Genomic and glycomic identifications of novel tumor markers for oral cancer

Abstract

Purpose: Oral cancer is one of the most commonly diagnosed tumors with increasing mortality worldwide especially in Taiwan in recent years Prevention of oral squamous carcinoma cancer metastasis to improve the overall survival has provided the rationale for biomarker development In addition specific glycans expressed in tumor cells have been identified as key mediators during the various progression steps of tumor including proliferation growth cell-cell adhesion migration and metastasis Here we are trying to explore novel therapeutic targets or tumor markers during oral cancer progression by genomics or glycomics approaches Experimental Design: A high metastatic sub-population was divided from human oral cancer HSC-3 by invasion assay in vitro Gene expression microarray technology was performed to compare the different gene profiles such as glycosyltransferases genes or others Consequently immunohistochemical staining was applied to verify expressions of identified genes Further N-glycans of cells were purified and subjected to Matrix-Assisted Laser Desorption Ionization –Time of Fight (MALDI-TOF) mass spectrometry analysis Results: We used Transwell invasion assay to successfully isolate a high-metastatic subpopulation HSC-3-5 cells which exhibited almost same genetic background with parental cells and higher metastatic capacities due to cytoskeletal rearrangement accompanied with epithelial mesenchymal transition HSC-3-5 cells also showed tumorigenic and metastatic characteristics in vivo In addition anterior gradient 2 (agr2) gene a pro-oncogenic signaling intermediate was identified from gene expression profiles Overexpression of AGR2 showed a high sensitivity which positively correlated with metastasis in 109 oral cancer patients and a poor specificity AGR2 was likely a novel sensitive diagnostic marker for oral cancer metastasis In the meanwhile down-regulation of fut8 gene which regulated the core-fucosylation process was recognized in HSC-3-5 cells from the gene expression microarray and verified in metastatic tissues by 40 oral cancer patients of immunohistochemical staining In addition the positive and negative prediction values of metastasis could be improved through combination with decreased core-fucosylation and overexpression of AGR2 Conclusions: AGR2 was suggested to be a novel sensitive biomarker for metastatic oral cancer And combined core-fucosylation with AGR2 promoted the positive and negative predictive value of metastasis

Date of Award	2014 Apr 22
Original language	English
Supervisor	Chuan-Fa Chang (Supervisor)