HCC is a heterogeneous type of tumor despite overall outcomes of poor prognosis. Depending on etiological and the accompanying pathological conditions, the survival or tumor recurrence vary considerably among HCC patients. The cellular origin of HCC may play key roles in determining the status of metastasis, intra-hepatic recurrence and patient survival. It has been debated for decades whether HCC arises exclusively by dedifferentiation of mature hepatocytes or maturation arrest of liver stem cells or progenitor cells (oval cells in rodents). Great efforts have been made in identifying bipotential hepatic progenitor cells that can differentiate into hepatocytes and cholangiocytes [43
]. Markers for hepatocytes, such as AFP and albumin, and cholangiocytes, mainly KRT7 and KRT19, are expressed in the progenitor cells. Evidence supporting progenitor cell origin of HCC is largely based on the fact that many HCCs concurrently express both hepatocytic markers and cholangiocytic markers along with stem cell markers including TACSTD1 (EpCAM), PROM1 (CD133) and THY1 (CD90) [41
]. The observation that a profound concordance of gene profiles for H-JNK1 HCC tissue with those of Lee et al.[22
] on HB-type HCC tissue and Cairo et al. [16
] on HB samples may support the hypothesis that H-JNK1 HCC is derived from the liver progenitor cells. Indeed, the genes for KRT7, KRT19, PROM1, AFP, as well as imprint genes are overexpressed in the H-JNK1 HCC tissue (Additional file 10
The HB-like features of the H-JNK1 HCC tissue are additionally supported by the recent characterization of the EpCAM positive cells in human HCC samples. By classifying 235 HCC tumor specimens with gene profiling and immunohistochemistry analyses, Yamashita et al.[12
] reported signature genes that were differentially expressed between EpCAM positive, stem cell-like HCC (HpSC-HCC) and the EpCAM negative mature hepatocyte-like HCC. A number of genes are commonly over-expressed between H-JNK1 HCC and the HpSC-HCC, such as S100P, S100A9, CCL20, PEG10, CD24, NTS, H19, UBE2C, TMED3, and KRT19 that were listed among the 30 most up-regulated genes in H-JNK1 HCC tissue (Table ). Majority of the 30 most down-regulated genes, 22 genes, were also under-expressed in HpSC-HCC tissue. Interestingly, both H-JNK1 HCC and HpSC-HCC samples showed poorer prognosis in a Kaplan-Meier survival analysis.
Most recently, Villanueva et al.[11
] reported signature genes for HCC samples with an aberrant mTOR signaling. About 40% of the 193 up-regulated genes in this type of HCC were found in the up-regulated gene list for H-JNK1 HCC samples. The coverage was increased to 86% if one relaxed the 5-fold cutoff to 1.5 fold and removed those uncharacterized genes (data not shown). For the down-regulated genes, more than 91% of the known genes were represented in the list of the down-regulated genes in H-JNK1 HCC samples. Vice versa, the genes for CCL20, CD24, GALNT7, AMIGO2, AFP, UBE2C, and SOX4 in the 30 most up-regulated genes in the H-JNK1 HCC samples were represented in the HCC samples with an aberrant activation of mTOR signaling (Table ). The similarity in gene expression pattern between H-JNK1 HCC and the HCC with abnormal mTOR signaling further supports the assumption that H-JNK1 HCCs are the tumors with a highly aggressive nature and poorer prognosis.
It is worth to mention that there appears to be a gender disparity in JNK1 activation and HCC survival probability between male and female patients (Fig. ). A strong correlation between higher JNK1 activation and lower survival probability was noted in male, but not in female patients. Such disparity may be possibly attributed to the different levels of the sex steroids between two genders. It has long been hypothesized that certain female sex hormone, esp. estrogen, is repressive for the expression of inflammatory genes, such as IL-6, leading to tumor suppression [44
]. In contrast, male sex hormone, androgen, appears to be a promoting factor for HCC [45
]. It is unclear at the present whether the higher JNK1 activity or its down-stream effect in the female HCC patients is antagonized by the sex hormone. Nevertheless, the observed disparity in JNK1 activation and HCC prognosis between male and female patients is compensatory to the human epidemiological and animal tumorigenic studies demonstrating that the HCC incidence rate in male is about 3–5 times higher than that in female [8