There has been a long-standing interest in the discovery of signature genes for hepatocellular carcinoma (HCC). Concern has been expressed about the inconsistency of the identified signature genes reported by different laboratories. The discrepancy in HCC signature genes could stem from the differences in pathological features of the HCC samples used in gene profiling and the algorithms for data analysis. Benefiting from the improvement and standardization of the DNA microarray technology, several groups in recent years reported reproducible HCC signature gene sets that are able to predict tumor cell ongmating, intrahepatic recurrence, metastasis, and patient survival possibility. Our research group and Nishino et at. recently reported signature genes for HCC with high c-Jun N-terminal kinase 1 (JNK1) activation and intrahepatic cholangiocarcinoma (ICC), respectively. In this study, we first determined changes of gene expression between HCC tissues and the matched distal nontumor liver tissues using Affymetrix HG-U133 plus 2 microarray (Affymetrix, Inc., Santa Clara, California, USA) followed by false discovery rate correction. The gene expression pattern associated with the status of JNK1 activation was then examined by comparing the genes in HCC samples with high JNK1 activation to the HCC samples with low JNK1 activation. The signature genes for ICC were identified through a serial analysis of gene expression using eDNA libraries from ICC and HCC by Nishino et at.. They found that genes for KRT7, KRT19, S100A6, IGFBP5, SPP1, CD24, and BGN, etc. are upregulated in ICC relative to HCC . By comparing the data from Nishino et at. and our high JNK1 HCC gene profiling, a significant agreement between those ICC signature genes and the genes associated with the JNK1 activation status in HCC was noted. For the genes that were upregulated in ICC, including CLDN4, IGFBP5, and 19 genes listed of Nishino's report, 17 out of 21 genes are commonly presented among the increased expressed genes in the HCC with high JNK1 activation. Only four out of 21 genes, including IGFBP5, CITED4, SCGN, and C0L4A1, were downregulated in the HCC with high JNK1 activation. Intriguingly, 18 genes that showed the greatest degree of downregulation in ICC were also significantly downregulated in the HCC samples with high JNK1 activation, except GSTA1. There were obvious differences between this study  and the experiment of Nishino et at. in the selection of tumor type and method for gene profiling. The high similarity of the gene expression pattern between ICC and the HCC with high JNK1 activation, thus, indicates potential common origination of both high JNK1 HCC and ICC from the bipotential hepatic progenitor cells. The hepatic progenitor cells can differentiate into hepatocytes and cholangiocytes, which usually express both hepatocyte markers, such as AFP and albumin, and cholangiocyte markers, mainly KRT7 and KRT19. Although other markers for hepatic progenitor cells were not mentioned in the study of Nishino et at., the genes for TACSTD1 (EpCAM), PORM1 (CD133), THY1 (CD90), and those imprinted genes were overexpressed in high JNK HCC. In addition, SPP1 and CD24, which are highly expressed in both high JNK1 HCC and ICC, had been previously shown to be expressed in certain types of stem cell or progenitor Letters to the Editor 1321 cells, such as hemopoietic stem cells and adipocyte progenitors. Thus, all of these notions strongly support the hypothesis that high JNK1 HCC and I CC are derived from the same source of the cells in the liver, the bipotential progenitor cells or stem cells. Accordingly, the finding revealing similarity in gene signature between high JNK1 HCC and ICC will open up a new possibility for the targeted therapy of liver malignancy. Compared with the wide spectrum of genes that are overexpressed in HCC or ICC, targeting JNK1 is easily manageable and clinically feasible.
Dr Fei Chen, PhD, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505