Novel mutations in transthyretin gene associated with hepatocellular carcinoma

Abstract

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 4 ), 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. K E Y W O R D S2-aminoacetylfluorine, apolipoprotein A1, diethylnitrosamine, expression, mutations, tetramer formation

Transthyretin as a Novel Biomarker for Diagnosis of Hepatocellular Carcinoma in cirrhotic patients

“…Our result was similar to a finding of Liao et al, [17] who showed that cirrhotic patients with HCC had lower pre-albumin level. While in disagreement to result of Katare et al who observed that serum TTR level showed 4 times increase in HCC patients than in control [13].…”

“…TTR is considered as a sensitive marker for the diagnosis of patients with liver cell damage, liver cirrhosis or hepatocellular carcinoma, reflecting the impaired liver synthetic function [12] . Katare et al [13] was the first to report that development of HCC is associated with increased level of serum TTR, where serum TTR level showed 4 times increase in HCC patients than in control. Therefore, detection of increased level of TTR alone or in combination with other validated markers may be potentially informative biomarker for detection of HCC at early noninvasive stage.…”

Midnolin Regulates Liver Cancer Cell Growth In Vitro and In Vivo

“…Furthermore, hepatic Lpl, which supports clearance of blood triglyceride [17], Lrp1, which participates in uptake by liver of chylomicrons and very low-density lipoproteins from blood [18], and Acsl1, which activates long-chain fatty acids and facilitates lipid biosynthesis [19], were highly down-regulated (−90%, −87%, and −70%, respectively) in midnolin knockdown cells. Indeed, dysregulation of Aldh1a1 [20], Ttr [21], Rbp1 [22], Lpl [23], Lrp1 [24], and Acsl1 [25] in HCC has previously been reported. Given the important role of retinoic acid metabolism [26] and that of lipid metabolism [27] in regulating cell growth/transient amplification of cells and differentiation in cancer, we propose that midnolin knockdownmediated disruption of such metabolic pathways may explain the observed reduction in tumorigenic potential of midnolin knockdown cells in vitro and in mice.…”

Effect and Mechanism of Transthyretin Over-Expression on Proliferation and Cell Cycle of Lung Cancer A549 Cells

“…The differential expression of TTR had important biological significance in the development of cutaneous T-cell lymphoma ( 20 ). Katare et al found four mutations of TTR gene in LC rats, which changed three amino acids at positions 61, 100 and 115 ( 21 ). The mutation at position 115 interfered with the formation of TTR tetramer, leading to TTR accumulation ( 21 ).…”

“…Katare et al found four mutations of TTR gene in LC rats, which changed three amino acids at positions 61, 100 and 115 ( 21 ). The mutation at position 115 interfered with the formation of TTR tetramer, leading to TTR accumulation ( 21 ). With the deepening of TTR research, TTR could be used as a potential biomarker for pancreatic ductal adenocarcinoma ( 12 ).…”