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CD133 and EpCAM as Biomarkers in Liver Diseases

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Biomarkers in Liver Disease

Abstract

Liver cancer is the sixth commonest malignancy and the second leading cause of cancer-associated death worldwide in 2012. Tumor recurrence after curative treatment and resistance to chemo-/radiotherapy are two important factors contributing to poor prognosis of liver cancer. Cancer stem cell (CSC) is postulated to be responsible for tumor initiation, recurrence, dissemination, and therapeutic resistance. CD133 and EpCAM are putative stemness markers of stem/progenitor cells and CSC in the liver. CD133 has unclear normal physiological function but is suggested to be in intercellular communication. Several aberrant signaling pathways are participated in CD133-positive hepatic cancers: Hedgehog, mTOR, IL-8/CXCL1, BMP/Smad, MAPK/Erk, and hypoxia-inducible factor 1-α/Notch signaling pathways. EpCAM has complex physiological functions including cell-cell adhesion, regulation of proliferation, differentiation, migration, and cell survival. Wnt/β-catenin signaling pathway is the major pathway involved in EpCAM-positive hepatic cancers. CD133 and EpCAM have several significant clinical implications in diagnosis, prognosis, and therapy of human liver cancers. Recently defined histological types of liver cancer, namely, combined hepatocellular-cholangiocarcinoma with stem cell features and hepatocellular carcinoma expressing stemness marker, require CD133, EpCAM, and/or other stemness markers to establish the diagnosis. CD133 and EpCAM are also important prognostic biomarkers. CD133 is expressed in 22.0 ± 12.1 % of hepatocellular carcinoma and associated with higher histological grade, more advanced tumor stage, and worse overall and disease-free survival. EpCAM is expressed in 32.4 ± 12.8 % of hepatocellular carcinoma and associated with younger age, higher histological grade, vascular invasion, more advanced tumor stage, and worse overall and disease-free survival. The prognostic roles of CD133 and EpCAM in intrahepatic cholangiocarcinoma and hepatoblastoma are less well defined. Although targeted therapies against CD133 and EpCAM against liver cancers are still in preclinical stages, they are promising new therapeutic research areas to combat the key player, cancer stem cell, responsible for tumor recurrence and therapeutic resistance liver cancers.

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Abbreviations

AFP:

Alpha-fetoprotein

AJCC:

American Joint Committee on Cancer

BCLC:

Barcelona clinic liver cancer

BMP:

Bone morphogenetic protein

CAM:

Cell adhesion molecule

CK19:

Cytokeratin 19

CSC:

Cancer stem cell

CXCL1:

Chemokine C-X-C motif ligand 1

DNMT:

DNA methyltransferase

EpCAM:

Epithelial cell adhesion molecule

EpEx:

EpCAM extracellular domain

EpICD:

EpCAM intracytoplasmic domain

EZH2:

Enhancer of zeste homologue 2

HCC:

Hepatocellular carcinoma

HCC-CC:

Combined hepatocellular-cholangiocarcinoma

HH:

Hedgehog

HSPC:

Hepatic stem/progenitor cell

IHCC:

Intrahepatic cholangiocarcinoma

IL-8:

Interleukin-8

Line-1:

Long interspersed nucleotide element-1

MAPK:

Mitogen-activated protein kinase

miR:

microRNA

mTOR:

Mechanistic target of rapamycin

NCAM:

Neural cell adhesion molecule

TGF:

Transforming growth factor

TP53INP1:

Tumor protein 53-induced nuclear protein 1

TROP1:

Trophoblast cell-surface antigen 1

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Chan, A.W.H., To, KF. (2015). CD133 and EpCAM as Biomarkers in Liver Diseases. In: Preedy, V. (eds) Biomarkers in Liver Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7742-2_12-1

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