Elsevier

Clinica Chimica Acta

Volume 441, 20 February 2015, Pages 156-162
Clinica Chimica Acta

Serum CD166: A novel hepatocellular carcinoma tumor marker

https://doi.org/10.1016/j.cca.2014.12.034Get rights and content

Highlights

  • We evaluated tissue and serum expression of CD166 in HCC patients.

  • CD166 is highly up-regulated in both HCC tissues and circulation.

  • Serum-CD166 is associated with impaired liver function in HCC patients.

  • Serum-CD166 distinguished patients with 100% sensitivity and 89.41% specificity.

  • Serum-CD166 may be a promising tumor marker for predicting HCC.

Abstract

Background

We evaluated the diagnostic value of serum-CD166 in patients with hepatocellular carcinoma (HCC).

Methods

Tissue-CD166 was measured using immunohistochemistry. Cell proliferation and migration were evaluated using MTT and Transwell assays, respectively. Serum-CD166 was examined using ELISA and western blotting.

Results

CD166 was up-regulated in HCC compared to those in normal liver tissues. Cell proliferation was positively correlated and cell migration was negatively correlated with endogenous CD166 expression in HCC cells. CD166 inhibition using specific shRNA decreased cell proliferation but increased cell migration. Serum CD166 concentrations were much higher in HCC than in colon cancer, hepatitis B, hepatitis C, cirrhosis, gastric cancer, breast cancer, lung cancer and healthy individuals. Serum CD166 also decreased dramatically after curative surgery. A positive correlation was found between serum CD166 and AFP (R = 0.7141, p = 0.000). Serum CD166 was also positively correlated with γ-GT, bile acid, ALT, AST, and ALP but was negatively correlated with Alb and pre-Alb. The area under the receiver operating characteristic curve for serum-CD166 was 0.9860, which was better than AFP (AUC-ROC, 0.9354) for the differentiation of HCC patients from healthy individuals, with a cut-off of 261 ng/ml (sensitivity: 100.00%, specificity: 89.41%).

Conclusion

Serum CD166 is a novel diagnostic tumor marker for HCC.

Introduction

Hepatocellular carcinoma (HCC) is a major health problem worldwide, and it is the sixth most common malignancy in the world, with more than half a million new cases annually [1]. Recently, YAP was revealed to promote HCC cell proliferation and transformation [2], [3], [4], [5], [6], [7]. YAP over-expression in HCC is significantly associated with poorer tumor differentiation [8]. In addition, clinical studies revealed that YAP was overexpressed in 62% of HCC patients, and it was an independent predictor of poor disease-free survival and overall survival in HCC [8]. These results suggest that YAP activation plays an important role in liver cancer development. However, proteins that reflect YAP function in HCC, which may be used as non-invasive diagnostic tumor markers, remain unknown. Membrane proteins are promising candidates because these proteins derive from tumor lesions, and they are easily released into the blood flow. However, HCC-specific and YAP-dependent membrane proteins have not been fully described.

Recently, we reported that membrane protein CD166 enhances YAP function to exert a carcinogenetic role in HCC, which demonstrated that CD166 is an upstream regulator of YAP. We also revealed that CD166 and YAP are closely correlated in HCC patients, which suggests an important relationship [9]. However, whether CD166 is detected in the sera of HCC patients and the use of this protein a valuable HCC tumor marker has not been identified.

Section snippets

Blood samples

All patients who were diagnosed with HCC (mean age ± SD, 54.89 ± 9.21 years; male:female ratio, 18:1), colon cancer (mean age ± SD, 63.31 ± 11.5 years; male:female ratio, 1.21:1), hepatitis B (mean age ± SD, 39.4 ± 14.5 years; male:female ratio, 1.4:1), hepatitis C (mean age ± SD, 55.7 ± 15.6 years; male:female ratio, 1.35:1), cirrhosis (mean age ± SD, 57.6 ± 14.2 years; male:female ratio, 2.73:1), gastric cancer (mean age ± SD, 54.9 ± 14.6 years; male:female ratio, 6:1), breast cancer (mean age ± SD, 49.2 ± 13.3 years; all

CD166 is highly up-regulated in HCC

We performed IHC on TMA slides that contained 24 normal liver tissue samples and 403 HCC tissue samples using an anti-CD166 antibody to investigate the up-regulation of CD166 in HCC. CD166 was highly up-regulated in HCC tissues compared to those in normal control tissue (Fig. 1). We also observed that CD166 was recruited to the cell membrane in HCC tissues, while this protein was not detected in normal liver tissues (Fig. 1). These observations suggest that membrane protein CD166 is easily

Discussion

The treatment options for liver cancer are extremely limited primarily because the pathogenetic mechanisms of this disease are not completely known. CD166 is a cell surface member of the immunoglobulin superfamily [10] that is over-expressed in several types of epithelial tumors, and it is a valuable prognostic marker of disease progression and poor survival [11], [12], [13]. Our previous study revealed that the activation of anti-apoptotic canonical NF-κB signaling greatly induced CD166

Acknowledgments

This work was wholly or partially supported by the National Natural Science Foundation of China (Grants 81201884, 81201363 and 81301689), Shanghai Committee of Science and Technology Yangfan Project (Grant 14YF1412300, to Jiayi Wang), Young College Teachers' Training Scheme of Shanghai (ZZjdyx13007, to Yongxia Qiao) and the Tongji University Outstanding Youth Training Project (1501219080, to Jiayi Wang).

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1

These two authors contributed equally to this study.

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