The galanin signaling cascade is a candidate pathway regulating oncogenesis in human squamous cell carcinoma.

To identify putative biomarkers in squamous cell carcinoma (SCC), a survey of parallel chromosomal alterations and gene expression studies in 10 SCC cell lines were performed using array-comparative genomic hybridization (CGH) and oligo-microarray techniques. The most frequent changes were gains of 11q13.1-13.3 and losses of 18q12.1-23 in SCC. Furthermore, the expression levels of the sets of genes at both these loci in SCC were measured using microarray analysis. By combining the array-CGH with the microarray data, 10 genes at 11q13.1-13.3 and 6 genes at 18q12.1-23 whose expression correlated with chromosomal alterations were identified. To verify the expression levels of the identified genes, we used expression analysis data derived from our earlier study of clinical specimens. In clinical samples, six genes (GAL, GSTP1, MRPL11, MRPL21, SF3B2, and YIF1A) at 11q13.1-13.3 and one gene (GALR1) at 18q23 showed a significant difference between normal and tumor samples. GAL, coding for the neuropeptide galanin, and GALR1, a galanin receptor, were identified as candidate genes of oncogenesis in SCC. The expression levels of GAL, GALR1, GALR2, and GALR3 were confirmed by real-time PCR. The expression ratio between GAL and GALR1 showed a significant negative correlation. GALR1 is a G-protein-coupled receptor that activates GTP-binding proteins to trigger signaling cascades such as the mitogen-activated protein kinase pathway, and is a well-established mitogenic pathway. This further supports the hypothesis that the genes involved in the GAL signaling cascade are candidates for regulation of oncogenesis in SCC.

Aberrant internal carotid artery in the middle ear with a deficiency in the origin of the anterior cerebral artery: a case report.

An aberrant internal carotid artery (ICA) in the middle ear is rare and difficult to diagnose, and may lead to severe complications. We present here a case of aberrant ICA with a deficiency in the origin of the anterior cerebral artery. The only symptom was aural fullness, and a nonpulsatile and white tympanic mass in the anteroinferior area was noted. Computed tomography (CT) and magnetic resonance angiography (MRA) are useful tools that provide excellent visualization of the temporal bone for the diagnosis of aberrant ICA by the following features: intratympanic mass, enlarged inferior tympanic canaliculus, absence of the vertical segment of the ICA canal, and absence of bone covering the tympanic portion of the ICA. In addition, in this case, a deficiency in the origin of the anterior cerebral artery on the same side was identified by MRA, and cerebral arteriography and a carotid occlusion test were performed. Because of the deficiency in the origin of the anterior cerebral artery, the ICA compression revealed that there was almost no cross flow from the other ICA. Our experience illustrates that after confirmation of the diagnosis of aberrant ICA, localized treatment and/or surgical procedures should be considered carefully.

Identification of a novel therapeutic target for head and neck squamous cell carcinomas: a role for the neurotensin-neurotensin receptor 1 oncogenic signaling pathway.

Distant metastasis is a major factor associated with poor prognosis in head and neck squamous cell carcinomas (HNSCC), but little is known of its molecular mechanisms. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Based on a genome-wide gene expression analysis using clinical specimens of HNSCC, we narrowed our focus to the analysis of the neurotensin (NTS) and neurotensin receptor 1 (NTSR1) oncogenic signal pathways. Kaplan-Meier curves and log rank tests revealed that high mRNA expression levels of NTS and NTSR1 had a significant adverse effect on metastasis-free survival rate, suggesting a contribution of this pathway in HNSCC cancer progression. In HNSCC cells, which expressed NTSR1, a NTS agonist promoted cellular invasion, migration and induction of several mRNAs, such as interleukin 8 and matrix metalloproteinase 1 transcripts. In addition, knock down of NTSR1 expression with small interfering RNAs resulted in reduction of cellular invasion and migration in HNSCC cell lines. Our findings suggest a critical role for the NTS and NTSR1 oncogenic pathways in invasion and migration of HNSCC cells during the metastatic process. Our study raises the possibility that NTS and NTSR1 could be a useful predictive marker of poor prognosis in patients with HNSCC and a molecular therapeutic target in antimetastatic strategies for HNSCCs.

Identification of molecular targets in head and neck squamous cell carcinomas based on genome-wide gene expression profiling.

DNA amplifications activate oncogenes and are hallmarks of nearly all advanced cancers including head and neck squamous cell carcinoma (HNSCC). Some oncogenes show both DNA copy number gain and mRNA overexpression. Chromosomal comparative genomic hybridization and oligonucleotide microarrays were used to examine 8 HNSCC cell lines and a plot of gene expression levels relative to their position on the chromosome was produced. Three highly up-regulated genes, NT5C3, ANLN and INHBA, were identified on chromosome 7p14. These genes were subjected to quantitative real-time RT-PCR on cDNA and genomic DNA derived from 8 HNSCC cell lines. ANLN and INHBA showed a strong positive correlation between mRNA expression and genomic DNA levels and a similar relationship was shown for the known oncogene, EGFR, at 7p11.2. In clinical samples, ANLN and INHBA showed a significantly higher expression in tumors than in normal tissues. Patients with high expression levels of INHBA had a shorter disease-free survival rate. Therefore, INHBA may be a promising prognostic marker of HNSCC.