Abstract
Metastasis of head and neck tumors is responsible for a high mortality rate. Understanding its biochemistry may allow insights into tumorigenesis. To that end we carried out RNA-Seq analyses of 5 SCC9 derived oral cancer cell lines displaying increased invasive potential. Differentially expressed genes (DEGs) were annotated based on p-values and false discovery rate (q-values). All 292 KEGG pathways related to the human genome were compared in order to pinpoint the absolute and relative contributions to the invasive process considering the 8 hallmarks of cancer plus 2 new defined categories, as well as we made with our transcriptomic data. In terms of absolute contribution, the highest correlations were associated to the categories of evading immune destruction and energy metabolism and for relative contributions, angiogenesis and evading immune destruction. DEGs were distributed into each one of all possible modes of regulation, regarding up, down and continuum expression, along the 3 stages of metastatic progression. For p-values twenty-six genes were consistently present along the tumoral progression and 4 for q-values. Among the DEGs, we found 2 novel potentially informative metastatic markers: PIGG and SLC8B1. Furthermore, interactome analysis showed that MYH14, ANGPTL4, PPARD and ENPP1 are amenable to pharmacological interventions.
Highlights
We found that the principal inputs of the hallmarks corresponded to those with highest number of pathways and differentially expressed genes (DEGs), namely evading immune destruction (22 pathways, 1542 genes) and energy metabolism (25 pathways, 1536 genes) (Fig. 2)
Of the subgroup of down regulated genes, we found 3 genes described as biomarkers of HNSCC (RAB1734, NMU35 and ANGPTL436), and one of EMT (CXADR37)
coxsackie virus and adenovirus receptor (CXADR) was reported to be down regulated[38], agreeing with our results; no expression data for RAB17 was found in our results we found to be down regulated; ANGPTL4 was reported to be overexpressed[39] in contrast to our result showing it was down regulated; neuromedin U (NMU) protein was proposed as biomarker, in our data measuring RNA/cDNA levels, this gene was down regulated
Summary
Cell lines SCC9, and transformed ZsG, LN1, LN2 and LN3 were a kind gift from Agostini and collaborators. For details of model development, see reference[7]. Cells were cultured in Ham’s F12 medium (DMEM/F12; Invitrogen, USA) supplemented with. 10% fetal bovine serum (FBS) and hydrocortisone 400 ng/ml (Sigma-Aldrich, USA). 1.1 × 106 cells of SCC9, ZsG and LN1; 1.5 × 106 cells of LN2 and 2 × 106 cells of LN3 were transferred to 60.1 cm[2] Petri dishes, for 48 hours, using an incubator series 8000 water-jacketed CO2 (Thermo Scientific), in humidity atmosphere of 5% of CO2. Three independent biological replicates of each cell line were used for the transcriptomic analysis. The cell lines were genotyped and tested free for Mycoplasma sp. The cell lines were genotyped and tested free for Mycoplasma sp. infection
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