽

Vol 10 (12) ◽

pp. 509

Author(s):

Giuseppe Lucarelli ◽

Matteo Ferro ◽

Davide Loizzo ◽

Cristina Bianchi ◽

Daniela Terracciano ◽

...

Keyword(s):

Fatty Acids ◽

Renal Cell Carcinoma ◽

Lipid Metabolism ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cell ◽

Clear Cell ◽

Chemotherapy Resistance ◽

Neoplastic Tissue ◽

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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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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Robustness of the 16-gene signature for prediction of recurrence-free interval in localized clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.455 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 455-455

Author(s):

Bernard J. Escudier ◽

Serge Koscielny ◽

Tara Maddala ◽

Christer Svedman ◽

Virginie Verkarre ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cancer ◽

Renal Cell ◽

Clear Cell ◽

Gene Signature ◽

Stage I ◽

Rt Pcr ◽

Cell Renal Cell Carcinoma ◽

Risk Of Recurrence

455 Background: The Renal Cancer assay is a clinically validated RT-PCR assay developed to estimate the risk of recurrence in stage I-III clear cell renal cell carcinoma (ccRCC) patients (pts) treated with nephrectomy. The assay measures expression of 16 genes that are combined to calculate the Recurrence Score result (RS). The RS is associated with recurrence, renal cancer-specific survival and overall survival (all p<0.001) (Escudier, ASCO 2014). The performance of the RS in clinically relevant subgroups, compared to the Leibovich score, and its within-patient variability was examined. Methods: The algorithm, endpoints, methods, and analysis plan were pre-specified prior to merging clinical and molecular data. RT-PCR of RNA from fixed paraffin-embedded ccRCC tissue was performed without knowledge of clinical data. Recurrence-free internval (RFI) was analyzed using Cox regression stratified by stage with data censored at 5 years, and Kaplan-Meier methods. Multivariable models incorporating the Leibovich score were used to assess the additional contribution of the RS to prediction of recurrence. Within- and between-tumor block reproducibility was assessed in an independent study using two separate tumor blocks from 8 pts, where each block was analyzed at 3 depths. Results: RS was generated in 626/645 pts (97%): 398 stage I, 54 stage II, 174 stage III. Median follow up was 5.5 yrs. The RS was significantly associated with risk of recurrence after adjustment for the Leibovich score (HR=4.20, p<0.001). Additionally, the performance of RS was similar across age groups (<60, 60-70 or ≥70), gender, nephrectomy type, tumor size (≤4, 4-7 or >7cm), grade, and presence/absence of invasion (all interaction p>0.29). Within-patient variability in the score (std. dev. of 1.73 and 4.74 RS units for within- and between-tumor block, respectively) was lower than patient-to-patient variability (std. dev. of 15.6 in validation study). Conclusions: The 16-gene signature remains strongly associated with risk of recurrence after adjustment for the Leibovich score and performs consistently across clinically relevant subgroups. Examination of within-patient and between-patient variability indicates that the score is robust to tumor heterogeneity.

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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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Porcupine Inhibitor LGK974 Downregulates the Wnt Signaling Pathway and Inhibits Clear Cell Renal Cell Carcinoma

BioMed Research International ◽

10.1155/2020/2527643 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Jianyi Li ◽

Guangzhen Wu ◽

Yingkun Xu ◽

Jiatong Li ◽

Ningke Ruan ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Wnt Signaling ◽

Cell Carcinoma ◽

Signaling Pathway ◽

Renal Cancer ◽

Renal Cell ◽

Clear Cell ◽

Wnt Signaling Pathway ◽

Cell Renal Cell Carcinoma ◽

Wnt Proteins

Targeted therapy for kidney cancer has achieved significant clinical results. However, because most patients who use targeted therapy will develop drug resistance, we still need to constantly explore new therapeutic targets. Although porcupine (PORCN) as a palmitoyltransferase plays a crucial role in the activation and secretion of Wnt proteins and affects the activity of the Wnt signaling pathway, little is known about the role of PORCN in clear cell renal cell carcinoma (ccRCC). We found that PORCN is highly expressed in renal cancer cell lines and patients with renal cell carcinoma with high expression of PORCN have a poor prognosis. Pathway analysis of PORCN and its related proteins showed that PORCN played a role through the Wnt signaling pathway, and there was a strong coexpression relationship between PORCN and Wnt proteins. Therefore, PORCN may be a potential and effective target for ccRCC. In the present study, we found that LGK974 could inhibit proliferation and colony formation and induce apoptosis in ccRCC cells. We also found that LGK974 could inhibit the migration and invasion of renal cell carcinoma and reduce the expression of mesenchymal markers. After treatment with LGK974, the expression level of β-catenin, a key protein in the classical Wnt pathway, was significantly decreased, and the expression levels of the target genes cyclin D1, c-Myc, MMP9, and MMP2 in the Wnt signaling pathway were also significantly decreased, which represented a significant decrease in the activity of the Wnt signaling pathway. At the same time, the cycle of renal cancer cells was significantly blocked. In conclusion, our results indicate that LGK974 could significantly inhibit the progression of renal cancer cells in a safe concentration range, so PORCN may be a safe and effective target for patients with renal cancer.

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mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

10.1101/2020.01.13.905521 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xuyang Zhao ◽

Yadong Ma ◽

Jie Cui ◽

Haiyang Zhao ◽

Lei Liu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Molecular Mechanism ◽

Renal Cancer ◽

Cancer Progression ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Invasion And Migration ◽

And Migration

AbstractClear cell renal cell carcinoma (ccRCC), as the most important type of renal carcinoma, has a high incidence and easy metastasis. Folliculin (FLCN) was identified as a tumor suppressor gene. Its deletions and mutations are associated with a potential risk of kidney cancer. At present, the specific molecular mechanism of FLCN-induced proliferation, invasion and migration in clear cell renal cell carcinoma remains elusive.In this study, we demonstrated that FLCN controled cell proliferation, invasion and migration through PI3K/mTORC2 pathway. FLCN combined with HIF2α in various normal and cancerous renal cells, and mTORC2 mediate FLCN effectively alleviated the deterioration of renal cancer cells by degrading HIF2α. Silencing of FLCN showed promotion of HIF2α protein expression, which in turn led to an increase in downstream target genes Cyclin D1 and MMP9. Moreover, when interfering with siFLCN, HIF2α degradation rate was delayed, and the time of entry into the nucleus was advanced. Taken together, our study illustrated that mTORC2 promoted the specific molecular mechanism of HIF2α by down-regulated FLCN, and might be a new therapeutic target against renal cancer progression.

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CTR2 Identifies a Population of Cancer Cells with Stem Cell-like Features in Patients with Clear Cell Renal Cell Carcinoma

The Journal of Urology ◽

10.1016/j.juro.2014.06.070 ◽

2014 ◽

Vol 192 (6) ◽

pp. 1831-1841 ◽

Cited By ~ 26

Author(s):

Vanessa Galleggiante ◽

Monica Rutigliano ◽

Fabio Sallustio ◽

Domenico Ribatti ◽

Pasquale Ditonno ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Stem Cell ◽

Cell Carcinoma ◽

Cancer Cells ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma

AJP Renal Physiology ◽

10.1152/ajprenal.00148.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. F780-F788 ◽

Cited By ~ 35

Author(s):

Adolfo Varona ◽

Lorena Blanco ◽

José I. López ◽

Javier Gil ◽

Ekaitz Agirregoitia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cancer ◽

Renal Cell ◽

Clear Cell ◽

Aminopeptidase N ◽

Aminopeptidase Activity ◽

Peptidase Activity ◽

Cell Renal Cell Carcinoma ◽

Aspartyl Aminopeptidase

Peptides play important roles in cell regulation and signaling in many tissues and are regulated by peptidases, most of which are highly expressed in the kidney. Several peptide convertases have a function in different tumor stages, and some have been clearly characterized as diagnostic and prognostic markers for solid tumors, including renal cancer; however, little is known about their in vivo role in kidney tumors. The present study compares the activity of a range of peptidases in human tumor samples and nontumor tissue obtained from clear cell renal cell carcinoma (CCRCC) patients. To cover the complete spectrum and subcellular distribution of peptide-converting activity, acid, neutral, basic, and omega activities were selected. CCRCC displays a selective and restricted pattern of peptidase activities. Puromycin-sensitive aminopeptidase activity in the tumor increases [tumor (t) = 10,775 vs. nontumor (n) = 7,635 units of peptidase (UP)/mg protein; P < 0.05], whereas aminopeptidase N decreases (t = 6,664 vs. n = 33,381 UP/mg protein; P < 0.001). Aminopeptidase B activity of the particulate fraction in tumors decreases (t = 2,399 vs. n = 13,536 UP/mg protein; P < 0.001) compared with nontumor tissues, and aspartyl-aminopeptidase activity decreases significantly in CCRCC (t = 137 vs. n = 223 UP/mg protein; P < 0.05). Soluble and particulate pyroglutamyl peptidase I activities, aminopeptidase A activity, and soluble aminopeptidase B activity do not vary in renal cancer. The relative expression for the aforementioned peptidases, assayed using quantitative RT-PCR, increases in CCRCC for aminopeptidases B (1.5-fold) and A (19-fold), aspartyl-aminopeptidase (3.9-fold), puromycin-sensitive aminopeptidase (2.5-fold), and pyroglutamyl peptidase I (7.6-fold). Only aminopeptidase N expression decreases in tumors (1.3-fold). This peptidase activity profile in the neoplastic kidney suggests a specific role for the studied convertases and the possible involvement of an intracrine renin-angiotensin system in the pathogenesis of CCRCC.

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