Abstract
We sought to identify a secreted biomarker for β-catenin activation commonly seen in hepatocellular carcinoma (HCC). By examination of our previously published genearray of hepatocyte-specific β-catenin knockout (KO) livers, we identified secreted factors whose expression may be β-catenin-dependent. We verified expression and secretion of the leading factor in HCC cells transfected with mutated (Hep3BS33Y)-β-catenin. Serum levels of biomarker were next investigated in a mouse model of HCC with β-catenin gene (Ctnnb1) mutations and eventually in HCC patients. Leukocyte cell-derived chemotaxin-2 (LECT2) expression was decreased in KO livers. Hep3BS33Y expressed and secreted more LECT2 in media as compared to Hep3BWT. Mice developing HCC with Ctnnb1 mutations showed significantly higher serum LECT2 levels. However patients with CTNNB1 mutations showed LECT2 levels of 54.28±22.32 ng/mL (Mean ± SD; n = 8) that were insignificantly different from patients with non-neoplastic chronic liver disease (32.8±21.1 ng/mL; n = 15) or healthy volunteers (33.2±7.2 ng/mL; n = 11). Intriguingly, patients without β-catenin mutations showed significantly higher serum LECT2 levels (54.26 ± 22.25 ng/mL; n = 46). While β-catenin activation was evident in a subset of non-mutant β-catenin HCC group with high LECT2 expression, serum LECT2 was unequivocally similar between β-catenin-active and -normal group. Further analysis showed that LECT2 levels greater than 50 ng/ml diagnosed HCC in patients irrespective of β-catenin mutations with specificity of 96.1% and positive predictive value of 97.0%. Thus, LECT2 is regulated by β-catenin in HCC in both mice and men, but serum LECT2 reflects β-catenin activity only in mice. Serum LECT2 could be a potential biomarker of HCC in patients.
Highlights
Primary liver cancer, which is predominantly hepatocellular carcinoma (HCC), is the sixth most common cancer worldwide and the third most frequent cause of cancer mortality [1]. bCatenin gene (CTNNB1) mutations are one of the major oncogenic gene alterations in HCC seen in 10–40%, while mutations affecting Axin1 are seen in around 10% of all HCCs [2]
To validate if Leukocyte cell-derived chemotaxin-2 (LECT2) expression could be induced by b-catenin activation, we used two previously generated stable human cell lines, Hep3B cells expressing wild type b-catenin (Hep3BWT) and Hep3B cells expressing serine 33 to tyrosine (S33Y)-mutated b-catenin (Hep3BS33Y), the latter showing highest b-catenin levels (Figure 1B) [17]
Using hepatocyte-specific b-catenin KO livers as well as Hep3B cells expressing stable form of b-catenin, we show that LECT2 expression was bcatenin-dependent
Summary
Primary liver cancer, which is predominantly hepatocellular carcinoma (HCC), is the sixth most common cancer worldwide and the third most frequent cause of cancer mortality [1]. bCatenin gene (CTNNB1) mutations are one of the major oncogenic gene alterations in HCC seen in 10–40%, while mutations affecting Axin are seen in around 10% of all HCCs [2]. CTNNB1 mutations are observed in exon-3 that contain phosphorylation sites essential for b-catenin degradation leading to its stabilization and enhanced expression of target genes such as glutamine synthetase (GS), axin and regucalcin [3,4,5,6]. This mutation is mutually exclusive to p53 mutation, which is the most common mutation in HCC [7,8]. LECT2 is a direct target of bCatenin and has been shown to have a role in the pathogenesis of HCC [11]. Its role is well known as chemokine-like secreted protein involved in inflammation, there is no investigation about its serum levels especially in the setting of liver tumor development
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