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We previously produced mice with human hepatocyte (h-hep) chimeric livers by transplanting h-heps into albumin enhancer/promoter-driven urokinase-type plasminogen activator-transgenic severe combined immunodeficient (SCID) mice with liver disease. The chimeric livers were constructed with h-heps, mouse hepatocytes, and mouse hepatic sinusoidal cells (m-HSCs). Here, we investigated the morphological features of the chimeric livers and the h-hep gene expression profiles in the xenogeneic animal body. To do so, we performed immunohistochemistry, morphometric analyses, and electron microscopic observations on chimeric mouse livers, and used microarray analyses to compare gene expression patterns in hepatocytes derived from chimeric mouse hepatocytes (c-heps) and h-heps. Morphometric analysis revealed that the ratio of hepatocytes to m-HSCs in the chimeric mouse livers were twofold higher than those in the SCID mouse livers, corresponding to twin-cell plates in the chimeric mouse liver. The h-heps in the chimeric mouse did not show hypoxia even in the twin-cell plate structure, probably because of low oxygen consumption by the h-heps relative to the mouse hepatocytes (m-heps). Immunohistochemical and electron microscopic examinations revealed that the sinusoids in the chimeric mouse livers were normally constructed with h-heps and m-HSCs. However, a number of microvilli projected into the intercellular clefts on the lateral aspects of the hepatocytes, features typical of a growth phase. Microarray profiles indicated that ∼82% of 16 605 probes were within a twofold range difference between h-heps and c-heps. Cluster and principal component analyses showed that the gene expression patterns of c-heps were extremely similar to those of h-heps. In conclusion, the chimeric mouse livers were normally reconstructed with h-heps and m-HSCs, and expressed most human genes at levels similar to those in human livers, although the chimeric livers showed morphological characteristics typical of growth.

Because importin-α1 might be closely associated with HCC progression, further analysis should be pursued to evaluate it as a novel prognostic target.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies because of recurrence and/or metastasis even after curative resection. Emerging evidence suggests that tumor metastasis and recurrence might be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). Previous investigations have revealed that glioma and breast CSCs exhibit intrinsically low proteasome activity and that breast CSCs also reportedly contain a lower reactive oxygen species (ROS) level than corresponding nontumorigenic cells. Here we visualized two stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using two-color fluorescence activated cell sorting to isolate cells with stem cell features. These cells were then analyzed for their division behavior in normoxia and hypoxia, expression of stem cell markers, tumorigenicity, metastatic potential, specific gene expression signatures, and their clinical implications. A visualized small subpopulation of HCC cells demonstrated asymmetric divisions. Their remarkable tumorigenicity in nonobese diabetic/severe combined immunodeficient mice suggested the cancer initiation potential of these HCC CSCs. Comprehensive gene expression analysis revealed that chemokinerelated genes were up-regulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potential by way of recruitment of macrophages in vivo. In patients who undergo curative operation for HCC, the CSC-specific gene signature in the liver microenvironment significantly correlates with recurrence. Conclusion: Based on these findings, the stem cell feature monitoring system proposed here is a promising tool to analyze the in vivo significance of CSC microenvironments in human HCCs. (HEPATOLOGY 2013;58:218-228) H epatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer death worldwide. 1 The primary curative treatment for HCC is surgical resection; however, even after curative resection patient prognosis remains poor because of frequent recurrence and/or metastasis. 2,3 Because cancer stem cells (CSCs) possess self-renewal capacity, multilineage potency, and increased tumorigenicity, it has been hypothesized that CSCs exist as a small population within the bulk tumors and play a critical role in cancer progression, metastasis, and recurrence. 4 Various tools have been reported for identification of the CSC population, including the cell surface markers CD44, CD133, CD90, and ESA/EpCAM. [5][6][7][8] In addition, specific stemness properties based on stem cell biology of their Abbreviations: CSC, cancer stem cells; FDR, false discovery rate; GSEA, gene set enrichment analysis; HCC, hepatocellular carcinoma; NOD/SCID, nonobese diabetic / severe combined immunodeficient; ODC, ornithine decarboxylase; ROS, reactive oxygen species.From the

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Thin films of AgInO2 were prepared to find a transparent and n-type conducting oxide with a delafossite structure. This is a candidate material for fabricating a pn junction with the recently found p type conducting and transparent CuAlO2 delafossite. Nondoped and 5% Sn-doped thin films were deposited on a silica glass substrate by radio-frequency sputtering. The crystalline phase in the films was identified to be the delafossite structure by x-ray diffraction and chemical composition was confirmed to be an Ag/In ratio=1.00/0.97 by inductively coupled plasma emission spectroscopy. The optical band gap was estimated from absorption spectra to be ∼4.4 eV, and the thin films were transparent up to near ultraviolet region. Electrical conductivities of the nondoped and 5% Sn-doped AgInO2 films at room temperature were 1×10−5 and 6×100 S cm−1, respectively. Measurements of Hall voltage and Seebeck coefficient (−50 μV K−1) suggested the conduction in the Sn-doped film to be n type. Carrier concentration and Hall mobility in the doped film were 2.7×1019 cm−3 and 0.47 cm2 V−1 s−1, respectively.

Our studies suggest that the distinct signature of gene expression is closely related to morphological progression in HCC. Especially, EpCAM might play a critical role in the aggressiveness of CM-type HCC.