探討糖化最終產物羧甲基離氨基酸促進骨癌之惡性及其機制

Advanced Glycation End Product Nε-carboxymethyllysine Exerts Malignancy on Bone Tumors via the Activation of Skeletal Cancer Stemness

吳佳鴻(Chia-Hung Wu)

指導教授 ： 劉興華

國立臺灣大學/醫學院/毒理學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202002672

摘要

糖尿病在現今社會當中是常見的慢性疾病，根據國際糖尿病聯合會的預估，在2045年時約有7億的人會得到糖尿病。糖尿病會引發一些併發症像是眼睛病變、心血管疾病、腎臟病變以及可能會增加得到癌症的風險。有許多的流行病學統計指出糖尿病會提高得到癌症的風險並且有實驗證明在糖尿病患者體內較一般人含有較多的糖化最終產物也發現會促進癌症的增生及轉移。雖然已有研究證明糖尿病和癌症的正相關性，不過卻很少有研究去探討糖尿病與骨癌之間的關聯，因此想了解糖化最終產物是否會促進骨癌的惡化。在本實驗所使用的細胞為人類骨肉瘤MG63細胞以及人類軟骨肉瘤JJ012細胞，實驗結果發現雖然糖化最終產物Nε-carboxymethyllysine (CML)並不會影響到骨癌細胞的存活率，不過卻會增加骨癌細胞在懸浮生長形成球體的數目(MG63)或面積(JJ012)而且糖化最終產物的受體(RAGE)以及與癌幹細胞有相關的基因MRP1、MDR1、CD44、ALDH1A1以及NANOG的蛋白表現量以及mRNA的表現量有顯著增加；除此之外，在transwell的實驗中發現CML也會增加骨癌細胞轉移以及侵入的數量，由以上的實驗得知，CML會促進骨癌細胞的惡化情形。

關鍵字

糖尿病 ； 糖化最終產物 ； 糖化最終產物受體 ； 骨癌 ； 癌幹細胞

並列摘要

Diabetes mellitus is now common disease with critical impacts on human health. According to the International Diabetes Federation, approximately 700 million people will get diabetes by 2045. Also, diabetes mellitus can cause many complications such as eye disease, cardiovascular disease, kidney failure and cancer. The association of diabetes mellitus and an increased cancer risk have been demonstrated from numerous epidemiological studies. Advanced glycation end products have been investigated to promote proliferation, tumorigenesis and metastasis of cancer cells. Despite there is an evidence of positive correlation between diabetes mellitus and cancer risk, much less attention is paid to link between diabetes mellitus and bone cancer. Therefore, we investigated the role of advanced glycation end products in bone cancer cells. The osteosarcoma, MG63 cells and chondrosarcoma, JJ012 cells were used in this study. Although Nε-carboxymethyllysine (CML) would not change the cell viability in bone cancer cells in a dose-dependent manner (0-100 μM) and time-dependent manner (24-72 h), but increase the sphere number of MG63 cells and the area of JJ012 cells. Also, CML would increase the protein expression of receptor for advanced glycation end products (RAGE) and cancer-stemness associated protein like MRP1, MDR1, CD44, ALDH1A1, and NANOG. Furthermore, in transwell migration and invasion assay, CML could increase the cell migration and invasion numbers and increase the protein expression of epithelial-mesenchymal transition markers in MG63 cells and JJ012 cells. As a result, CML could promote the malignancy of bone cancer cells.

並列關鍵字

diabetes mellitus ； advanced glycation end products ； receptor for advanced glycation end products ； bone cancer ； cancer stem cells

參考文獻

1. Diane M, et al. β-cell death during progression to diabetes. Nature. 2001;414:792-798.

2. Christopher JR. Type 2 diabetes — a matter of β-cell life and death? Science. 2005;307:380-383.

3. International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: 2019 [cited 2020 Jul 12]. 176 p. Available at: https://www.diabetesatlas.org

4. Edward G, et al. Diabetes and cancer. Diabetes Care. 2010; 33:1674–1685.

5. World Health Organization. WHO report on cancer: setting priorities, investing wisely and providing care for all. Geneva: World Health Organization; 2020 [cited 2020 Jul 12]. 149 p. Available at: https://apps.who.int/iris/handle/10665/330745