Immunohistochemical Localization of Transforming Growth Factor Alpha in Chemically Induced Rat Hepatocellular Carcinomas with Reference to Differentiation and Proliferation

Kobayashi, Kiyoshi; Kusakabe, Manami; Okada, Mitsuru; Sakairi, Tetsuya; Goto, Kazuhiro; Tsuchiya, Takayuki; Sugimoto, Jiro; Sano, Fumiko; Mutai, Mamoru

doi:10.1177/019262330002800505

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…These results are in line with the previous report describing increased TGF-alpha mRNA expression in proliferating hepatocytes [8] and neoplastic rat liver lesions [5,6,10].…”

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confidence: 93%

“…TGF-alpha tended to be positive and localized in the nucleus in highly proliferating areas zones 1 and 2, with peaks at 24-36 hr after PH. Kobayashi et al [6] demonstrated that expression of TGFalpha and its immunohistochemical localization was linked to cell proliferation in chemically induced rat hepatocellular carcinoma. Likewise, we recently reported TGF-alpha expression in the nucleus to be associated with malignancy and cell proliferation in chemically induced mouse hepatocellular tumors [10].…”

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confidence: 99%

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Immunohistochemical Localization of Transforming Growth Factor Alpha in Regenerating Rat Liver.

Okada¹,

Sakairi²,

Kusakabe³

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. Immunohistochemical localization of TGF-alpha and cell proliferation kinetics during liver regeneration after two-thirds partial hepatectomy (PH) were investigated. Twenty-four to 72 hr after PH, appreciable increase in the number of TGF-alpha-positive hepatocytes was observed in zones 1 and 2. At the peak at 36 hr, almost all positive cells were stained in their nuclei. Considerable increase in the BrdU labeling index was observed 24-36 hr after PH with a peak at 24 hr in zones 1 and 2. These results indicated an ass ociation between TGF-alpha expression and hepatocyte regeneration. It is suggested that immunohistochemical localization of TGF-alpha may be a useful marker of cell proliferation activity in rat liver. KEY WORDS: immunohistochemistry, liver, TGF-alpha.J. Vet. Med. Sci. 64(11): 1045-1048, 2002 Transforming growth factor alpha (TGF-alpha), a member of the epidermal growth factor (EGF) family, is a 50 amino acid polypeptide [12]. It shares about 30% structural similarity with EGF and binds to the EGF receptor [3]. Several reports have suggested TGF-alpha to play important roles during hepatic development and regeneration as a potent stimulator of hepatocyte [2,8]. However, there are few reports describing TGF-alpha expression and its intracellular localization in relation to cell proliferation in the liver.In the present immunohistochemical study, we investigated localization of TGF-alpha in different zones of the liver after partial hepatectomy (PH), and analyzed its links with cell kinetics.Male Fischer 344 rats weighing around 200 g were purchased from Charles River Japan (Yokohama, Japan) and acclimatized for 1 week in an air-conditioned animal room at 22°C with a 12-hr light/dark cycle. They were given Oriental MF diet (Oriental Yeast Co., Tokyo, Japan) and tap water ad libitum.All animals underwent two-thirds partial hepatectomy under light ether anesthesia. For the cell proliferation kinetic study, the rats were given an intraperitoneal injection of BrdU (100 mg/kg i.p.) (Sigma Chemical Co., St. Louis, MO) 1 hr before sacrifice at 6, 12, 24, 36, 48 or 72 hr after PH under ether anesthesia. Number of rats in each group was 9.Livers were excised, fixed in 10% neutral-buffered formalin, embedded in paraffin, cut into 3-4 µm sections and examined immunohistochemically using anti-BrdU (Dako Japan Co., Kyoto) and anti-TGF-alpha (Oncogene Research Products, Cambridge, MA, U.S.A.) antibodies by avidinbiotin-peroxidase complex method. For quantitative comparisons, 1,000 nuclei were counted for each zone of the liver, and the percentages of BrdU-positive nuclei at different time points after PH were calculated. Similarly, 1,000 cells were counted for each zone and the percentages of TGF-alpha-positive hepatocytes with staining of their nuclei or cytoplasm were calculated.Representative immunohistochemical localization of TGF-alpha and BrdU labeling in each zone of the liver are illustrated in Fig. 1. Data for the numbers of hepatocytes with TGF-alpha-positive nuclei or cytoplasm are summarized ...

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“…These results are in line with the previous report describing increased TGF-alpha mRNA expression in proliferating hepatocytes [8] and neoplastic rat liver lesions [5,6,10].…”

supporting

confidence: 93%

mentioning

confidence: 99%

Immunohistochemical Localization of Transforming Growth Factor Alpha in Regenerating Rat Liver.

Okada¹,

Sakairi²,

Kusakabe³

et al. 2002

The Journal of Veterinary Medical Science

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“…Several studies have pointed to TGF-a overexpression playing an important role in hepatocarcinogenesis (12,25,29). Recently, we reported linkages to cell proliferation in chemically induced rat HCCs (16). From the literature, as well as the present study, TGF-a expression may be associated with cell proliferation activity of hepatocellular tumor cells.…”

Section: Discussionsupporting

confidence: 71%

Greater Expression of Transforming Growth Factor α and Proliferating Cell Nuclear Antigen Staining in Mouse Hepatoblastomas Than Hepatocellular Carcinomas Induced by a Diethylnitrosamine-Sodium Phenobarbital Regimen

Sakairi¹,

Kobayashi²,

Goto³

et al. 2001

Toxicol Pathol

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Transforming growth factor a (TGF-a) is a potent stimulator of normal hepatocyte proliferation, considered to have relationship to the liver regeneration or carcinogenesis . In this study, we investigated immunohistochemicall y the association between expression of TGF-a and cell proliferation activity in mouse hepatoblastoma s (HBs) and hepatocellular carcinomas (HCCs) induced in B6C3F1 mice by diethylnitrosamin e and sodium phenobarbital . The TGF-a-positive rate in HBs (29.2%) was signi cantly higher than that in HCCs (12.7%). Likewise, the proliferating cell nuclear antigen-positive rate (22.2%) was higher than the HCC value (14.5%). On the individual data for both TGF-a and PCNA, most of the HBs showed higher positive rates than HCCs. In HBs, TGF-a was localized only in the nuclei, whereas some HCC cells stained positive both in their nuclei and cytoplasm (0.6%). These results suggest expression of TGF-a and its localization might be linked to cell proliferation and play a role in malignant progression of mouse HBs.

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“…Recently, we and others observed positive immunostaining of TGF-␣ in the nucleus of hepatocytes. [13][14][15][16] Nuclear location has been reported for many other polypeptide ligands (e.g., EGF, insulin, platelet-derived growth factor, nerve growth factor, parathyroid hormone-related protein, prolactin, interleukin 1, somatostatin, and fibroblast growth factor 1 and 2). Sometimes polypeptide ligands seem to colocalize with their respective receptors in the nucleus [17][18][19] ; the nuclear location of some of these growth factors coincided with DNA replication, as documented best for fibroblast growth factor 2.…”

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A novel mechanism for mitogenic signaling via pro-transforming growth factor α within hepatocyte nuclei

et al. 2002

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Immunohistochemical Localization of Transforming Growth Factor Alpha in Chemically Induced Rat Hepatocellular Carcinomas with Reference to Differentiation and Proliferation

Abstract: Hepatocellular carcinomas (HCCs) were induced in male Fischer 344 rats with dietary 3'-methyl-4-(dimethylamino)-azobenzene treatment and were classified into solid, glandular (well-or

Cited by 7 publications

References 23 publications

Immunohistochemical Localization of Transforming Growth Factor Alpha in Regenerating Rat Liver.

Immunohistochemical Localization of Transforming Growth Factor Alpha in Regenerating Rat Liver.

Greater Expression of Transforming Growth Factor α and Proliferating Cell Nuclear Antigen Staining in Mouse Hepatoblastomas Than Hepatocellular Carcinomas Induced by a Diethylnitrosamine-Sodium Phenobarbital Regimen

A novel mechanism for mitogenic signaling via pro-transforming growth factor α within hepatocyte nuclei

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