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Research Outline      2014-11-05 11:48:28

Anaplastic thyroid cancer (ATC) is a fatal malignancy, and it usually progressed rapidly with distant metastasis due to deficiency of apoptotic regulation with de-differentiation, and the average survival would be less than six months. Clinical practitioners knew that this disease canno be cured in combination with operation, radiotherapy and chemotherapy. We initially treated ATC cell line (ARO cells) with TNF-α, later the evidences of re-differentiation were firstly observed were also observed in ARO culture medium after treatment of lovastatin. Apoptosis could be found in ARO cells treated with higher concentrations, however, re-differentiation was noted in cells treated with lower concentrations (25 μM), while re-differentiation with higher concentration (50 μM). Molecular mechanism revealed that small G-protein (prenylated proteins) in cell membrane, especially for Rho. These results were published in Journal of Clinical Endocrinology & Metabolism, Endocrinology and Endocrine Related Cancer, respectively. In 2006, our animal model was carried out, nude mice implanting with ARO cells was established for lovastatin treatment. We found that tumor growth was prominent suppressed in nude mice treated with lovastatin, 5 and 10 mg/kg/day in comparison (higher dose) in comparison] with positive control group. Meanwhile, tumor growth was significantly promoted in mice treated with 1 mg/kg/day as unexpected finding. Lovastatin showed the “duality effects” for tumor apoptosis and progression. Such results were published in 2010 International Journal of Cancer (IF: 6.198). In addition, we use proteomic analysis to prove up-regulation of FLOT1 to be the pivotal role in re-differentiation of ATC cells. This finding was published in 2012 Journal of Proteomis (IF: 4.088). Based on pentose phosphate pathway(PPP), PPP is the shunt for phosphogluconate stream。PPP could play a role in synthesis of lipid in cells and transferring glucose to pentose. Pentose was recognized the energy resource for synthesis of nucleic acid in mammals. In our previous study, Lovastatin will activate transketolase (TKT) in ARO cells with dose-dependent manner. Therefore, TKT may play certain key role in tumorgenesis. Furthermore, we use lovastatin及oxythiamine(OXY, inhibitor of TKT) to treat ARO cells in cellular and nude mice model, we found that lovastatin together with OXY could inhibit ARO tumor growth in nude mice via suppressing the expression of TKT. We proved that lovastatin can accelerate ARO tumor growth in nude mice via activation of TKT in certain dose, in addition, OXY could inhibit expression of TKT to prohibit tumor growth in nude mice, via cellular apoptosis in cellular model. Under the fact of lovastatin could promote tumor growth via activation of TKT, but tumor growth will inhibited by OXY. We found one new therapeutic strategy in treating ATCvia inhibition of cellular expression of TKT. We prepared these results for publication and will enter the process of filing patent. On the other hand, Dipeptidyl peptidase-IV (DPP-IV) could be only express in follicular thyroid cancer, but not in normal thyrocytes. We now use DPP-IVinhibitor (Vildagliptin) in inducing re-differnetiationof ARO cells. However, we unexpectedly found that whole ARO cells and ARO cell-derived Exosomal proteomic analysis indicate Vildagliptine will increase expression of sodium iodine symptor (NIS) in whole cellular protein, but decrease the expression of NIS in cell-derived exosomal protein. In the very next two years, we will use cell-derived exosomal proteomic analysis in Vildagliptin / Lovastatin /OXT treated ARO and SW579 cells。We hope to find newly biological markers in predicting de-differentiation or re-differentiationin in thyroid cancer model, and enter the protocol of treatment in such ATC patients.