Identification of potential crucial genes associated with carcinogenesis of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy with high mortality. However, the molecular pathogenesis of ccRCC remains unclear and effective biomarkers for daily practice are still limited. Thus, we aimed to identify the potential crucial genes and pathways associated with carcinogenesis of ccRCC and further analyze the molecular mechanisms implicated in tumorigenesis. In the present study, expression profiles GSE 66270, GSE 53757, GSE 36895, and GSE 76351 were downloaded from GEO database, including 244 matched primary and adjacent normal tissues, furthermore, the level 3 RNAseq dataset (RNAseqV2 RSEM) of KIRC was also downloaded from The Cancer Genome Atlas (TCGA), which consist of 529 ccRCC tumors and 72 normal tissues. Then, differentially expressed genes (DEGs) and pathway enrichment were analyzed by using R software. A total of 129 up‐ and 123 down‐regulated genes were identified, which were aberrantly expressed both in GEO and TCGA data. Second, Gene ontology (GO) analyses revealed that most of the DEGs were significantly enriched in integral component of membrane, extracellular exosome, plasma membrane, cell adhesion, and receptor binding. Signaling pathway analyses indicated that DEGs had common pathways in signal transduction, metabolism, and immune system. Third, hub genes were identified with protein‐protein interaction (PPI) network, including PTPRC, TGFB1, EGF, MYC, ITGB2, CTSS, FN1, CCL5, KNG1, and CD86. Additionally, sub‐networks analyse was also performed by using MCODE plugin. In conclusion, the novel DEGs and pathways in ccRCC identified in this study may provide new insight into the underlying molecular mechanisms that facilitates RCC carcinogenesis.

[1]  P. Liu,et al.  A functional polymorphism in the epidermal growth factor gene is associated with risk for glioma in a Chinese population. , 2012, Genetic testing and molecular biomarkers.

[2]  P. Stephens,et al.  Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations. , 2016, European urology.

[3]  J. Cheville,et al.  Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[4]  F. Waldman,et al.  EGF‐r gene copy number changes in renal cell carcinoma detected by fluorescence in situ hybridization , 1998, The Journal of pathology.

[5]  Hong-zhao Li,et al.  Robot-assisted Laparoscopic Inferior Vena Cava Thrombectomy: Different Sides Require Different Techniques. , 2016, European urology.

[6]  M. Duffy Use of Biomarkers in Screening for Cancer , 2010, EJIFCC.

[7]  R. Montironi,et al.  The prospect of precision therapy for renal cell carcinoma. , 2016, Cancer treatment reviews.

[8]  N. Grishin,et al.  BAP1 loss defines a new class of renal cell carcinoma , 2012, Nature Genetics.

[9]  D. Radisky,et al.  Neuronal pentraxin 2 supports clear cell renal cell carcinoma by activating the AMPA-selective glutamate receptor-4. , 2014, Cancer research.

[10]  E. Prochownik,et al.  MYC oncogenes and human neoplastic disease , 1999, Oncogene.

[11]  A. Steiner,et al.  Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis. , 2013, The Journal of investigative dermatology.

[12]  Nicholas J Vogelzang,et al.  Novel Therapies for Metastatic Renal Cell Carcinoma: Efforts to Expand beyond the VEGF/mTOR Signaling Paradigm , 2012, Molecular Cancer Therapeutics.

[13]  X. Chen,et al.  Effect of RhoC on the epithelial-mesenchymal transition process induced by TGF-β1 in lung adenocarcinoma cells , 2016, Oncology reports.

[14]  Klaus Jung,et al.  Integrated microRNA and mRNA Signature Associated with the Transition from the Locally Confined to the Metastasized Clear Cell Renal Cell Carcinoma Exemplified by miR-146-5p , 2016, PloS one.

[15]  E. Diamandis,et al.  Strategies for discovering novel cancer biomarkers through utilization of emerging technologies , 2008, Nature Clinical Practice Oncology.

[16]  Stella Pelengaris,et al.  c-MYC: more than just a matter of life and death , 2002, Nature Reviews Cancer.

[17]  Kumardeep Chaudhary,et al.  Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer , 2017, Scientific Reports.

[18]  S. Perner,et al.  Identification of novel long non-coding RNAs in clear cell renal cell carcinoma , 2015, Clinical Epigenetics.

[19]  J. Stetefeld,et al.  Epidermal growth factor cytoplasmic domain affects ErbB protein degradation by the lysosomal and ubiquitin-proteasome pathway in human cancer cells. , 2012, Neoplasia.

[20]  P. Zhang,et al.  Retroperitoneal Laparoscopic Partial Nephrectomy for Tumors Larger than 7 cm in Renal Cell Carcinoma: Initial Experience of Single-Institution. , 2017, Journal of laparoendoscopic & advanced surgical techniques. Part A.

[21]  Xiaolong Li,et al.  The critical role of EGF-β-catenin signaling in the epithelial-mesenchymal transition in human glioblastoma , 2017, OncoTargets and therapy.

[22]  Lindsay A. Williams,et al.  MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma , 2017, Nature Communications.

[23]  E. Stefan,et al.  MYC and RAF: Key Effectors in Cellular Signaling and Major Drivers in Human Cancer. , 2017, Current topics in microbiology and immunology.

[24]  J. Gautier,et al.  Cdc45 is a critical effector of myc-dependent DNA replication stress. , 2013, Cell reports.

[25]  Sai-Wen Tang,et al.  MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells. , 2009, Cancer letters.

[26]  Han Yong Choi,et al.  The epidemiology of renal cell carcinoma. , 2011, European urology.

[27]  S. Dadras,et al.  An unexpected role for EGF in lymphangiogenesis-mediated melanoma metastasis to sentinel lymph nodes. , 2013, The Journal of investigative dermatology.

[28]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[29]  Rafael A. Irizarry,et al.  A framework for oligonucleotide microarray preprocessing , 2010, Bioinform..

[30]  Roy S Herbst,et al.  Review of epidermal growth factor receptor biology. , 2004, International journal of radiation oncology, biology, physics.

[31]  Bruno Amati,et al.  Oncogenic activity of the c-Myc protein requires dimerization with Max , 1993, Cell.

[32]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[33]  Lorenzo Marconi,et al.  EAU guidelines on renal cell carcinoma: 2014 update. , 2010, European urology.

[34]  Houjie Liang,et al.  Distinct Role of CD86 Polymorphisms (rs1129055, rs17281995) in Risk of Cancer: Evidence from a Meta-Analysis , 2014, PloS one.

[35]  Jianmin Wu,et al.  KOBAS server: a web-based platform for automated annotation and pathway identification , 2006, Nucleic Acids Res..

[36]  S. Culine,et al.  Kidney Cancer Pathology in the New Context of Targeted Therapy , 2011, Pathobiology.

[37]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[38]  K. Mimori,et al.  A single nucleotide polymorphism in fibronectin 1 determines tumor shape in colorectal cancer. , 2014, Oncology reports.

[39]  L. Larsson,et al.  MYC Modulation around the CDK2/p27/SKP2 Axis , 2017, Genes.

[40]  V. Yassaee,et al.  Mutation spectra of the ITGB2 gene in Iranian families with leukocyte adhesion deficiency type 1. , 2016, Human immunology.

[41]  Gary D Bader,et al.  Biological Network Exploration with Cytoscape 3 , 2014, Current protocols in bioinformatics.

[42]  H. Verheul,et al.  Novel drugs that target the metabolic reprogramming in renal cell cancer , 2016, Cancer & Metabolism.

[43]  V. Margulis,et al.  Integrin signaling potentiates transforming growth factor‐beta 1 (TGF‐&bgr;1) dependent down‐regulation of E‐Cadherin expression – Important implications for epithelial to mesenchymal transition (EMT) in renal cell carcinoma , 2017, Experimental cell research.

[44]  Gerard I. Evan,et al.  Induction of apoptosis in fibroblasts by c-myc protein , 1992, Cell.

[45]  W. Dippold,et al.  Expression of differentiation antigens and growth-related genes in normal kidney, autosomal dominant polycystic kidney disease, and renal cell carcinoma. , 1992, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[46]  Wancai Yang,et al.  Identification of Key Candidate Genes and Pathways in Colorectal Cancer by Integrated Bioinformatical Analysis , 2017, International journal of molecular sciences.

[47]  W. Hahn,et al.  Analysis of tumor- and stroma-supplied proteolytic networks reveals a brain metastasis-promoting role for cathepsin S , 2014, Nature Cell Biology.

[48]  Alec Smith,et al.  Critical Role , 2019, They Create Worlds.

[49]  L. Gossage,et al.  Alterations in VHL as potential biomarkers in renal-cell carcinoma , 2010, Nature Reviews Clinical Oncology.