EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma.
The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways.
Yamashita
Taro
T
Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4258, USA.
Forgues
Marshonna
M
Wang
Wei
W
Kim
Jin Woo
JW
Ye
Qinghai
Q
Jia
Huliang
H
Budhu
Anuradha
A
Zanetti
Krista A
KA
Chen
Yidong
Y
Qin
Lun-Xiu
LX
Tang
Zhao-You
ZY
Wang
Xin Wei
XW
D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D000071858:Epithelial Cell Adhesion Molecule; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008113:Liver Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000378:metabolism*; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015398:Signal Transduction; D000509:alpha-Fetoproteins / Q000096:biosynthesis*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D000509:alpha-Fetoproteins