scholarly journals Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

2020 ◽  
Vol 21 (14) ◽  
pp. 5042
Author(s):  
Seon-Hyeong Lee ◽  
Joon Hee Kang ◽  
Ji Sun Ha ◽  
Jae-Seon Lee ◽  
Su-Jin Oh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Renal Cell ◽  
Nuclear Translocation ◽  
Xenograft Model ◽  
Transglutaminase 2 ◽  
P300 Binding

Angiogenesis and the expression of vascular endothelial growth factor (VEGF) are increased in renal cell carcinoma (RCC). Transglutaminase 2 (TGase 2), which promotes angiogenesis in endothelial cells during wound healing, is upregulated in RCC. Tumor angiogenesis involves three domains: cancer cells, the extracellular matrix, and endothelial cells. TGase 2 stabilizes VEGF in the extracellular matrix and promotes VEGFR-2 nuclear translocation in endothelial cells. However, the role of TGase 2 in angiogenesis in the cancer cell domain remains unclear. Hypoxia-inducible factor (HIF)-1α-mediated VEGF production underlies the induction of angiogenesis in cancer cells. In this study, we show that p53 downregulated HIF-1α in RCC, and p53 overexpression decreased VEGF production. Increased TGase 2 promoted angiogenesis by inducing p53 degradation, leading to the activation of HIF-1α. The interaction of HIF-1α and p53 with the cofactor p300 is required for stable transcriptional activation. We found that TGase 2-mediated p53 depletion increased the availability of p300 for HIF-1α-p300 binding. A preclinical xenograft model suggested that TGase 2 inhibition can reverse angiogenesis in RCC.

scholarly journals The anti-angiogenic tyrosine kinase inhibitor Pazopanib kills cancer cells and disrupts endothelial networks in biomimetic three-dimensional renal tumouroids

2020 ◽  
Vol 11 ◽  
pp. 204173142092059
Author(s):  
Katerina Stamati ◽  
Patricia A Redondo ◽  
Agata Nyga ◽  
Joana B Neves ◽  
Maxine GB Tran ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Endothelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Three Dimensional ◽  
Carcinoma Cells

Pazopanib is a tyrosine kinase inhibitor used to treat renal cell carcinoma. Few in vitro studies investigate its effects towards cancer cells or endothelial cells in the presence of cancer. We tested the effect of Pazopanib on renal cell carcinoma cells (CAKI-2,786-O) in two-dimensional and three-dimensional tumouroids made of dense extracellular matrix, treated in normoxia and hypoxia. Finally, we engineered complex tumouroids with a stromal compartment containing fibroblasts and endothelial cells. Simple CAKI-2 tumouroids were more resistant to Pazopanib than 786-O tumouroids. Under hypoxia, while the more ‘resistant’ CAKI-2 tumouroids showed no decrease in viability, 786-O tumouroids required higher Pazopanib concentrations to induce cell death. In complex tumouroids, Pazopanib exposure led to a reduction in the overall cell viability (p < 0.0001), disruption of endothelial networks and direct killing of renal cell carcinoma cells. We report a biomimetic multicellular tumouroid for drug testing, suitable for agents whose primary target is not confined to cancer cells.

scholarly journals ACE2 in tumor cells and tumor vasculature: Negligible intercellular transfer from cancer cells into endothelial cells

2021 ◽  
Vol 2 ◽  
pp. 3
Author(s):  
Zhi-Jie Liu ◽  
Yan Mei ◽  
Jiang-Li Lu ◽  
Jia-Bin Lu ◽  
Yun Cao ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Endothelial Cells ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Gastric Adenocarcinoma ◽  
Renal Cell ◽  
Colorectal Adenocarcinoma ◽  
Tumor Vasculature ◽  
Intercellular Transfer

Cancer patients are more susceptible to severe coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Angiotensin-converting enzyme 2 (ACE2) is the functional host receptor for SARS-CoV-2 entering into human cells. Bioinformatics’ analyses have revealed that ACE2 is upregulated in some cancer cells. In the present study, we evaluated ACE2 protein expression levels in several common malignancies compared to non-cancerous normal tissues. ACE2 expression was elevated in colorectal adenocarcinoma, pancreatic adenocarcinoma, gastric adenocarcinoma, and papillary renal cell carcinoma cancer. Yet, it was suppressed in chromophobe renal cell carcinoma, testicular germ cell tumors, and papillary thyroid carcinoma. Two tumor tissue microarrays were used to evaluate the prognostic value of ACE2 expression in patients with gastric adenocarcinoma, and colorectal adenocarcinoma without COVID-19. No significant survival benefit was found for patients with overexpression of ACE2 in the tumor. In the tumor vasculature, ACE2 expression was observed in only 54% of the tumor micro-vessels. Using an in vitro co-culture of endothelial cells and tumor cells overexpressing fusion protein ACE2-red fluorescent protein, we did not observe any clear and convincing intercellular transfer of ACE2 from cancer cells into endothelial cells. In summary, alteration of ACE2 expression was found in common malignancies, but there is no evidence of intercellular transfer of ACE2 from cancer cells to endothelial cells.

Effect of host immunity on metastatic potential in renal cell carcinoma: the assessment of optimal in vivo models to study metastatic behavior of renal cancer cells

Tumor Biology ◽  
2012 ◽  
Vol 33 (2) ◽  
pp. 551-559 ◽  
Author(s):  
Minoru Kobayashi ◽  
Tatsuo Morita ◽  
Nicole A. L. Chun ◽  
Aya Matsui ◽  
Masafumi Takahashi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Renal Cell ◽  
Metastatic Potential ◽  
Host Immunity ◽  
In Vivo Models ◽  
Metastatic Behavior

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

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

<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusions:</i></b> INHBE might be involved in the pathogenesis of ccRCC and function as a tumor promoter.

scholarly journals Combining differential expression, chromosomal and pathway analyses for the molecular characterization of renal cell carcinoma

2012 ◽  
Vol 1 (2S) ◽  
Author(s):  
Kyle A. Furge ◽  
Karl Dykema ◽  
David Petillo ◽  
Michael Westphal ◽  
Zhongfa Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Gene Expression Profiling ◽  
Cancer Cells ◽  
Expression Profiling ◽  
Renal Cell ◽  
Molecular Signatures ◽  
Genetic Makeup ◽  
Papillary Rcc

Using high-throughput gene-expression profiling technology, we can now gaina better understanding of the complex biology that is taking place in cancer cells. This complexity is largely dictated by the abnormal genetic makeup ofthe cancer cells. This abnormal genetic makeup can have profound effectson cellular activities such as cell growth, cell survival and other regulatory processes. Based on the pattern of gene expression, or molecular signatures of the tumours, we can distinguish or subclassify different types of cancers according to their cell of origin, behaviour, and the way they respond to therapeuticagents and radiation. These approaches will lead to better molecularsubclassification of tumours, the basis of personalized medicine. We have, todate, done whole-genome microarray gene-expression profiling on several hundredsof kidney tumours. We adopt a combined bioinformatic approach, based on an integrative analysis of the gene-expression data. These data are used toidentify both cytogenetic abnormalities and molecular pathways that are deregulatedin renal cell carcinoma (RCC). For example, we have identified the deregulationof the VHL-hypoxia pathway in clear-cell RCC, as previously known,and the c-Myc pathway in aggressive papillary RCC. Besides the more commonclear-cell, papillary and chromophobe RCCs, we are currently characterizingthe molecular signatures of rarer forms of renal neoplasia such ascarcinoma of the collecting ducts, mixed epithelial and stromal tumours, chromosomeXp11 translocations associated with papillary RCC, renal medullarycarcinoma, mucinous tubular and spindle-cell carcinoma, and a group of unclassified tumours. Continued development and improvement in the field of molecular profiling will better characterize cancer and provide more accurate diagnosis, prognosis and prediction of drug response.

scholarly journals Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1469 ◽  
Author(s):  
Chung-Sheng Shi ◽  
Kuan-Lin Kuo ◽  
Mei-Sin Chen ◽  
Po-Ming Chow ◽  
Shing-Hwa Liu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Endothelial Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Antitumor Effects ◽  
Angiogenic Activity ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells

Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. In this study, we investigated the role and therapeutic potential of CDK7 in regulating the angiogenic activity of endothelial cells and human renal cell carcinoma (RCC). Our results revealed that vascular endothelial growth factor (VEGF), a critical activator of angiogenesis, upregulated the expression of CDK7 and RNAPII, and the phosphorylation of RNAPII at serine 5 and 7 in human umbilical vein endothelial cells (HUVECs), indicating the transcriptional activity of CDK7 may be involved in VEGF-activated angiogenic activity of endothelium. Furthermore, through suppressing CDK7 activity, THZ1 suppressed VEGF-activated proliferation and migration, as well as enhanced apoptosis of HUVECs. Moreover, THZ1 inhibited VEGF-activated capillary tube formation and CDK7 knockdown consistently diminished tube formation in HUVECs. Additionally, THZ1 reduced VEGF expression in human RCC cells (786-O and Caki-2), and THZ1 treatment inhibited tumor growth, vascularity, and angiogenic marker (CD31) expression in RCC xenografts. Our results demonstrated that CDK7-mediated transcription was involved in the angiogenic activity of endothelium and human RCC. THZ1 suppressed VEGF-mediated VEGFR2 downstream activation of angiogenesis, providing a new perspective for antitumor therapy in RCC patients.

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

Metabolites ◽  
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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