Cellular and Molecular Regulations of Hyperglycemia Mediated Head and Neck Carcinogenesis

• Main Authors: Wan-Jung Chang, 張婉容
• Other Authors: Wan-Chun Li
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/91863404787939434300

碩士 === 國立陽明大學 === 口腔生物研究所 === 102 === Background: Head and Neck (H&N) cancer is one of the most prevalent neoplasias worldwide. Aging associated physiology in company with potent dietary stimulations and environmental challenges were considered as oncogenic cues for development of H&N cancer. In contrast to other factors, the impact of hyperglycaemia/diabetes mellitus (DM) induced imbalanced metabolism during carcinogenesis was less emphasized. Recent study described an anti-cancer effect of glucose-lowing agent metformin during H&N carcinogenesis suggesting a potential link between hyperglycaemia and H&N cancer formation. Although several preclinical and epidemiological investigations have shown that hyperglycaemic/DM condition possibly correlated with greater incidence and poorer prognosis in subjects with H&N cancer, the outcomes from different groups are contradictive and underlying mechanisms require to be explored. Materials and Methods: To better define progressive hyperglycaemia/DM-mediated regulation for H&N cancer development, current experimental scheme was two-folds. In the aspect of in vitro analysis, dynamic changes for cell malignancy using H&N cancer cells from different origins (tongue, oropharyngeal or oral squamous cells) in response to prolonged glucose challenge were examined. Further histological analysis for tumour lesions and molecular expression using animals bearing 4-Nitroquinoline 1-oxide (4-NQO) induced oral cancer with/without administration of DM inducer streptozotocin (STZ) was also carried out. Results and Discussion: Current results demonstrated that hyperglycaemia promoted H&N cancer malignancy in through (1) modulation of cell growth; (2) suppression of cell differentiation; (3) enhancement of epithelial mesenchymal transition (EMT) mediated cell motility (4) increased drug resistance; and (5) up-regulation of nutrient mediated oncogenic molecules. In vivo study detected tongue epithelial thickness after 12-week exposure of 4-NQO as histological analysis indicated progressive hyperplasia/dysplasia correlated with longer 4-NQO treatments. Under combinational experimental scheme using 4-NQO and multiple low-dose STZ injection, greater tumor mass was observed on tongues of DM mice confirming DM mediated tumour promotion. Interestingly, the detection of accelerated establishment of hyperglycaemia in mice treated with 4-NQO suggested reciprocal interplay between hyperglycaemia and oral carcinogenesis. Conclusion: Present study confirmed that elevated glycaemic challenge enhanced tumor malignancy in H&N cancer both in vitro and in vivo. The outcomes are of great benefit in understanding how hyperglycaemic insult regulates H&N cancer development and in providing better anti-cancer treatment strategy for DM patients.