Investigation of NDRG1 on the Carcinogenesis of Head-Neck Cancer---From Basic to Translational Research

Head-neck cancer (HNC) is one of the most frequent cancer in the world with an estimated over 500,000 new cases being diagnosed annually. In Taiwan, the incidence of HNC is increasing in the recent years, and has become the 6th leading cancer, the 4th leading cancer in male in year 2007. Since this cancer usually occurs in the middle age male, at the high peak of life responsibility, it has tremendous impact of family and society. For treatment, although local control is generally acceptable for early staged tumor, in advanced tumor, the aggressive feature is the common cause of treatment failure. Therefore, this malignant disease cannot be controlled, unless the better understanding of the molecular pathology in cancer aggressiveness as well as the advances of therapeutic techniques can been developed. Through differential display technique, we have previously identified several native HNCassociated genes, including NDRG1, which is over-expressed in the cancer tissues. NDRG1 has been reported to participate in multiple functions on cellular homeostasis, including differentiation, stress response and metastasis. We therefore hypothesize that over-expression of NDRG1 is involved in the aggressiveness of HNC, and that NDRG1 is a potential target for molecular therapy of this disease. The main objectives of this proposal are to investigate what and how of the cellular functions of NDRG1 in HNC, and examine the potential application of modulating this molecule in the intervention of carcinogenic phenotype. The following specific aims will be accomplished to unveil such questions. Aim #1: Study in cellular level. Examination of the cellular effects after alteration of the NDRG1 expression in cells. (1) Construction of the NDRG1 knockdown (RNAi) and overexpressed (full length and various transact forms) plasmids and transfection of the gene into head neck cancer cells. (2) To study the effects of the plasmids in cellular homeostatsis, including cell growth/viability, colony formation, cell cycle distribution, apoptosis, migration, invasion and stress response. Aim #2: Study in biochemical level. Examination of the mechanism that NDRG1 functions in cancer cells. (1) To examine potential casual relationship of NDRG1 with PI3K/Akt pathway. (2) To examine the function of the 3R domain in NDRG1. Aim #3: Study in animal level. (1) To verify the NDRG1 expression in the tumor sections by immunohistochemistry, after NDRG1-RNAi delivery to the xenografted tumor in mice. (2) To examine the effects of tumor growth and survival after NDRG1-RNAi delivery into subcutaneous (for growth evaluation) or intravenous (for invasion evaluation) injected xenograft tumor mice using subcutaneous (for growth evaluation) or intravenous (for invasion evaluation) injection technique. Aim #4: Study in clinical level. (1) Evaluation of NDRG1 protein levels in the cancer tissues. (2) Correlation of NDRG1 expression with the cliniclpathological features and treatment outcome.

Project ID:PC10001-0222
External Project ID:NSC98-2320-B182-006-MY3