Biomedical subjects

Masato Nakamura

Publications and source records attributed to Masato Nakamura.

At least 19 recordsLinked to original sources

PubMed2007

Molecular effects of sodium hyaluronate on the healing of avian supracoracoid tendon tear: according to in situ hybridization and real-time polymerase chain reaction.

Hyluronic acid (HA) on tissue healing has been controversial. We examined the molecular pharmacology of HA injection at the suture site in an acute model of supracoracoid tendon laceration using chickens, an injury of a nonweight-bearing joint considered similar to the human shoulder. Expression of mRNAs encoding alpha I (I) and alphaI (III) procollagens was localized using in situ hybridization (ISH). Intensities of mRNA expression for alpha I (I) and alpha I (III) procollagens, transforming growth factor-beta1 (TGF- beta1), basic fibroblast growth factor (bFGF), and insulin-like growth factor (IGF) were determined by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Histologically, chickens with HA injection (HA group) showed early restoration of continuity at the laceration site than saline-injection controls (saline-injection group). By ISH, the expression rate of cells at the lesion site that contained alpha I (I) and alpha I (III) procollagen mRNAs were somewhat higher in the HA group than in the saline-injection group. By RT-PCR, the HA- and saline-injection groups showed no significant difference in expression of alpha I (I) and alpha I (III) procollagen mRNA between weeks 1 and 6. The saline -injection group exhibited significant decrease in TGF-beta1 expression between weeks 1 and 3, and in bFGF expression between weeks 1 and 2; however, the HA group showed no such decrease. As for IGF, no difference was appreciable in both groups between weeks 1 and 6. A single injection of HA could cause earlier restoration of continuity at the lacerated site of the supracoracoid tendon.

Adjuvants, Immunologic↗

PubMed2007

Impact of cutting balloon angioplasty (CBA) prior to bare metal stenting on restenosis.

BACKGROUND: While stent restenosis and late thrombosis still occur even with drug-eluting-stents (DES), there remains a need to explore other strategies for preventing restenosis. METHODS AND RESULTS: Five hundred and twenty-one patients were randomized: 260 to cutting-balloon angioplasty (CBA) before bare-metal stent (CBA-BMS) and 261 to balloon-angioplasty (BA) before BMS (BA-BMS). Intravascular ultrasound (IVUS)-guided procedures were performed in 279 (54%) patients and angiographic guidance was used in the remainder. Minimal lumen diameter was significantly greater in CBA-BMS than BA-BMS (2.65+/-0.40 mm vs 2.52+/-0.4 mm, p<0.01) and % diameter stenosis (%DS)-post was less in CBA-BMS than BA-BMS (14.0+/-5.9% vs 16.3+/-6.8%, p<0.01). %DS-follow-up was subsequently less in CBA-BMS than BA-BMS (32.4+/-15.1% vs 35.4+/-15.3%, p<0.05) associated with lower rates of restenosis in CBA-BMS than BA-BMS (11.8% vs 19.6%, p<0.05) and less target lesion revascularization (TLR) in CBA-BMS than BA-BMS (9.6% vs 15.3%, p<0.05). Patients were divided into 4 groups based on the device used before stenting and IVUS use (IVUS-CBA-BMS: 137 patients; Angio-CBA-BMS: 123; IVUS-BA-BMS: 142; and Angio-BA-BMS: 119). At follow-up IVUS-CBA-BMS had a significantly lower restenosis rate (6.6%) than Angio-CBA-BMS (17.9%), IVUS-BA-BMS (19.8%) and Angio-BA-BMS (18.2%, p<0.05). CONCLUSIONS: Restenosis and TLR were significantly lower in CBA-BMS than BA-BMS. This favorable outcome was achieved because of the lower restenosis rate conferred by the IVUS-guided-CBA-BMS strategy (6.6%). The restenosis rates obtained with this strategy were comparable to those achieved with DES.

Aged↗

PubMed2007

Stronger growth-inhibitory effect of interferon (IFN)-beta compared to IFN-alpha is mediated by IFN signaling pathway in hepatocellular carcinoma cells.

Interferon (IFN) is a promising drug for prevention and treatment of hepatocellular carcinoma (HCC) in combination with chemotherapeutic agents. We previously reported that the spectra of antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha in HCC cells. However, the mechanism of the diverse antitumor effects of the IFNs is not understood yet. We studied the expression of IFN alpha receptor 2 (IFNAR2), STATs, and IFN-alpha, IFN-beta's growth-inhibitory effect, signal transduction and binding to IFNAR2 on three HCC cell lines and a tumor xenografted mouse model (12 animals/group). From the results, IFN-beta showed a significantly stronger growth-inhibitory effect than IFN-alpha on the HuH7 cell line (expressing low IFNAR2), however it was similarly high on PLC/PRF/5 and weak on HLE. In the nude mouse tumor xenograft model, IFN-beta injection significantly suppressed tumor volume relative to vehicle injection, while IFN-alpha showed weaker growth-inhibition. IFN signal transduction (phosphorylated-STAT1, 3) induced by IFN-beta was higher than that by IFN-alpha in HuH7 and tumor xenografts. Pretreatment of hepatoma cells with anti-IFNAR2 antibody blocked the IFN signaling, more for IFN-alpha. IFN-alpha's antiproliferative effect was reduced by the antibody in lower concentrations compared to that of IFN-beta. Taken together, the HCC cells that express low IFNAR2 and are resistant to IFN-alpha were sensitive to the growth-inhibitory effect of IFN-beta, which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-alpha.

Antineoplastic Agents↗

PubMed2006

A case of hepatocellular carcinoma with multiple lung, spleen, and remnant liver metastasis successfully treated by combination chemotherapy with the novel oral DPD-inhibiting chemotherapeutic drug S-1 and interferon-alpha.

A 54-year-old man was admitted Osaka University Hospital for hepatocellular carcinoma (HCC) with portal vein thrombus and multiple intrahepatic metastases that extended to the bilateral lobes of the liver. He underwent multimodal therapy, including extended left lobectomy followed by intra-arterial 5-fluorourcil (5-FU) infusion chemotherapy combined with subcutaneous interferon-alpha (IFN-alpha) to treat the lesions in the residual liver. Seven months after the initial resection, recurrent tumors in the spleen, lung, and residual liver were detected by follow-up examination. We started a new regimen of per oral administration of S-1 and subcutaneous IFN-alpha injection, because the combined therapy with intra-arterial 5-FU infusion was not considered effective for distant metastases. After two cycles of S-1 and IFN-alpha, the metastatic tumor in the spleen and the recurrence in the residual liver had disappeared, and the diagnosis was complete remission with no adverse effect; the pulmonary metastasis showed a partial response, and was finally resected. This patient is still alive with no recurrence 32 months after initial hepatic resection. This outcome suggests that combination therapy with S-1 and IFN-alpha may be a promising treatment modality against advanced HCC with distant metastasis.

Administration, Oral↗

PubMed2006

A change in the pattern of vasospasm after stenting in a patient with vasospastic angina.

We report an unusual case of a male patient with vasospastic angina in whom the pattern of coronary artery spasm changed after coronary stenting. The patient was admitted to our hospital with an acute coronary syndrome. Coronary angiography revealed an intermediate grade stenosis in the right coronary artery, and focal coronary spasm was provoked by intracoronary acetylcholine. A diagnosis of vasospastic angina was made, and the patient was followed medically. He subsequently was readmitted with refractory vasospastic angina and underwent coronary stenting. He was pain-free after stent implantation. Repeat angiography 6 months later showed no restenosis in the stented segment; however, coronary spasm was provoked in all areas except the stented segment by intracoronary acetylcholine injection.

Acetylcholine↗

PubMed2006

Role of the Fas/FasL pathway in combination therapy with interferon-alpha and fluorouracil against hepatocellular carcinoma in vitro.

BACKGROUND/AIMS: Several studies have reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the mechanism underlying the clinical anti-tumor effects of this treatment is not well understood. The aim of this study was to determine the role of Fas/FasL signaling in the anti-tumor effect of this combination therapy. METHODS AND RESULTS: We used six human hepatoma cell lines, three of which are known Fas-expressing cells. Growth of Fas-positive hepatoma cell lines was inhibited by an agonistic anti-Fas antibody in a dose-dependent manner, and these effects were enhanced by IFNalpha or 5-FU alone, but even more so by combination therapy using both agents. Annexin-V assay implicated apoptosis as the main mechanism underlying these growth inhibitory effects, although changes in Fas expression regulated by IFNalpha and/or 5-FU did not correlate with increased apoptosis. Caspase-3 activation was exclusively increased by IFNalpha/5-FU combination treatment, which was compatible with enhancement of the synergistic apoptotic effect, and other caspases and apoptotic factors (FLIP, BCL-xl, and Bax) were also regulated by IFNalpha/5-FU. 51Cr-release assay revealed that pretreatment with IFN activated cytotoxicity of peripheral blood mononuclear cells (PBMCs) against HCC cells. The largest interaction was observed when both PBMC and HCC cells were pretreated with the combination of IFNalpha/5-FU. These cytotoxicities were markedly inhibited by a neutralizing anti-Fas antibody. CONCLUSIONS: Our results indicated that IFNalpha/5-FU combination treatment enhances the induction of apoptosis and the cytotoxic effect of PBMCs via the Fas/FasL pathway. The Fas/FasL pathway seems, at least in part, to contribute to the anti-tumor effects of IFNalpha/5-FU against HCCs.

Antibodies↗

PubMed2006

Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-alpha and fluorouracil in vitro.

Several studies have recently reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the clinical effect of this treatment was not complete. The new therapeutic modality should be necessary to rise up this clinical response rate. Recently, the anti-tumor effect of Vitamin K2 has been reported in terms of decreased recurrence rate of HCC patients. The aim of this study was to explore the additive or synergistic effect of Vitamin K2 to combined therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) against hepatocellular carcinoma (HCCs). The study was conducted using three hepatoma cell lines (PLC/PRF/5, Hep3B and HepG2). The 3-(4-5-dimethylthiazol-2-yl)-2, 5-dyphenyl tetrazolium bromide (MTT) assay (48h) revealed anti-tumor effect of IFNalpha and 5-FU. Cell growth assay (3-7 days) showed growth inhibitory effect of Vitamin K2 on three cell lines after day 5. But additional effect of combination treatment of Vitamin K2 and IFNalpha/5-FU was not observed in any time course from 48h to 7 days. Cell cycles were assessed with flowcytometry. Although either Vitamin K2 or IFNalpha/5-FU alone has the influence to the cell cycles, no significant change was shown in the combination of Vitamin K2 and IFNalpha/5-FU. In conclusion, Vitamin K2 itself has potentially growth inhibitory effect for HCC cell lines, but does not enhance the anti-tumor effect of IFNalpha and 5-FU.

Journal Article↗

PubMed2006

Role of stent design and coatings on restenosis and thrombosis.

More than 15 years have passed since stent technology was introduced by Sigwart et al. [U. Sigwart, J. Puel, V. Mirkovitch, F. Joffe, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N. Engl. J. Med. 316 (1987) 701-706.] among interventional cardiologists. Recently drug eluting stents have assumed dominance in the interventional world as positive trial results revealed their efficacy for preventing restenosis. Stent design, delivery-vehicle materials, and drug properties affect the function of these stents. Stainless steel stents with tubular and multicellular design have proven superior to coil or hybrid stent models. This chapter describes stents which have subtle influences of modular design, metal coverage, strut thickness, strut shape, surface smoothness, and coating materials like an alloy composition.

Biomedical Engineering↗

PubMed2006

Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential.

3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 5 (MGS0039) is a highly selective and potent group II metabotropic glutamate receptor (mGluR) antagonist (antagonist activities for mGluR2; IC50=20.0 nM, mGluR3; IC50=24.0 nM) and is detected in both plasma (492 ng/mL) and brain (13.2 ng/g) at oral administration of 10 ng/mL [J. Med. Chem.2004, 47, 4750], but the oral bioavailability of 5 was 10.9%. In order to improve the oral bioavailability of 5, prodrugs of 5 were discovered by esterification of carboxyl group on C6-position of bicyclo[3.1.0]hexane ring. Among these compounds, 6-alkyl esters exhibited approximately 10-fold higher concentrations of 5 in the plasma and brain of rats after oral administration (e.g., ethyl ester of 5; plasma, Cmax=20.7+/-1.3 microM) compared to oral administration of 5 (plasma, Cmax=2.46+/-0.62 microM). 3-(3,4-Dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-heptyl ester (7ao), a prodrug of MGS0039, showed antidepressant-like effects in rat forced swimming test and mouse tail suspension test following oral administration. Moreover, following oral administration of 7ao in mice, high concentrations of MGS0039 were detected in both the brain and plasma, while 7ao was barely detected. In this paper, we report the synthesis, in vitro metabolic stabilities, and pharmacokinetic profiles of the prodrugs of 5, and the antidepressant-like effects of 7ao.

Administration, Oral↗

PubMed2006

Relationship between serum albumin level before initiating haemodialysis and angiographic severity of coronary atherosclerosis in end-stage renal disease patients.

BACKGROUND: In patients with chronic kidney disease (CKD), although strong associations have been observed between malnutrition and atherosclerosis, the relationship between serum albumin concentration and angiographic changes of coronary artery disease (CAD) remains poorly explored. The goal of the present study was, in patients with CKD, to clarify the relationship between the angiographic severity of CAD and serum albumin concentration reflecting either inflammation or nutrition or both. METHODS: In this study, 100 end-stage renal disease (ESRD) patients were enrolled, who commenced long-term dialysis therapy at our hospital and underwent coronary angiography within 3 months of the first haemodialysis (HD) session. Mean age was 63+/-11 years, 20% of the subjects were female and 62% had diabetes. Severity of CAD was evaluated in terms of (i) number of vessels exhibiting CAD (>or=75% stenosis) and (ii) Gensini score (GS). Clinical characteristics and laboratory findings were recorded at initiation of long-term HD therapy. We then evaluated a possible association with the presence and degree of CAD. RESULTS: Sixty-four patients exhibited signs of CAD. Forty-one among them (64%) had multivessel disease. On univariate logistic regression analysis, age, diabetes and hypoalbuminaemia were significantly associated with multivessel CAD. Univariate linear regression analysis demonstrated a positive correlation of age and diabetes with GS, and an inverse correlation of BMI and serum albumin level with GS. Stepwise regression analysis showed age and serum albumin level to be independently associated with multivessel CAD and GS. The ROC curves demonstrated best cut-off levels of age and albumin for predicting multivessel CAD to be 70 years and 3.15 g/dl, respectively. CONCLUSION: Hypoalbuminaemia at the initiation of dialysis is an important predictor of advanced CAD, particularly in male and in diabetic patients. It may reflect mainly a state of inflammation. However, malnutrition as a confounding factor cannot be entirely excluded.

Aged↗

PubMed2006

Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists.

Chemical modification of the bicyclo[3.1.0]hexane ring C-3 position led to the discovery of 3-alkoxy-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 3-benzylthio-, and 3-benzylamino-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, metabotropic glutamate receptor 2 (mGluR2) antagonists. In particular, 3-(3,4-dichlorobenzyloxy)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15ae), (1R,2S,5R,6R)-2-amino-3-(3,4-dichlorobenzylthio)-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic acid (15at), and (1R,2S,5R,6R)-2-amino-3-(N-(3,4-dichlorobenzylamino))-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic (15ba) showed high affinity for the mGluR2 receptor (15ae: K(i) = 2.51 nM, 15at: K(i) = 1.96 nM, and 15ba: K(i) = 3.29 nM) and potent antagonist activity for mGluR2 (15ae; IC50 = 34.21 nM, 15at; IC50 = 13.34 nM, and 15ba; IC50 = 35.96 nM). No significant agonist activity for mGluR2 was observed with 15ae, 15at, or 15ba. This paper reports on the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

Animals↗

PubMed2006

An example that presented giant aneurysm of the angina pectoris after percutaneous coronary intervention.

We present the case of a 70-year-old woman who was admitted to our hospital with heart failure due to a giant left ventricular aneurysm involving the apex and severe mitral regurgitation. Three months before the hospitalization, percutaneous coronary intervention was performed for severe stenosis of the left main trunk. During the procedure, there were no abnormalities of distal coronary flow due to problems like embolization, and repeat coronary angiography, performed after stabilization of heart failure, showed no new significant stenosis. We diagnosed her condition as a subepicardial aneurysm by pathological examination of the resected specimen.

Aged↗

PubMed2006

Ultrasound attenuation behind coronary atheroma without calcification: mechanism revealed by autopsy.

When performing intravascular ultrasound studies, the backward echo image can show marked attenuation, although there are no calcified deposits and it may be impossible to detect the intraplaque architecture. The pathology underlying this phenomenon was investigated in autopsy specimens. We hypothesize that the mechanism responsible for the attenuation involves micro-calcification and lipid in unstable plaques causing ultrasonic wave reflection and dispersion.

Atherosclerosis↗

PubMed2006

Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin-2 and hypoxia-induced factor-1 alpha.

BACKGROUND: Hepatocellular carcinoma (HCC) is a hypervascular tumor and angiogenesis plays an important role in its progression. Angiogenesis is regulated by a balance between pro and antiangiogenic molecules. The aim of this study was to investigate the expressions of angiogenic factors and elucidate their roles in angiogenesis in HCC. METHODS: We investigated immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2), hypoxia-induced factor-1alpha (HIF-1alpha) and thrombospondin-1 (TSP-1) in 60 specimens of surgically resected HCC. We investigated the relationship between their expressions and clinicopathological factors or prognosis. RESULTS: Ang-2 staining had a significant correlation with the grade of differentiation of HCC cells (P=0.0082). VEGF and Ang-2 expression correlated positively with microvessel density (MVD) (P=0.0061 and 0.0374, respectively). MVD of well-differentiated HCC were significantly lower than those of moderately and poorly differentiated HCC. The disease-free survival time of patients with high Ang-2 and/or HIF-1alpha expression was significantly shorter than that of the low expression group (P=0.0278 and 0.0374, respectively). CONCLUSION: Our study showed that the expression of VEGF and Ang-2 correlated with MVD. Strong Ang-2 expression and/or high nuclear expression of HIF-1alpha is a significant predictive factor for recurrence after curative resection in HCC patients.

Adult↗

PubMed2006

Independent risk factors for progression of coronary atherosclerosis in hemodialysis patients.

Not uncommonly, hemodialysis patients with normal results in myocardial perfusion tests can still have a cardiac event within 2 years of evaluation. We examined possible risk factors for progression of coronary atherosclerosis in hemodialysis patients. We prospectively evaluated ability of myocardial perfusion imaging carried out under pharmacologic stress to predict 2-year outcomes in 77 hemodialysis patients, specifically thallium-201 single-photon emission computed tomography (SPECT) using high-dose adenosine triphosphate as the stressor. The primary end-point was a cardiac event (cardiac death, non-fatal acute coronary syndrome, or hospitalization for acute ischemic heart failure). Factors independently influencing duration until a cardiac event in hemodialysis patients were identified using stepwise multiple regression analysis. Myocardial perfusion defects were shown in 36 patients. Patients with a perfusion defect were more likely to have cardiac events than those with normal perfusion (78% vs. 15%, P < 0.001). Time until occurrence of a cardiac event in hemodialysis patients showed a significant, independent association with known coronary artery disease [regression coefficient (RC) = -3.391, P = 0.046], elevated C-reactive protein (RC = -5.813, P = 0.005), and a reversible myocardial perfusion defect (RC = -7.386, P < 0.001). An analysis based on the 'best cut-off' of CRP as identified on the basis of the ROC curve augmented the positive and negative predict value of CRP for the prediction of coronary events to 65 and 74%, respectively. Myocardial perfusion SPECT and measuring the plasma concentration of CRP might be useful for the prediction of hemodialysis patients with progression of coronary atherosclerosis.

Adenosine Triphosphate↗

PubMed2006

Presence and severity of Chlamydia pneumoniae and Cytomegalovirus infection in coronary plaques are associated with acute coronary syndromes.

Although an association between Chlamydia pneumoniae (Cpn) or Cytomegalovirus (CMV) infection and coronary atherosclerosis has been reported, such an association is less clear for acute coronary syndromes (ACS). The purpose of this study was to investigate the pathogenic roles of Cpn and CMV infection of coronary plaques in ACS. We divided 38 coronary plaque specimens obtained from 38 patients who underwent directional coronary atherectomy or thrombectomy into an ACS group (n = 21) and a non-ACS group (n = 17). Cpn and CMV in specimens were stained using immunohistochemical techniques and analyzed quantitatively. The detection rate for either Cpn- or CMV-positive cells in ACS patients was slightly higher compared with non-ACS patients. Detection rates for both Cpn- and CMV-positive cells were significantly higher in ACS patients than in non-ACS patients (P = 0.010). Furthermore, the density of Cpn- and CMV-positive cells in plaques was significantly higher in ACS patients than in non-ACS patients (P < 0.003). The results indicate that the presence and severity of Cpn and CMV infection in coronary plaques are greater in patients with ACS compared with non-ACS patients. We conclude that infection with Cpn and CMV in coronary plaques may be involved in the pathogenesis of ACS.

Aged↗

PubMed2006

The preserved expression of neuropilin (NRP) 1 contributes to a better prognosis in colon cancer.

Vascular endothelial growth factor A (VEGF-A) plays an essential role in tumor progression through stromal neovascularization in malignant solid tumors. Neuropilin (NRP) is considered to be the specific receptor for limited types of VEGF-A isoform, VEGF165. The clinicopathological implications of NRP are not well understood in colon cancer, while almost all colon cancers overexpressed VEGF-A. We examined the expression levels of NRP1 and NRP2 genes in 54 colon cancer cases and paired extraneoplastic tissue with quantitative real-time polymerase chain reaction. The gene expression levels of NRP1 in the tumor (0.431+/-0.583) were significantly decreased compared to those in the extraneoplastic tissue (0.754+/-0.799) (paired t-test, p=0.0208). On the other hand, the gene expression levels of NRP2 in the tumor (0.763+/-0.791) were not decreased compared to those in the extraneoplastic tissue (0.508+/-0.386) (paired t-test, p=0.0511). Twenty cases, with preserved expression of the NRP1 gene in the tumor, showed a better prognosis as compared to the 34 cases with decreased NRP1 expression (p=0.0258, log-rank test). No significant relationship was noted between NRP2 gene expression and prognosis. The results suggested that preserved NRP1 expression provides colon cancer patients with a better prognosis.

Adenocarcinoma↗

PubMed2006

TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells.

Transforming growth factor beta 1 (TGF-beta1) is a proposed regulator of Ids (inhibitors of DNA binding/differentiation) gene expression in epithelial cells. We previously reported that Id proteins are variously expressed in human hepatocellular carcinomas (HCC). However, the mechanism of regulation of Ids in HCC remains obscure. Here, we examined the relationship between Id1 and TGF-beta1 in four HCC cell lines, and studied the changes in cell proliferation, cell cycle and differentiation. The four HCC cell lines expressed Id1, TGF-beta1 and their receptors at various levels. TGF-beta1 strongly inhibited the growth of HuH7 cells, while the growth inhibition was moderate in PLC/PRF/5, and was not observed in HLE and HLF cell lines. TGF-beta1-induced growth inhibition in HuH7 cells was associated with cell accumulation in the G1 phase and partial induction of differentiation (with reduction of AFP and AFP-L3). Induction by TGF-beta1 dose-dependently suppressed Id1 expression in HuH7 cells; 1 ng/ml TGF-beta1 inhibited Id1 by 84.0 and 78.6% that of the untreated control at transcriptional and protein levels, respectively. HLE and HLF cells, which did not exhibit a TGF-beta1 growth inhibitory effect, lacked TGF-beta receptors and Id1 expression was not altered. In PLC/PRF/5 cells, Id1 augmentation was not observed in response to TGF-beta1, indicating that TGF-beta1-induced growth inhibition was not related to Id1 in this cell line. Our results suggest that, in some HCC cells, the pathway of suppression of Id1 by TGF-beta1 may be important in TGF-beta1-induced growth inhibition and partial differentiation.

Blotting, Western↗