Activation of MAP Kinase Signaling Through ERK5 But Not ERK1 Expression Is Associated with Lymph Node Metastases in Oral Squamous Cell Carcinoma (OSCC)

Abstract

In an attempt to further elucidate the pathomechanisms in oral squamous cell carcinoma (OSCC), gene expression profiling was performed using a whole-transcriptome chip that contains 35,035 gene-specific 70 mere oligonucleotides (Human OligoSet 4.0; Operon, Cologne, Germany) to a set of 35 primary OSCCs. Altogether, 7390 genes were found differentially expressed between OSCC tumor samples and oral mucosa. To characterize the major biologic processes in this tumor collection, MAPPFinder, a component of GenMAPP version 2.1, was applied to this data set to generate a statistically ranked list of molecular signaling pathways. Among others, cancer-related pathways, such as mitogen-activated protein (MAP) kinase signaling (z score = 4.6, P < .001), transforming growth factor-beta signaling (z score = 3.0, P = .015), and signaling pathways involved in apoptosis (z score = 2.1, P = .037), were found deregulated in the OSCC collection analyzed. Focusing on the MAP kinase signaling pathway, subsequent tissue microarray analyses by immunohistochemistry revealed an increase in protein expression of MAP kinase-related proteins ERK1 in 22.8% (48 of 209) and ERK5 in 27.4% (76 of 277), respectively. An association of high ERK5 but not of high ERK1 expression with advanced tumor stage and the presence of lymph node metastases was found (P = .008 and P = .016, respectively). Our analysis demonstrates the reliability of the combined approach of gene expression profiling, signaling pathway analyses, and tissue microarray analysis to detect novel distinct molecular aberrations in OSCC.

Expression and influence of Notch signaling in oral squamous cell carcinoma

“…Expression datasets of human cell line were excluded in the study. The included GEO datasets (GSE) are shown in Table 1 (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Recurrent copy number gain of transcription factor SOX2 and corresponding high protein expression in oral squamous cell carcinoma

“…To further define the potential role of candidate proto-oncogenes in initiation and progression of OSCC, a subsequent tissue mRNA expression analysis and a microarray analysis (TMA) applying fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were performed for selected candidate genes. Combining DNA array technology with high throughput tumor analysis using tissue microarray technology allows the rapid assessment of overall prevalence of candidate oncogene aberrations in representative tumor series (Freier et al, 2006;Sticht et al, 2008). In this respect, the actual prevalence of individual candidate gene copy number gains and consecutive high protein expression in a representative collection of 308 OSCC specimen was determined.…”

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

“…Furthermore, ERK5 signalling has also been implicated in human mesothelioma cell proliferation, migration, invasion, and resistance to therapy [100] and, more importantly, has been suggested as a potential beneficial therapeutic target for the development of treatment strategies in patients with malignant mesothelioma [100]. Lastly, ERK5 overexpression has also been implicated in head and neck squamous carcinoma, and associated with advanced tumour stage and lymph node metastasis [101]. In fact, subsequent studies demonstrated that miRNA-143 upregulation led to the inhibition of cell migration and invasion [102], possibly related to ERK5 targeting.…”