title: Impact of S100A8 expression on kidney cancer progression and molecular docking studies for kidney cancer therapeutics.
abstract: OBJECTIVE
  The proinflammatory protein S100A8, which is expressed in myeloid cells under physiological conditions, is strongly expressed in human cancer tissues. Its role in tumor cell differentiation and tumor progression is largely unclear and virtually unstudied in kidney cancer. In the present study, we investigated whether S100A8 could be a potential anticancer drug target and therapeutic biomarker for kidney cancer, and the underlying molecular mechanisms by exploiting its interaction profile with drugs.
  
  
  METHODS
  Microarray-based transcriptomics experiments using Affymetrix HuGene 1.0 ST arrays were applied to renal cell carcinoma specimens from Saudi patients for identification of significant genes associated with kidney cancer. In addition, we retrieved selected expression data from the National Center for Biotechnology Information Gene Expression Omnibus database for comparative analysis and confirmation of S100A8 expression. Ingenuity Pathway Analysis (IPA) was used to elucidate significant molecular networks and pathways associated with kidney cancer. The probable polar and non-polar interactions of possible S100A8 inhibitors (aspirin, celecoxib, dexamethasone and diclofenac) were examined by performing molecular docking and binding free energy calculations. Detailed analysis of bound structures and their binding free energies was carried out for S100A8, its known partner (S100A9), and S100A8-S100A9 complex (calprotectin).
  
  
  RESULTS
  In our microarray experiments, we identified 1,335 significantly differentially expressed genes, including S100A8, in kidney cancer using a cut-off of p<0.05 and fold-change of 2. Functional analysis of kidney cancer-associated genes showed overexpression of genes involved in cell-cycle progression, DNA repair, cell death, tumor morphology and tissue development. Pathway analysis showed significant disruption of pathways of atherosclerosis signaling, liver X receptor/retinoid X receptor (LXR/RXR) activation, notch signaling, and interleukin-12 (IL-12) signaling. We identified S100A8 as a prospective biomarker for kidney cancer and in silico analysis showed that aspirin, celecoxib, dexamethasone and diclofenac binds to S100A8 and may inhibit downstream signaling in kidney cancer.
  
  
  CONCLUSIONS
  The present study provides an initial overview of differentially expressed genes in kidney cancer of Saudi Arabian patients using whole-transcript, high-density expression arrays. Our analysis suggests distinct transcriptomic signatures, with significantly high levels of S100A8, and underlying molecular mechanisms contributing to kidney cancer progression. Our docking-based findings shed insight into S100A8 protein as an attractive anticancer target for therapeutic intervention in kidney cancer. To our knowledge, this is the first structure-based docking study for the selected protein targets using the chosen ligands.
authors.affiliation: King Abdulaziz University, PO BOX 80216, Jeddah 21589, Kingdom of Saudi Arabia. Tel: +1 96626401000 ext. 25123, skarim1@kau.edu.sa; sajjad_k_2000@yahoo.com.
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Mirza
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Schulten
authors.forename: Hasan Ma
authors.initials: HM
authors.lastname: Farsi
authors.forename: Jaudah A
authors.initials: JA
authors.lastname: Al-Maghrabi
authors.forename: Mamdooh A
authors.initials: MA
authors.lastname: Gari
authors.forename: Adeel Ga
authors.initials: AG
authors.lastname: Chaudhary
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Al-Qahtani
authors.forename: Sajjad
authors.initials: S
authors.lastname: Karim
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D040501:Calgranulin A / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009367:Neoplasm Staging; D011485:Protein Binding; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D040501:Calgranulin A
keywords: Kidney cancer; S100A8; Saudi Arabia; anticancer target; docking; gene expression profiling