Soft tissue sarcoma.
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Chemotherapy, Adjuvant↗
Biomedical subjects
Patrick Gullane
Publications and source records attributed to Patrick Gullane.
Molecular cytogenetic analysis of head and neck squamous cell carcinoma: By comparative genomic hybridization, spectral karyotyping, and expression array analysis.
BACKGROUND: A combination of molecular cytogenetic and expression array analysis has been performed on head and neck squamous cell carcinoma (HNSCC) of the oral cavity and supraglottis. These studies were performed to identify consensus regions of chromosomal imbalance and structural rearrangement to determine whether genes located in these genomic regions are subject to alterations in gene expression. Such combinatorial studies may help to identify recurrent patterns of altered gene expression in the context of specific chromosomal changes. METHODS: Comparative genomic hybridization (CGH) was used to identify net genomic imbalances and spectral karyotyping (SKY) to visualize the numerical and structural chromosomal changes in metaphase preparations. Expression microarray analysis of HNSCC cell lines and primary tongue tumors was also performed to identify genes that were commonly overexpressed or underexpressed compared with adjacent normal tissue. RESULTS: CGH detected gains at 3q (64%), 8q (45%) and 6q22-qter (45%) and losses at 18q22-qter (27%). SKY analysis of seven cell lines identified frequent structural rearrangement of the following chromosomal regions: 3q, 5p13-q11.2, 5q32-q34, 7p12-q11.2, 8p12-q12, 9p, 10p, 13p13-q12, 14q11.1-q11.2, 15p13-q11.2, 16p11.1-q11.1, 18q22-q23, and 22p13-q11.2. Consistent deregulation of interleukin 8, integrin alpha-6, c-MYC, epithelial discoidin domain receptor 1, and sterol regulatory element binding protein were apparent by expression analysis. Interestingly, some of these genes map to regions of genomic imbalance and chromosomal rearrangement as determined by our molecular cytogenetic analysis. CONCLUSIONS: In this small study, a combinatorial analysis using SKY, CGH, and microarray provides a model linking the changes in gene expression to changes in chromosomal dosage and structure. This approach has identified a subset of genetic changes that provide new opportunities for investigating the genetic basis of tumorigenesis in HNSCC.
Carcinoma, Squamous Cell↗
Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas.
We recently identified 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, as a potential therapeutic target of the head and neck squamous cell carcinomas (HNSCC) and cervical carcinomas (CC). The products of this complex biochemical pathway, including de novo cholesterol, are vital for a variety of key cellular functions affecting membrane integrity, cell signaling, protein synthesis, and cell cycle progression. Lovastatin, a specific inhibitor of HMG-CoA reductase, induces a pronounced apoptotic response in a specific subset of tumor types, including HNSCC and CC. The mediators of this response are not well established. Identification of differentially expressed genes represents a feasible approach to delineate these mediators as lovastatin has the potential to modulate transcription indirectly by perturbing levels of sterols and other mevalonate metabolites. Expression analysis following treatment of the HNSCC cell lines SCC9 or SCC25 with 10 microM lovastatin for 1 day showed that less than 2% (9 cDNAs) of the 588 cDNAs on this microarray were affected in both cell lines. These included diazepam-binding inhibitor/acyl-CoA-binding protein, the activated transcription factor 4 and rhoA. Because the biosynthesis of mevalonate leads to its incorporation into more than a dozen classes of end products, their role in lovastatin-induced apoptosis was also evaluated. Addition of the metabolites of all the major branches of the mevalonate pathway indicated that only the nonsterol moiety, geranylgeranyl pyrophosphate (GGPP), significantly inhibited the apoptotic effects of lovastatin in HNSCC and CC cells. Because rhoA requires GGPP for its function, this links the microarray and biochemical data and identifies rhoA as a potential mediator of the anticancer properties of lovastatin. Our data suggest that the depletion of nonsterol mevalonate metabolites, particularly GGPP, can be potential mediators of lovastatin-induced apoptosis of HNSCC and CC cells.
Activating Transcription Factors↗