No abstract

SUMMARY BackgroundModerate alcohol consumption may have certain beneficial effects against non-alcoholic fatty liver disease, which is associated with metabolic syndrome.

HARUSHIGE NAKATSUKASA, KOUZOU ASHIDA, TOSHIHIRO HIGASHI, SOUHEI OHGUCHI, SO TSUBOI, NAOKI HINO, KAZUHIRO NOUSO, YOSHIAKI URABE, NOBUYUKI KINUGASA, KEIGO YOSHIDA, SHUJI UEMATSU, MASAHIKO ISHIZAKI, YOSHIYUKI KOBAYASHI, AND TAKAO TSUJI Hepatocellular carcinoma (HCC) is one of the most prevaThe cellular distribution of tissue inhibitor of melent malignancies in Japan and China, and frequently occurs talloproteinases (TIMP)-1, and TIMP-2 was studied by in hepatitis B or C virus-related chronic hepatitis or cirrhousing in situ hybridization in surgically removed husis. In particular, cirrhosis has been regarded as a high-risk man hepatocellular carcinomas (HCCs) and cholandisease state for developing HCCs. A unique feature of HCC giocellular carcinomas (CCCs). The purpose of this development is the occurrence of the tumor in fibrotic or cirstudy was to characterize the potential involvement rhotic liver that contains abundant extracellular matrices of TIMPs in the development of HCCs and CCCs. All (ECMs). Therefore, the capacity of HCC to degrade the surHCCs and CCCs expressed TIMPs. The distribution rounding ECMs may be an important trait for growth, invaof transcripts for TIMPs in the tumors was mostly sion, and metastasis. homogeneous. Expression of TIMPs in cancer cellsThe characteristic features of malignant tumors are the was more intense than that in the surrounding noninvasion to cross tissue boundaries and the metastasis to cancerous liver (either, cirrhosis, chronic hepatitis, distant organs. Many steps that occur during cancer invasion or normal), and expression of TIMP-1 was stronger and metastasis require specific interactions between maligthan that of TIMP-2. Expression of TIMPs varied nant cells and the ECMs, 1 particularly in regard to HCC and among HCC nodules, but there was no obvious associcirrhotic liver. Multiple humoral factors are involved in this ation between the expression level of TIMPs and difprocess: matrix metalloproteinases (MMPs), tissue inhibitor ferentiation stages or invasiveness of the HCCs. Tranof metalloproteinases (TIMPs), and various cytokines. An imscripts for TIMPs were clearly demonstrated in the balance between TIMPs and MMPs may be an important metastatic HCC nodules in the lung. Expression of factor in tumor invasion and metastasis. TIMP-1 in CCC was strong, and small nodules of CCC Three members of the TIMP family have been described. 2 were recognized in the liver. ImmunohistochemicalEach TIMP is the product of a separate gene. TIMP-1 is a 28-study for TIMP-1 revealed a consistent staining of the kd glycoprotein, whereas TIMP-2 is a 21-kd nonglycosylated TIMP-1 protein with the transcripts. In the perituprotein. Between TIMP-1 and TIMP-2, there is 37% amino moral histologically normal liver, which was not inacid identity and 65.6% overall homology. 3 TIMP-3 has been fected with either hepatitis B or C virus, expression identified as a 21-kd protein and shares an amino acid seof TIMP-1 was found in various cell types, but that of quence homology of 40% with TIMP-1 and 45%...

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies, and the treatment has been extremely difficult, although several treatment modalities are available, including liver transplantation. 1 An approach involving retrovirus-2,3 or adenovirus-4,5 mediated gene therapy for the treatment of HCCs has recently been described, attempting differential expression of particular genes (e.g., suicide genes such as herpes simplex virus/thymidine kinase gene) controlled by transcriptional regulatory sequence (TRS) of liverspecific genes such as ␣-fetoprotein (AFP) or albumin. These ideas are based on the fact that AFP, normally expressed only in the fetus, is frequently reactivated in many cases of HCC, and that, in the case of albumin, retrovirus is only integrated into the host genome of the cells that are in cell cycle.Of particular importance in the genetic treatment of malignancies is that transduced genes must be expressed tumor-specifically in response to particular transcriptional signals. For targeting genes being expressed in HCC cells, the choice of the TRS is the first key step, and either AFP-or albumin-TRS has been frequently chosen for this purpose. [2][3][4][5][6][7][8] In this regard, it is necessary to have the knowledge as to how and up to what differentiation stages of HCC the AFP and/or albumin genes are expressed.AFP is a plasma protein produced by fetal liver, yolk sac, and mostly by HCCs in adults. 9 The expression of the AFP gene has been studied in three HCC samples by in situ hybridization, and it has shown even hybridization signals in the majority of HCC cells. 10 Albumin is one of the major plasma proteins and is synthesized mostly in hepatocytes. Albumin gene expression can be used as a diagnostic tool in the differential diagnosis of HCC from cholangiocellular carcinomas or other metastatic liver cancers. 11,12 Thus, the expressions of AFP and albumin have been used as specific markers of HCC cells and the cells of hepatocellular lineage, respectively.Although the needs of specific TRSs for gene therapy are expanding, the lack of knowledge on cellular distribution of transcripts for AFP or albumin genes in human HCCs makes the accurate targeting difficult, and the validity of using these Abbreviations: AFP, ␣-fetoprotein; DIG, digoxigenin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HCC, hepatocellular carcinoma; SSC, standard saline citrate; TRS, transcriptional regulatory sequence.

Minimal alcohol consumption appears to have protective effects against nonalcoholic FL disease in women, although an increase in the amount of alcohol consumed appears to nullify the protective effect.