P Katare Deepshikha, Malik Shabnam, J Mani Ruchi, Ranjpour Maryam, Jain Swatantra K
Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India.
Faculty of Chemical and Life Sciences, Department of Biotechnology, Hamdard Institute of Medical Sciences and Research, Hamdard University, New Delhi, India.
Mol Carcinog. 2018 Jan;57(1):70-77. doi: 10.1002/mc.22732. Epub 2017 Sep 21.
Hepatocellular carcinoma (HCC) is one of the major health problems with increasing incidence worldwide. We report the elevation in transthyretin (TTR) expression following HCC induction using diethylnitrosamine (DEN) and 2-aminoacetylfluorine (2-AAF) in male Wistar rats. The increase in its expression took place at very early stage and remained elevated throughout HCC progression. The analysis of TTR gene in HCC bearing rats revealed four novel mutations that alter three amino acids at positions 61, 100, and 115. While these mutations do not directly affect the binding of TTR to thyroxine (T ), the mutation in amino acid 115 interferes with TTR tetramer formation that leads to its accumulation. Further, the mutated TTR is unable to cleave C-terminal of apolipoprotein A1 (APOA1) that results in abnormal lipid metabolism. This has correlation with development of liver cirrhosis and HCC. Furthermore, the mutated TTR seems to have potential as biomarker for early detection of HCC.
肝细胞癌（HCC）是全球发病率不断上升的主要健康问题之一。我们报告了在雄性Wistar大鼠中使用二乙基亚硝胺（DEN）和2-氨基乙酰氟（2-AAF）诱导HCC后转甲状腺素蛋白（TTR）表达的升高。其表达的增加发生在非常早期阶段，并且在整个HCC进展过程中一直保持升高。对荷瘤大鼠的TTR基因分析发现了四个新的突变，这些突变改变了第61、100和115位的三个氨基酸。虽然这些突变不会直接影响TTR与甲状腺素（T）的结合，但第115位氨基酸的突变会干扰TTR四聚体的形成，导致其积累。此外，突变的TTR无法切割载脂蛋白A1（APOA1）的C末端，从而导致脂质代谢异常。这与肝硬化和HCC的发展相关。此外，突变的TTR似乎有潜力作为HCC早期检测的生物标志物。
