Dataset Information

High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma.

ABSTRACT:

Background

Although metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC.

Methodology/principal findings

The expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1. Compared to the corresponding controls, all cell lines demonstrated significant promotion in cell proliferation and migration while cell cycle remained unaffected.

Conclusions/significance

High-level expression of Notch signaling increased the risk of metastasis in T1 stage ccRCC by stimulating the proliferation and migration of tumor cells, which may be helpful for the selection of suitable operation method and prognosis of ccRCC.

SUBMITTER: Ai Q

PROVIDER: S-EPMC3323638 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma.

Ai Qing Q Ma Xin X Huang Qingbo Q Liu Shangwen S Shi Taoping T Zhang Chao C Zhu Mingyang M Zhang Yu Y Wang Baojun B Ni Dong D Li Hongzhao H Zheng Tao T Zhang Xu X

PloS one 20120410 4

<h4>Background</h4>Although metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signali ...[more]

PMID: 22506064

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Project description:ObjectivesTo develop and validate a radiomics nomogram to improve prediction of recurrence and metastasis risk in T1 stage clear cell renal cell carcinoma (ccRCC).MethodsThis retrospective study recruited 168 consecutive patients (mean age, 53.9 years; range, 28-76 years; 43 women) with T1 ccRCC between January 2012 and June 2019, including 50 aggressive ccRCC based on synchronous metastasis or recurrence after surgery. The patients were divided into two cohorts (training and validation) at a 7:3 ratio. Radiomics features were extracted from contrast enhanced CT images. A radiomics signature was developed based on reproducible features by means of the least absolute shrinkage and selection operator method. Demographics, laboratory variables (including sex, age, Fuhrman grade, hemoglobin, platelet, neutrophils, albumin, and calcium) and CT findings were combined to develop clinical factors model. Integrating radiomics signature and independent clinical factors, a radiomics nomogram was developed. Nomogram performance was determined by calibration, discrimination, and clinical usefulness.ResultsTen features were used to build radiomics signature, which yielded an area under the curve (AUC) of 0.86 in the training cohort and 0.85 in the validation cohort. By incorporating the sex, maximum diameter, neutrophil count, albumin count, and radiomics score, a radiomics nomogram was developed. Radiomics nomogram (AUC: training, 0.91; validation, 0.92) had higher performance than clinical factors model (AUC: training, 0.86; validation, 0.90) or radiomics signature as a means of identifying patients at high risk for recurrence and metastasis. The radiomics nomogram had higher sensitivity than clinical factors mode (McNemar's chi-squared = 4.1667, p = 0.04) and a little lower specificity than clinical factors model (McNemar's chi-squared = 3.2, p = 0.07). The nomogram showed good calibration. Decision curve analysis demonstrated the superiority of the nomogram compared with the clinical factors model in terms of clinical usefulness.ConclusionThe CT-based radiomics nomogram could help in predicting recurrence and metastasis risk in T1 ccRCC, which might provide assistance for clinicians in tailoring precise therapy.

Project description:Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer. Due to inactivation of the von Hippel-Lindau tumour suppressor, the hypoxia-inducible transcription factors (HIFs) are constitutively activated in these tumours, resulting in a pseudo-hypoxic phenotype. The HIFs induce the expression of genes involved in angiogenesis and cell survival, but they also reset the cellular metabolism to protect cells from oxygen and nutrient deprivation. ccRCC tumours are highly vascularized and the cytoplasm of the cancer cells is filled with lipid droplets and glycogen, resulting in the histologically distinctive pale (clear) cytoplasm. Intratumoural heterogeneity may occur, and in some tumours, areas with granular, eosinophilic cytoplasm are found. Little is known regarding these traits and how they relate to the coexistent clear cell component, yet eosinophilic ccRCC is associated with higher grade and clinically more aggressive tumours. In this study, we have for the first time performed RNA sequencing comparing histologically verified clear cell and eosinophilic areas from ccRCC tissue, aiming to analyse the characteristics of these cell types. Findings from RNA sequencing were confirmed by immunohistochemical staining of biphasic ccRCC. We found that the eosinophilic phenotype displayed a higher proliferative drive and lower differentiation, and we confirmed a correlation to tumours of higher stage. We further identified mutations of the tumour suppressor p53 (TP53) exclusively in the eosinophilic ccRCC component, where mTORC1 activity was also elevated. Also, eosinophilic areas were less vascularized, yet harboured more abundant infiltrating immune cells. The cytoplasm of clear cell ccRCC cells was filled with lipids but had very low mitochondrial content, while the reverse was found in eosinophilic tissue. We herein suggest possible transcriptional mechanisms behind these phenomena. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is a tumor that frequently shows the hematogenous pathway and tends to be resistant to radiotherapy and chemotherapy. However, the exact mechanism of ccRCC metastasis remains unknown.MethodsDifferentially expressed genes (DEGs) of three gene expression profiles (GSE85258, GSE105288 and GSE22541) downloaded from the Gene Expression Omnibus (GEO) database were analyzed by GEO2R analysis, and co-expressed DEGs among the datasets were identified using a Venn drawing tool. The co-expressed DEGs were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and hub genes were determined based on the protein-protein interaction network established by STRING. After survival analysis performed on UALCAN website, possible key genes were selected and verified in ccRCC cell lines and ccRCC tissues (n = 44). Statistical analysis was conducted using GraphPad Prism (Version 8.1.1).ResultsA total of 104 co-expressed DEGs were identified in the three datasets. Pathway analysis revealed that these genes were enriched in the extracellular matrix (ECM)-receptor interaction, protein digestion and absorption and focal adhesion. Survival analysis on 17 hub genes revealed that four key genes with a significant impact on survival: procollagen C-endopeptidase enhancer (PCOLCE), prolyl 4-hydroxylase subunit beta (P4HB), collagen type VI alpha 2 (COL6A2) and collagen type VI alpha 3 (COL6A3). Patients with higher expression of these key genes had worse survival than those with lower expression. In vitro experiments revealed that the mRNA expression levels of PCOLCE, P4HB and COL6A2 were three times higher and that of COL6A3 mRNA was 16 times higher in the metastatic ccRCC cell line Caki-1 than the corresponding primary cell line Caki-2. Immunohistochemistry revealed higher expression of the proteins encoded by these four genes in metastatic ccRCC compared with tumors from the corresponding primary sites, with statistical significance.ConclusionPCOLCE, P4HB, COL6A2 and COL6A3 are upregulated in metastatic ccRCC and might be related to poor prognosis and distant metastases.

Dataset Information

High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma.

Background

Methodology/principal findings

Conclusions/significance

Publications

High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma.

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