Abstract
BackgroundCytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. Nevertheless, the molecular consequences of numerous genetic alterations still remain unclear.MethodsTo identify novel genes implicated in HNSCC pathogenesis, we analyzed the genomic alterations present in five HNSCC-derived cell lines by array CGH, and compared high level focal gene amplifications with gene expression levels to identify genes whose expression is directly impacted by these genetic events. Next, we knocked down TRPC6, one of the most highly amplified and over-expressed genes, to characterize the biological roles of TRPC6 in carcinogenesis. Finally, real time PCR was performed to determine TRPC6 gene dosage and mRNA levels in normal mucosa and human HNSCC tissues.ResultsThe data showed that the HNSCC-derived cell lines carry most of the recurrent genomic abnormalities previously described in primary tumors. High-level genomic amplifications were found at four chromosomal sites (11q21-q22.2, 18p11.31-p11.21, 19p13.2-p13.13, and 21q11) with associated gene expression changes in selective candidate genes suggesting that they may play an important role in the malignant behavior of HNSCC. One of the most dramatic alterations of gene transcription involved the TRPC6 gene (located at 11q21-q22.2) which has been recently implicated in tumour invasiveness. siRNA-induced knockdown of TRPC6 expression in HNSCC-derived cells dramatically inhibited HNSCC-cell invasion but did not significantly alter cell proliferation. Importantly, amplification and concomitant overexpression of TRPC6 was also found in HNSCC tumour samples.ConclusionsAltogether, these data show that TRPC6 is likely to be a target for 11q21–22.2 amplification that confers enhanced invasive behavior to HNSCC cells. Therefore, TRPC6 may be a promising therapeutic target in the treatment of HNSCC.
Highlights
Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology
The broad application of cytogenetic and molecular genetics methods has led to the identification of tumorassociated chromosomal regions substantial for the tumorigenesis and progression of head and neck squamous cell carcinomas (HNSCC) [1,2,3]
Impact of focal high-level amplifications on gene expression To gain some insights into the role of genomic aberrations in HNSCC pathophysiology, we focused in focal amplification events for which it may be easier to pinpoint target genes involved in the pathogenesis of HNSCC
Summary
Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. The broad application of cytogenetic and molecular genetics methods has led to the identification of tumorassociated chromosomal regions substantial for the tumorigenesis and progression of head and neck squamous cell carcinomas (HNSCC) [1,2,3]. Our data showed that the cell lines analyzed here resemble most of the important genomic alterations previously described in primary HNSCC. It revealed the presence of several regions with high level focal amplifications (11q21-22.2, 18p11.31-p11.21, 19p13.2-p13.13, and 21q11) that have been previously identified in HNSCC [1,11]
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