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Role of leukocyte cell-derived chemotaxin 2 as a biomarker in hepatocellular carcinoma.

Okabe H, Delgado E, Lee JM, Yang J, Kinoshita H, Hayashi H, Tsung A, Behari J, Beppu T, Baba H, Monga SP - PLoS ONE (2014)

Bottom Line: Leukocyte cell-derived chemotaxin-2 (LECT2) expression was decreased in KO livers.Hep3BS33Y expressed and secreted more LECT2 in media as compared to Hep3BWT.Intriguingly, patients without β-catenin mutations showed significantly higher serum LECT2 levels (54.26 ± 22.25 ng/mL; n = 46).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.

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.

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The role of serum LECT2 level as a diagnostic biomarker in HCC.A. Serum LECT2 levels in all HCC patients as compared to patients with chronic liver fibrosis (CH/LC), and healthy volunteer (HV) as assessed by ELISA. (*p<0.01). B. ROC analysis for the utility of LECT2 as a diagnostic marker of HCC with AUC = 0.82. C. Fisher's Exact test shows that based on the cut-off value of serum LECT2 level at 50 ng/mL, sensitivity, specificity, positive predictive value, negative predictive value for the diagnosis of HCC were 59.3%, 96.1%, 97.0%, and 53.2%, respectively.
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pone-0098817-g004: The role of serum LECT2 level as a diagnostic biomarker in HCC.A. Serum LECT2 levels in all HCC patients as compared to patients with chronic liver fibrosis (CH/LC), and healthy volunteer (HV) as assessed by ELISA. (*p<0.01). B. ROC analysis for the utility of LECT2 as a diagnostic marker of HCC with AUC = 0.82. C. Fisher's Exact test shows that based on the cut-off value of serum LECT2 level at 50 ng/mL, sensitivity, specificity, positive predictive value, negative predictive value for the diagnosis of HCC were 59.3%, 96.1%, 97.0%, and 53.2%, respectively.

Mentions: Next, due to heterogeneity in HCC, we investigated if serum LECT2 levels may be a biomarker of HCC irrespective of a precise molecular basis. Intriguingly, Tukey-Kramer analysis revealed a significant difference in serum LECT2 levels in HCC patients when compared to chronic liver disease patients with cirrhosis (p = 0.0017) and healthy volunteers (p = 0.0078) (Figure 4A). Area Under the Curve (AUC) of 0.82 also highlights its value as a general biomarker of HCC (Figure 4B). A sub analysis was done next with LECT2 serum value cut-off at 50 ng/ml. Fisher Exact test showed significant utility of using >50 ng/ml of serum LECT2 as an indicator of HCC (two tailed p value< 0.0001) (Figure 4C). Serum LECT2 levels of greater than 50 ng/ml were able to detect HCC with a sensitivity of 59.3%, specificity of 96.1%, positive predictive value of 97.0% and negative predictive value of 53.2%.


Role of leukocyte cell-derived chemotaxin 2 as a biomarker in hepatocellular carcinoma.

Okabe H, Delgado E, Lee JM, Yang J, Kinoshita H, Hayashi H, Tsung A, Behari J, Beppu T, Baba H, Monga SP - PLoS ONE (2014)

The role of serum LECT2 level as a diagnostic biomarker in HCC.A. Serum LECT2 levels in all HCC patients as compared to patients with chronic liver fibrosis (CH/LC), and healthy volunteer (HV) as assessed by ELISA. (*p<0.01). B. ROC analysis for the utility of LECT2 as a diagnostic marker of HCC with AUC = 0.82. C. Fisher's Exact test shows that based on the cut-off value of serum LECT2 level at 50 ng/mL, sensitivity, specificity, positive predictive value, negative predictive value for the diagnosis of HCC were 59.3%, 96.1%, 97.0%, and 53.2%, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043833&req=5

pone-0098817-g004: The role of serum LECT2 level as a diagnostic biomarker in HCC.A. Serum LECT2 levels in all HCC patients as compared to patients with chronic liver fibrosis (CH/LC), and healthy volunteer (HV) as assessed by ELISA. (*p<0.01). B. ROC analysis for the utility of LECT2 as a diagnostic marker of HCC with AUC = 0.82. C. Fisher's Exact test shows that based on the cut-off value of serum LECT2 level at 50 ng/mL, sensitivity, specificity, positive predictive value, negative predictive value for the diagnosis of HCC were 59.3%, 96.1%, 97.0%, and 53.2%, respectively.
Mentions: Next, due to heterogeneity in HCC, we investigated if serum LECT2 levels may be a biomarker of HCC irrespective of a precise molecular basis. Intriguingly, Tukey-Kramer analysis revealed a significant difference in serum LECT2 levels in HCC patients when compared to chronic liver disease patients with cirrhosis (p = 0.0017) and healthy volunteers (p = 0.0078) (Figure 4A). Area Under the Curve (AUC) of 0.82 also highlights its value as a general biomarker of HCC (Figure 4B). A sub analysis was done next with LECT2 serum value cut-off at 50 ng/ml. Fisher Exact test showed significant utility of using >50 ng/ml of serum LECT2 as an indicator of HCC (two tailed p value< 0.0001) (Figure 4C). Serum LECT2 levels of greater than 50 ng/ml were able to detect HCC with a sensitivity of 59.3%, specificity of 96.1%, positive predictive value of 97.0% and negative predictive value of 53.2%.

Bottom Line: Leukocyte cell-derived chemotaxin-2 (LECT2) expression was decreased in KO livers.Hep3BS33Y expressed and secreted more LECT2 in media as compared to Hep3BWT.Intriguingly, patients without β-catenin mutations showed significantly higher serum LECT2 levels (54.26 ± 22.25 ng/mL; n = 46).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.

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.

Show MeSH
Related in: MedlinePlus