Biomedical subjects

Toshinari Minamoto

Publications and source records attributed to Toshinari Minamoto.

At least 19 recordsLinked to original sources

PubMed2023

Super-enhancer trapping by the nuclear pore via intrinsically disordered regions of proteins in squamous cell carcinoma cells.

Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.

Humans↗

PubMed2006

CRD-BP mediates stabilization of betaTrCP1 and c-myc mRNA in response to beta-catenin signalling.

Although constitutive activation of beta-catenin/Tcf signalling is implicated in the development of human cancers, the mechanisms by which the beta-catenin/Tcf pathway promotes tumorigenesis are incompletely understood. Messenger RNA turnover has a major function in regulating gene expression and is responsive to developmental and environmental signals. mRNA decay rates are dictated by cis-acting elements within the mRNA and by trans-acting factors, such as RNA-binding proteins (reviewed in refs 2, 3). Here we show that beta-catenin stabilizes the mRNA encoding the F-box protein betaTrCP1, and identify the RNA-binding protein CRD-BP (coding region determinant-binding protein) as a previously unknown target of beta-catenin/Tcf transcription factor. CRD-BP binds to the coding region of betaTrCP1 mRNA. Overexpression of CRD-BP stabilizes betaTrCP1 mRNA and elevates betaTrCP1 levels (both in cells and in vivo), resulting in the activation of the Skp1-Cullin1-F-box protein (SCF)(betaTrCP) E3 ubiquitin ligase and in accelerated turnover of its substrates including IkappaB and beta-catenin. CRD-BP is essential for the induction of both betaTrCP1 and c-Myc by beta-catenin signalling in colorectal cancer cells. High levels of CRD-BP that are found in primary human colorectal tumours exhibiting active beta-catenin/Tcf signalling implicates CRD-BP induction in the upregulation of betaTrCP1, in the activation of dimeric transcription factor NF-kappaB and in the suppression of apoptosis in these cancers.

Animals↗

PubMed2006

Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells.

AIM: To investigate the expression of genes involved in the gemcitabine-induced cytotoxicity in human pancreatic cancer cells. METHODS: A human pancreatic cancer cell line, PANC-1, was cultured. 1x10(4) PANC-1 cells were plated in 96-well microtiter plates. After being incubated for 24 h, gemcitabine was added to the medium at concentrations ranging 2.5-1000 mg/L. The AlamarBlue dye method was used for cell growth analysis. DNA fragmentation was quantitatively assayed using a DNA fragmentation enzyme-linked immunosorbent assay (ELISA) kit. PAP and TP53INP1 mRNA expression was determined using the reverse transcription-polymerase chain reaction with semi-quantitative analysis. The expression of GSK-3beta and phospho-GSK-3beta proteins was examined with Western blot analysis. RESULTS: The IC50 for the drug after a 48-h exposure to gemcitabine was 16 mg/L. The growth of PANC-1 cells was inhibited by gemcitabine in a concentration-dependent manner (P<0.0001) and the cell growth was also inhibited throughout the time course (P<0.0001). The DNA fragmentation rate in the gemcitabine-treated group at 48 h was 44.7%, whereas it was 25.3% in the untreated group. The PAP mRNA expression was decreased after being treated with gemcitabine, whereas the TP53INP1 mRNA was increased by the gemcitabine treatment. Western blot analysis showed that phospho- GSK-3beta (ser9) was induced by the gemcitabine treatment. CONCLUSION: Gemcitabine suppresses PANC-1 cell proliferation and induces apoptosis. Apoptosis is considered to be associated with the inhibition of PAP and GSK-3beta, and the activation of TP53INP1 and pospho-GSK-3beta (ser9).

Antigens, Neoplasm↗

PubMed2006

C-kit gene mutation: common and widely distributed in intracranial germinomas.

OBJECT: Of the intracranial germ cell tumors (IGCTs), 10% of germinomas and most nongerminomatous tumors remain refractory to multimodality therapy. The authors investigated the mutation of c-kit and the expression of its product KIT in IGCTs to identify tumors susceptible to imatinib mesylate, a synthetic agent targeting KIT. METHODS: The authors investigated 26 IGCTs, including 13 germinomas, five mixed germ cell tumors (MGCTs), four immature teratomas (ITs), and two each of yolk sac tumors and choriocarcinomas. These tumors were examined for the expression of KIT and CD34 by immunohistochemical analysis, and for mutations in exons 2, 8 to 11, 13, and 17 of c-kit. Strong KIT expression was found in the cell membrane of germinomas (100%) and germinomatous cells of MGCTs (80%), as well as in the cytoplasm of epithelial and smooth-muscle cells of ITs. The membranous expression of CD34 was found in the nongerminomatous tumor cells and the chondrocytes of MGCTs (60%), ITs (100%), and a choriocarcinoma (50%), but not in germinomas and germinomatous cells. A total of five missense mutations distributed in exons 2, 11, 13, and 17 of c-kit were detected in three (23%) of the 13 germinomas. The novel mutations E73K, T96M (both in exon 2), and A636V (in exon 13) were detected in a single tumor. The presence or type of c-kit mutation was not correlated with patient prognosis. CONCLUSIONS: Immunohistochemical analysis of KIT expression is useful for the diagnosis of germinoma. This study may help in clarifying the pathogenesis of IGCTs and in identifying tumors susceptible to drugs targeting KIT.

Adolescent↗

PubMed2006

Loss of imprinting in IGF2 in colorectal carcinoma assessed by microdissection.

To ascertain the implications of loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) for carcinogenesis, the precise frequency of LOI in colorectal carcinoma was examined using a laser capture microdissection method, and compared to the matched normal colorectal mucosa. LOI was examined by PCR-restriction fragment length polymorphism in combination with direct sequencing. The status was assigned as imprinting when PCR-RFLP showed only one band or sequence with a single peak, otherwise cases were classified as LOI. LOI was found in 13 of 24 informative cases of carcinoma (54%), which was higher than the ratios reported previously. LOI was also found in the normal colorectal mucosae in 14 cases (58%). The LOIs in carcinomas and in the normal mucosae were closely correlated: 10 of 13 LOI-positive carcinomas showed LOI in the matched normal mucosae. These results suggest that LOI of IGF2 in colorectal carcinoma and LOI in the background mucosa play important roles in carcinogenesis.

Binding Sites↗

PubMed2005

Oncogenic beta-catenin signaling networks in colorectal cancer.

Beta-catenin has two distinct functions, namely, maintaining cell-to-cell adhesion and mediating the Wnt/beta-catenin signal transduction pathway, which plays pivotal roles in embryogenesis and in malignant transformation of cells. The oncogenic properties of Wnt/beta-catenin signaling stem from alteration in phosphorylation-dependent protein degradation and subcellular localization of beta-catenin from cell membrane to the nucleus, where it binds to T-cell factor (Tcf) to form a bipartite transcription factor. The beta-catenin/Tcf complex facilitates transcription of target genes that encode effectors for activation of cell proliferation and invasion and inhibition of apoptosis, leading to colorectal cancer development. In addition, in the tumor invasion front, stabilized and activated beta-catenin interacts with other molecular pathways to facilitate tumor progression. This review highlights the beta-catenin-dependent oncogenic signaling network involved in the multi-step process of colorectal tumorigenesis. Wnt signaling evidently regulates stem cells, leading them to differentiate or self-renew. We address roles of oncogenic beta-catenin signaling in the microenvironment of the tumor-host interface that determine the individual tumor's malignant potential and in regulation of putative cancer stem or progenitor cells that represent plausible targets for cancer eradication.

Animals↗

PubMed2005

A genetic variant in the gene encoding the stress70 protein chaperone family member STCH is associated with gastric cancer in the Japanese population.

Association analysis, based on linkage disequilibrium between specific alleles in the candidate loci and nearby genetic markers, has been proposed to identify genes conferring susceptibility to multifactorial diseases. Using the affected sib-pair method, we previously mapped four candidate chromosomal regions, 1p32, 2q33-q35, 11p13-p14, and 21q21, for gastric cancer by linkage analysis. To identify genes involved in the disease, we performed a gene-based association analysis of 66 genes, located on 21p11-21q22, using 126 single nucleotide polymorphisms (SNPs) as genetic markers in 373 patients with 250 controls. We found a significant association of five SNPs in the stress70 protein chaperon family member STCH gene with gastric cancer, especially with the non-cardia localization subgroup (P=0.0005-0.02, odds ratio=1.44-1.72). Comparisons of haplotype frequency showed significant association between TTGGC haplotype and gastric cancer (P=0.0001, odds ratio=1.59). These results suggest that, in the Japanese population, STCH might be a new candidate for conferring susceptibility to this disease.

Alleles↗

PubMed2005

Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation.

Glycogen synthase kinase 3beta (GSK3beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappaB pathway on the other. The present investigation was undertaken to clarify the roles of GSK3beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells. Inhibition of GSK3beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3beta in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer.

Adult↗

PubMed2005

Adhesiveness of beta5 integrin variant lacking FNK767-769 is similar to that of the prototype containing FNKFNK764-769.

Little is known about the functions of two different beta5 integrins: repeated-FNK (FNKFNK764-769) and single-FNK (FNK764-766) amino acid sequences in the cytoplasmic domain. We examined whether they occurred as germ line mutations or somatic mutations associated with neoplastic transformation, and whether there were functional alterations. Out of six cultured cell lines, only KATO-III cells had the single-FNK beta5 sequence. The single-FNK beta5 was found in 9 out of 79 patients with colon carcinoma, but no somatic mutations were detected in cancerous tissues. CHO cells were transformed with expression vectors containing single-FNK or repeated-FNK beta5 cDNA, which were derived from KATO-III cells. CHO cells transfected with single-FNK and repeated-FNK showed similar adhesiveness to, and proliferative activity on, vitronectin substrates.

Amino Acid Sequence↗

PubMed2005

Detection and characterization of oncogene mutations in preneoplastic and early neoplastic lesions.

Although it has been more than 20 yr since its discovery, the ras family of genes has not yet lost its impact on basic and clinical oncology. These genes remain central to the field of molecular oncology as tools for investigating carcinogenesis and oncogenic signaling, as powerful biomarkers for the identification of those who have or are at high risk of developing cancer, and as oncogene targets for the design and development of new chemotherapeutic drugs. Mutational activation of the K-RAS proto-oncogene is an early event in the development and progression of the colorectal, pancreatic, and lung cancers that are the major causes of cancer death in the world. The presence of point mutational "hot spots" at sites necessary for the activation of this proto-oncogene has led to the development of a number of highly sensitive PCR-based methods that are feasible for the early detection of K-RAS oncogene mutations in the clinical setting. In light of these facts, mutation at the K-RAS oncogene has the potential to serve as a useful biomarker in the early diagnosis and risk assessment of cancers with oncogenic Ras signaling. This chapter describes a highly sensitive method for detecting mutant K-RAS, enriched PCR, and its application to early detection of this oncogene in preneoplastic and early neoplastic lesions of the colon and rectum.

Animals↗

PubMed2005

Primary minute invasive de novo colonic adenocarcinoma appearing as submucosal tumor.

A 4 mm white-yellow submucosal tumor-like lesion was detected in the sigmoid colon of an asymptomatic 52-yr-old Japanese man. Because the lesion was unexpectedly suspicious for adenocarcinoma by pathological examination of the biopsy specimen, it was treated by endoscopic mucosal resection. The specimen obtained demonstrated well-differentiated adenocarcinoma without any adenomatous element, and was located principally in the submucosal layer with a maximum depth of 1600 mum from the muscularis mucosae. The cancer exposed to the luminal surface was pathologically concluded to be diminutive. Intriguingly, aggregation of lymphocytes was found beneath the mucosal layer, which might have compromised the integrity of the muscularis mucosae. Because of deep submucosal infiltration and the latent aggressive nature of de novo cancer, the patient underwent an additional partial sigmoidcolectomy, which demonstrated no residual cancer and no regional lymph node metastasis. The lesion in this patient exhibited a previously undescribed appearance of de novo colon cancer as submucosal tumor in an early phase of growth.

Adenocarcinoma↗

PubMed2005

Correlation of gamma-catenin expression with good prognosis in medulloblastomas.

OBJECT: Medulloblastoma is a malignant cerebellar tumor of childhood and is difficult to cure due to frequent cerebrospinal fluid dissemination. Amplification of the c-myc gene (4%) and messenger (mRNA) overexpression (50%) are known to be adverse prognostic indicators. Because mRNA overexpression cannot be explained by gene amplification alone, mechanisms other than gene amplification are postulated. Molecules on the Wnt signal pathway in primary tumors were examined. METHODS: Immunohistochemical and cytogenetic examinations of beta- and gamma-catenin, c-myc, N-myc, and cyclin D1 in 24 primary medulloblastomas were conducted, and their clinical relevance was evaluated. Cytoplasmic/membranous staining of beta- and gamma-catenin was detected in 19 (79%) and nine (37%) cases, respectively, and nuclear expression of cyclin D1 and c-myc was detected in six (25%) and 21 (83%) cases, respectively. The expression levels of gamma-catenin in Western blot analysis and immunohistochemistry were similar. By differential polymerase chain reaction, c-myc and N-myc were amplified separately in two large cell/anaplastic medulloblastomas. No cyclin D1 amplification, or beta- or gamma-catenin mutations were found. Kaplan-Meier analysis revealed no dissemination at diagnosis (Chang Grade M0) and gamma-catenin expression was correlated with good prognosis (p = 0.0002 and 0.003, respectively). Expression of gamma-catenin was also significant in the M0 group (p = 0.022). Expression of cyclin D1 showed a trend toward adverse outcome (p = 0.057) and all patients in whom cyclin D1 expression was found died of disease. CONCLUSIONS: Expression of gamma-catenin is of great prognostic value and its immunohistochemistry may be useful for further stratification of treatment. Cyclin D expression may have the potential to be an adverse prognostic indicator.

Adolescent↗

PubMed2004

Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer.

BACKGROUND: The ubiquitin-proteasome pathway is important in regulating protein signaling pathways that are involved in tumorigenesis. beta-transducin repeat-containing proteins (beta-TrCP) are components of the ubiquitin ligase complex targeting beta-catenin and IkappaBalpha for proteasomal degradation and are thus a negative regulator of Wnt/beta-catenin signaling and a positive regulator of NF-kappaB signaling. We analyzed expression of beta-TrCP in colorectal cancers and its association with types of beta-catenin subcellular localization, an indirect measure of activation. METHODS: Levels of beta-TrCP1 mRNA and protein were measured by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively, in samples of tumor and normal tissues from 45 patients with colorectal cancer. Types of beta-catenin activation (diffuse or invasion edge) and NF-kappaB activation were examined by immunohistochemistry. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) assay. All statistical tests were two-sided. RESULTS: Compared with the beta-TrCP1 levels in normal tissues, 25 (56%) of 45 tumors had increased beta-TrCP1 mRNA and protein levels. Of the 22 (49%) tumors with beta-catenin activation, 12 had the diffuse type (i.e., nuclear accumulation throughout the tumor) and 10 had the invasion edge type (i.e., nuclear accumulation predominantly in the tumor cells that formed the invasion edge). Increased beta-TrCP1 levels were statistically significantly associated with beta-catenin activation (P =.023) and decreased apoptosis (P =.035). beta-TrCP accumulated in the nuclei of tumor cells that contained increased levels of beta-TrCP1 mRNA and the active form of NF-kappaB. Higher levels of beta-TrCP1 mRNA were detected in primary tumors of patients who had metastases (0.960 arbitrary units, 95% confidence interval = 0.878 to 1.042) than in the tumors of patients who did not (0.722 arbitrary units, 95% confidence interval = 0.600 to 0.844; P =.016). CONCLUSION: In colorectal cancer, increased expression of beta-TrCP1 is associated with activation of both beta-catenin and NF-kappaB, suggesting that the integration of these signaling pathways by increased beta-TrCP expression may contribute to an inhibition of apoptosis and tumor metastasis.

Adenocarcinoma↗

PubMed2004

Pilot study of low-dose, divided maximum tolerated dose of CPT-11 in 21 consecutive patients with metastatic colorectal or gastric cancer.

PURPOSE: We devised a new treatment regimen, delivering a frequent low dose of CPT-11, calculated by dividing the maximum tolerated dose (MTD) to reduce its toxicity without impairing its efficacy. METHODS: CPI-11, 25 mg/m2, determined by dividing the MTD dose per month by 12, was given on days 1, 2, and 3 of every week, to 21 consecutive patients; 12 with metastatic colon cancer and 9 with metastatic gastric cancers. RESULTS: The total delivered dose of CPI-11 per patient was more than 1,000 mg in 17 (80.1%) of the 21 patients. Grade 3 marrow depression developed in 3 (14.3%) patients, and although nausea, vomiting, alopecia, and diarrhea developed in some patients, these side effects were all categorized as grade 2 or milder. The antitumor effect was evaluated in 18 patients with measurable lesions, who had received CPI-11 according to our regimen for at least 3 weeks. Of these 18 patients, 10, 7, and 1, respectively, had a found to have partial response, no change, or progression of disease, demonstrating a 55.6% efficacy rate [colon 6/10 (60.0%) and stomach 4/8 (50.0%)]. Moreover, time to progression (TTP) was greater than 90 days in 12 (75.0%) of these 18 patients. CONCLUSION: These results show that our low-dose, divided MTD of CPI-11 regimen is a promising method of reducing toxicity and strengthening the antitumor effect, justifying further large-scale comparative clinical studies to verify this potential.

Aged↗

PubMed2003

beta-Catenin and ras oncogenes detect most human colorectal cancer.

UNLABELLED: PURPOSE AND STUDY DESIGN: Recent studies have shown that beta-catenin translocated into the cell nucleus functions like an oncogene. Accumulating evidence suggests that activation of the beta-catenin oncogenic signaling cascade along with its twin, the K-ras cascade, may exert syngeneic or synergistic effects on tumor development and progression. In the study reported here, we analyzed oncogenic beta-catenin activation on the basis of its nuclear accumulation (NA) and compared the results with those of mutational activation of K-ras in 74 patients with colorectal cancer to determine whether the two oncogene-mediated signaling cascades interact. RESULTS: We found two distinct patterns of beta-catenin activation, i.e., diffuse NA in 20 cases (27%) and selective NA at the tumor invasion front (NAinv) in 19 cases (26%). The presence of the NAinv pattern was significantly correlated with advanced Dukes' stage tumor (P = 0.0005) and the presence of distant metastases (P = 0.0064). K-ras proto-oncogene was mutated in the tumors of 31 cases (42%). Activated beta-catenin or K-ras was detected in most (78%) colorectal cancers analyzed, although a weak inverse correlation was found between the activities of the two oncogenes in the tumors. Importantly, most (7 of 8) patients with tumor showing both K-ras activation and the NAinv pattern of beta-catenin activation were in Dukes' stage C at surgery, and half of them developed distant metastases to the liver and lungs. CONCLUSION: The results suggest that although oncogenic activation of beta-catenin and K-ras is independent in the process of clinical cancer development, combined analysis of the two major oncogenes can detect most colorectal cancers and identify a subset of patients with poorer outcomes. Consequently, activation of either or both of these oncogenes may serve as a genetic marker for molecular diagnosis.

Adult↗

PubMed2003

Expression of alphav integrin family in gastric carcinomas: increased alphavbeta6 is associated with lymph node metastasis.

To investigate the alterations as to integrin expression in human gastric carcinomas, we analyzed the alphav subunit and 5 types of beta subunits using reverse transcription-polymerase chain reaction (RT-PCR) and competitive RT-PCR. The incidence of alphav, beta6 and beta8 expression was significantly higher in carcinoma tissues than in non-neoplastic gastric mucosal tissues (NGMTs). Out of 18 carcinoma cases with coexpression of alphav and beta6 subunits, which was demonstrated by RT-PCR, 17 cases (94%) showed lymph node metastasis (p = 0.0033). This tendency was confirmed by immunohistochemistry; most cases (23/28, 82%) in which alphavbeta6 integrin was immunohistochemically detected showed lymph node metastasis (p = 0.0193). RT-PCR and immunohistochemical studies showed that gastric carcinoma tissues expressed beta5 subunit in all cases. Furthermore, in a quantitative analysis using competitive RT-PCR, the mean level of beta5 expression was approximately 140 times higher in gastric carcinomas than in NGMTs. Most gastric carcinoma cases (27/38, 71%) were immunohistochemically positive for beta8 subunit. These findings suggest that some members of the alphav integrin family (alphavbeta5, alphavbeta6, alphavbeta8) are up-regulated, and that alphavbeta6 integrin may be involved in the lymphatic metastasis of gastric carcinomas.

Aged↗

PubMed2002

Collagenofibrotic glomerulopathy with a widespread expression of type-V collagen.

Collagenofibrotic glomerulopathy is considered as a form of glomerulopathy in which organized collagen type III progressively deposits. We report a case of this disease with widespread expression of collagen type V. A 65-year-old woman was admitted to our hospital for further evaluation of nephrotic-range proteinuria. The patient had had anemia and hypertension for 9 years, and proteinuria for 3 years. A renal biopsy specimen showed a remarkable mesangial expansion with Congo red-negative and periodic acid-Schiff-positive deposits. At the ultrastructural level, two forms of bundling fibers were found in the mesangium and subendothelial side of the glomerular basement membranes (GBM). The GBM itself appeared normal. Immunohistochemical investigation showed that the glomerular lesions were strongly reactive with both anti-collagen type-III and -V antibodies. Immunoelectron microscopy demonstrated collagen type V in both forms of bundling fibers. Despite therapy, her renal function declined. The clinical course and renal pathology of this case were in accordance with collagenofibrotic glomerulopathy except for the widespread expression of collagen type V. Collagen type V is a fibrillar collagen capable of forming banding fibrils. This report poses the question whether collagen type V accumulates only in this particular case or whether it is a normal component in collagenofibrotic glomerulopathy.

Aged↗

PubMed2002

Abnormal expression of E-cadherin, beta-catenin, and c-erbB-2 in advanced gastric cancer: its association with liver metastasis.

BACKGROUND AND AIMS: We investigated expression of E-cadherin, beta-catenin, and c-erbB-2 in gastric cancer to identify molecular factor(s) relevant to development of liver metastasis, which is a frequent cause of mortality in gastric cancer patients. PATIENTS AND METHODS: We analyzed by immunohistochemistry and compared expression patterns of E-cadherin, beta-catenin, and c-erbB-2 in the tumor between 40 cases of gastric cancer (GC) without (GC-H(-)) and 16 with concurrent liver metastasis (GC-H(+)). RESULTS: Loss of E-cadherin expression in the primary tumor was found in 18% of GC-H(-) and in 19% of GC-H(+). Oncogenic beta-catenin activation, represented by its nuclear translocation, was detected in 13% of GC-H(-) and in 31% of GC-H(+). There was no statistical difference in incidence of alteration in these molecules between the two groups of patients. c-erbB-2 overexpression was more frequently observed in GC-H(+) (10/16, 63%) than in GC-H(-) (5/40, 13%) while the distribution of histological types of the tumors was similar in the two groups of patients. This overexpression was also detected in metastatic liver tumors and biopsy specimens in the ten of the former group of patients. CONCLUSION: Our results strongly suggest a role of activated c-erbB-2 in the process of liver metastasis, and an importance of detection of this overexpression in biopsy specimens to identify GC patients who are at high risk of developing liver metastasis.

Adult↗