Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer development

Abstract

Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumourassociated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well.

Expression profile of skin papillomas with high cancer risk displays a unique genetic signature that clusters with squamous cell carcinomas and predicts risk for malignant conversion

“…The trend was similar, but expected variability in the ratios between the two methods was observed due to calculated average values obtained from different numbers of tissues and/or method sensitivity. Taken together these results as well as concordance of expression patterns in this dataset with published expression and array studies (Hummerich et al, 2006) show that the expression patterns observed with the oligo microarrays reflect valid differences in gene expression between groups of tumors.…”

“…Similar to published studies of short-term TPA treatment (Schlingemann et al, 2003;Hummerich et al, 2006), a number of genes were induced or downregulated in both TPA-treated skin and all tumors such as S100A8, several Sprr2 family members, PSG28, Esd, dynactin (dctn1) and myosin 1a Myo1A (Supplementary Table I). Many genes were distinctly regulated between tumor-promoted normal skin and all tumors including arginase and Stefin A1, which were induced 3-20-fold in tumors but were either unaffected or downregulated in chronically tumor-promoted skin.…”

“…Both analyses identified 514 genes (Supplementary Table I), with concordance of 87% between these two gene sets. Confirming the cross platform reproducibility of the mouse multistage skin model, this gene set contains highly induced and downregulated genes similar to another cDNA microarray study comparing pooled papillomas, SCC-and TPA-treated normal skin (Hummerich et al, 2006), such as S100a9, S100a8, S100a11, small proline-rich proteins Sprr2f, Sprr2k, Slpi, the ras family member Arhh, Fabp5 and several members of the glutathione S-transferase family (Supplementary online dataset). Additional highly induced genes across all tumors identified in our dataset include markers of inflammation such as interleukin-1b (IL-1b), Ear5, pregnancy-specific glycoprotein 28 (Psg28) and the cysteine protease inhibitor stefin A1.…”

Screening and Identification of Distant Metastasis‐Related Differentially Expressed Genes in Human Squamous Cell Lung Carcinoma

“…It has been also reported to participate in the progression of many malignancies such as mammary tumor (Stoesz et al, 1998;Soiland et al, 2009;Yang et al, 2009), digestive tumors (Kubben et al, 2007;Zhang et al, 2007Zhang et al, , 2009), but except lung cancer. In addition, the high transcription level of LCN2 was detected in human skin squamous cell cancers, which suggested LCN2 has a close association with epithelial-derived malignancies (Hummerich et al, 2006). It was known that LCN2 could activate and protect the activity of matrix metalloproteinase-9 (MMP-9) by interacting with it and preventing tissue inhibitor of metalloproteinase-1 to degrade it.…”

Downregulation of Annexin A1 is correlated with radioresistance in nasopharyngeal carcinoma

“…The research evidence indicated that ANXA1 may specifically function as either a tumor suppressor or an oncogene candidate for certain cancers depending on the particular type of tumor cells/tissues (9). The upregulation of ANXA1 has been cor related with the development of hepatocellular carcinoma, colorectal cancer, lung cancer, pancreatic cancer, melanoma, skin cancer and endometrial carcinoma (21)(22)(23)(24)(25)(26)(27). Furthermore, its downregulation, as well as the translocation of ANXA1, has been shown to be a positive indicator for the development, progression and metastasis of prostate cancer, esophageal cancer, oral carcinoma, cervical cancer, intestinal-type sinonasal adenocarcinoma and NPC (17)(18)(19)28,29).…”