My laboratory currently has three research directions in head and neck cancer research: Discoveries, pathogenesis and oral fluid-based molecular diagnostics.
My laboratory spearheads the use of genome-wide and proteome-wide technologies to harness the diagnostic and biological determinants pertaining to the pathogenesis of oral/head and neck cancer. In particular we are focusing on the genomic and proteomic determinants of oral precancer progression. Using a patient-based genome/proteome-wide approaches; we are harnessing the genomic and proteomic determinants that distinguish progressing from non-progression oral precancers. For genomic defects, a concurrent approach to identify gene copy number abnormalities (CNA) by cDNA microarray comparative genomic hybridization (CGH) as well as SNP-based loss of heterozygosity (LOH) using the Affymetrix 100K SNP-based Mapping Arrays. For expression analysis, the Affymetrix 133+ 2 and all exon high-density oligonucleotide arrays are used. For proteomic analysis, LC-MS/MS as well as single cell proteomics are creatively being integrated. A key component to a systems approach to seek for molecular concordance of detectable molecular defects. A cellular gene has to exhibit molecular congruency at the genomic, mRNA expression as well as proteomic levels to qualify as a potential molecular marker. All of these approaches use patient-based materials and laser capture microdissection (LCM) is used to selectively procure homogeneous cell types from tissue sections to minimize contaminations by non-relevant cell types in these sensitive molecular analyses.
We subscribe to the belief that a central defect in human cancer lies in the dysregulation of cell cycle control. Establishing a molecular database of cell cycle regulatory genes dysregulated in head and neck cancer and understanding the molecular and biochemical pathways of these genes are of prime interest. Using differential expression screening assays we have identified a number of cellular genes that are differentially expressed in squamous cell carcinoma. p12CDK2-AP1 is a differentially expressed cellular gene that is currently being studied. p12CDK2-AP1 is a novel gene exhibiting growth suppressor properties. p12CDK2-AP1 exerts its growth suppressor function by negatively regulating the activities of DNA polymerase-??/primase and cyclin-dependent kinase 2 (CDK2). p12CDK2-AP1 associates with DNA polymerase-??/primase suppressing DNA replication, affecting predominantly the initiation step. p12CDK2-AP1 has recently been found to associates with the monomeric non-phosphorylated form of CDK2, suppressing CDK2-associated kinase activities and cell cycle progression. p12CDK2-AP1 also targets CDK2 for proteolysis. Currently we are investigating the detailed biochemical and genetic mechanisms of p12CDK2-AP1 in cell cycle regulation, normal development and carcinogenesis. Most recent excitement of this research include finding that p12CDK2-AP1-nulled mice are embryonically lethal and that p12CDK2-AP1 is necessary for differentiation competency for mouse embryonic stem cells.
The ability to monitor by non-invasive mean for the early detection of cancer has been a long time goal for cancer researchers. However progress towards this goal has not met expectations. My research group, with the support from NIDCR, has initiated a series of concerted efforts to spearhead the scientific and translational frontiers of salivary diagnostics. The potential use of saliva, a totally non-invasive biofluid, for oral and systemic disease detection, disease progression and therapeutic monitoring are highly desirable goals. We have harnessed and defined two diagnostic alphabets from human saliva, the salivary proteome and salivary transcriptome. The availability of these diagnostics alphabets greatly enhance the translational utilizations of saliva. In parallel to the biomarker efforts, we have been developing point of care technologies for using saliva for clinical diagnostics applications. The ???Oral Fluid NanoSensor Test (OFNASET)??? is a prototype nanotechnology point of care sensor that will have the ability to detect multiple analytes in saliva for disease detection. The concurrent biomarker and technology development initiatives at UCLA led to the establishment of the ???UCLA Collaborative Oral Fluid Diagnostics Research Center??? to fully explore the scientific, translational and clinical frontiers of salivary diagnostics, salivary pharmacogenomics and salivary pharmacogenomics. The utilization of saliva for personalized individual medicine applications is only footsteps away.
- Brinkmann O., Wong D.T., “Salivary transcriptome biomarkers in oral squamous cell cancer detection,” Adv Clin Chem. 2011;55:21-34.
- Farrell J.J., Zhang L., Zhou H., Chia D., Elashoff D., Akin D., Paster B.J., Joshipura K., Wong D.T., “Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer,” Gut. 2011 Oct 12. (Epub ahead of print)
- Lee Y.H., Zhou H., Reiss J.K., Yan X., Zhang L., Chia D., Wong D.T., “Direct saliva transcriptome analysis,” Clin Chem. 2011 Sep;57(9):1295-302. Epub 2011 Jul 26.
- Sharma S., Liao W., Zhou X., Wong D.T., Lichtenstein A., “Exon 11 skipping of E-cadherin RNA downregulates its expression in head and neck cancer cells,” Mol Cancer Ther. 2011 Sep;10(9):1751-9. Epub 2011 Jul 15.
- Hu S., Vissink A., Arellano M., Roozendaal C., Zhou H., Kallenberg C.G., Wong D.T., “Identification of autoantibody biomarkers for primary Sjögren’s syndrome using protein microarrays,” Proteomics. 2011 Apr;11(8):1499-507. Epub 2011 Mar 17.
- Zhang L., Xiao H., Karlan S., Zhou H., Gross J., Elashoff D., Akin D., Yan X., Chia D., Karlan B., Wong D.T., “Discovery and preclinical validation of salivary transcriptomic and proteomic biomarkers for the non-invasive detection of breast cancer,” PLoS One. 2010 Dec 31;5(12):e15573.
- Brinkmann O., Kastratovic D.A., Dimitrijevic M.V., Konstantinovic V.S., Jelovac D.B., Antic J., Nesic V.S., Markovic S.Z., Martinovic Z.R., Akin D., Spielmann N., Zhou H., Wong D.T., “Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population,” Oral Oncol. 2011 Jan;47(1):51-5. Epub 2010 Nov 24.
- Hu S., Jiang J., Wong D.T. “Proteomic analysis of saliva: 2D gel electrophoresis, LC-MS/MS, and Western blotting,” Methods Mol Biol. 2010;666:31-41.
- Hu S., Gao K., Pollard R., Arellano-Garcia M., Zhou H., Zhang L., Elashoff D., Kallenberg C.G., Vissink A., Wong D.T,. “Preclinical validation of salivary biomarkers for primary Sjögren’s syndrome,” Arthritis Care Res (Hoboken). 2010 Nov;62(100:1633-8. Epub 2010 Jul 8.
- Ai J., Smith B., Wong D.T., “Saliva Ontology: an ontology-based framework for a Salivaomics Knowledge Base,” BMC Bioinformatics. 2010 Jun 3;11:302.