Liver-Wrapping, Nitric Oxide-Releasing Nanofiber Downregulates Cleaved Caspase-3 and Bax Expression on Rat Hepatic Ischemia-Reperfusion Injury.

BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is an important determinant of the outcome of hepatic surgery, including re-section and transplantation. Previous studies have shown that nitric oxide (NO) has a protective effect against IRI. Therefore, many studies have examined methods for supplying NO. In this study, we investigated the effect of NO-releasing nanofibers on hepatic IRI in a rat model. METHODS: Male Sprague-Dawley rats were divided into 4 groups: control, IRI only (n = 3); group 1, hepatic IRI and liver-wrapping with nanofiber lacking NO (n = 4); group 2, hepatic IRI and liver-wrapping with NO rapid-releasing nanofiber (n = 4); and group 3, hepatic IRI and liver-wrapping with NO slow-releasing nanofiber (n = 5). RESULTS: The levels of aspartate aminotransferase and alanine aminotransferase were not significantly different between groups. On the basis of Western blots, Bax/ß-actin levels were significantly lower in group 2 than in group 3 (P < .01). Cleaved Caspase-3/ß-actin levels were significantly lower in group 2 than in the control, group 1, and group 3 (P < .05, .01, and .01, respectively). However, there were no significant differences in Bcl-2/ß-actin between groups. CONCLUSIONS: The liver-wrapping NO rapid-releasing nanofiber downregulated cleaved Caspase-3 and Bax expression. It has a protective effect by reducing apoptosis in hepatic IRI in rats.

Hypotonic stress induces RANKL via transient receptor potential melastatin 3 (TRPM3) and vaniloid 4 (TRPV4) in human PDL cells.

Bone remodeling occurs in response to various types of mechanical stress. The periodontal ligament (PDL) plays an important role in mechanical stress-mediated alveolar bone remodeling. However, the underlying mechanism at the cellular level has not been extensively studied. In this study, we investigated the effect of shear stress on the expression of bone remodeling factors, including receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) and osteoprotegerin (OPG), as well as its upstream signaling pathway in primary human PDL cells. We applied hypotonic stress to reproduce shear stress to PDL cells. Hypotonic stress induced the messenger RNA (mRNA) and protein expression of RANKL but not OPG. It also increased intracellular Ca(2+) concentration ([Ca(2+)]i). Extracellular Ca(2+) depletion and nonspecific plasma membrane Ca(2+) channel blockers completely inhibited the increase in both [Ca(2+)]i and RANKL mRNA expression. We identified the expression and activation of transient receptor potential melastatin 3 (TRPM3) and vaniloid 4 (TRPV4) channels in PDL cells. Pregnenolone sulfate (PS) and 4α-phorbol 12, 13-didecanoate (4α-PDD), which are agonists of TRPM3 and TRPV4, augmented Ca(2+) influx and RANKL mRNA expression. Both pharmacological (2-aminoethoxydiphenyl borate [2-APB], ruthenium red [RR], ononetin [Ono], and HC 067047 [HC]) and genetic (small interfering RNA [siRNA]) inhibitors of TRPM3 and TRPV4 reduced the hypotonic stress-mediated increase in [Ca(2+)]i and RANKL mRNA expression. Our study shows that hypotonic stress induced RANKL mRNA expression via TRPM3- and TRPV4-mediated extracellular Ca(2+) influx and RANKL expression. This signaling pathway in PDL cells may play a critical role in mechanical stress-mediated alveolar bone remodeling.

MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma.

Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3'-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.

Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling.

Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report the identification of a regulatory domain of ubiquitination (RDU) in the C-terminus of Dvl. Mutations in the RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63 linked. Small interfering RNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase in Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest that Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, tissue microarray analysis of colon cancer revealed a strong correlation between the levels of Usp14 and ß-catenin, which suggests an oncogenic role for Usp14 via enhancement of Wnt/ß-catenin signaling.

Effects of HB-EGF and epiregulin on wound healing of gingival cells in vitro.

OBJECTIVE: Gingival wound healing is important to periodontal disease and surgery. This in vitro study was conducted to assess the manner in which heparin-binding epidermal growth factor-like growth factor (HB-EGF) and epiregulin cooperatively participate in the wound-healing process in the gingival epithelial and fibroblast cells of the oral mucosa. MATERIAL AND METHODS: Gingival epithelium and fibroblast were separated from gingival tissue biopsies and prepared to primary cultures. The changes in the mRNA expression were evaluated via real-time PCR. The effects on cell proliferation, migration, and repopulation were evaluated in vitro. RESULTS: The different regulation of expressions of HB-EGF, epiregulin, and epidermal growth factor receptors was observed over time and with different gingival cell types. HB-EGF exerted a cell migration-inducing effect on both epithelial and fibroblast cells, whereas epiregulin did not. Both growth factors functioned as mitogens for epithelial cell proliferation, but not for fibroblast proliferation. HB-EGF strongly promoted epithelial cell repopulation and mildly promoted fibroblast repopulation, whereas epiregulin promoted only fibroblast repopulation. CONCLUSION: These results indicated that both growth factors might function importantly in the wound-healing process of human gingival tissue via the different regulation of the expression, cell migration, proliferation, and repopulation.

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling.

Axin, a negative regulator of Wnt signaling, is a key scaffold protein for the ß-catenin destruction complex. It has been previously shown that multiple post-translational modification enzymes regulate the level of Axin. Here, we provide evidence that protein arginine methyltransferase 1 (PRMT1) directly interacts with and methylates the 378th arginine residue of Axin both in vitro and in vivo. We found that the transient expression of PRMT1 led to an increased level of Axin and that knockdown of endogenous PRMT1 by short hairpin RNA reduced the level of Axin. These results suggest that methylation by PRMT1 enhanced the stability of Axin. Methylation of Axin by PRMT1 also seemingly enhanced the interaction between Axin and glycogen synthase kinase 3ß, leading to decreased ubiquitination of Axin. Consistent with the role of PRMT1 in the regulation of Axin, knockdown of PRMT1 enhanced the level of cytoplasmic ß-catenin as well as ß-catenin-dependent transcription activity. In summary, we show that the methylation of Axin occurred in vivo and controlled the stability of Axin. Therefore, methylation of Axin by PRMT1 may serve as a finely tuned regulation mechanism for Wnt/ß-catenin signaling.

Apicidin, the histone deacetylase inhibitor, suppresses Th1 polarization of murine bone marrow-derived dendritic cells.

Apicidin is a fungal metabolite shown to exhibit anti-proliferative, anti-invasive, and anti-inflammatory properties by the inhibition of histone deacetylase (HDAC). However, the effects of apicidin on the maturation and immunostimulatory function of dendritic cells (DCs) remain unknown. In this study, we investigated whether apicidin modulates surface molecule expression, cytokine production, endocytosis capacity, and underlying signaling pathways in murine bone marrow-derived DCs. We observed that apicidin significantly attenuated surface molecule expression in LPS-stimulated DCs, suppressed production of interleukin (IL)-12 and proinflammatory cytokines (IL-6 and TNF-alpha) by DCs, and reduced IFN-gama production by T cells. The apicidin-treated DCs were found to be highly efficient in antigen capture via mannose receptor-mediated endocytosis. Apicidin also inhibited LPS-induced MAPK activation and NF-kB nuclear translocation in DCs. Moreover, the apicidin-treated DCs were incapable of inducing Th1 responses and normal cell-mediated immune responses. These novel findings not only provide new insights into the immunopharmacological role of apicidin in terms of its effects on DCs, but also broaden current perspectives of the immunopharmacological functions of apicidin, and have implications for the development of therapeutic adjuvants for the treatment of DC-related acute and chronic diseases.

Low frequency mutation of the Ephrin receptor A3 gene in hepatocellular carcinoma.

EphA3 is a component of the Eph/ephrin tyrosine kinase system, which participates in vasculature development. This receptor/ligand system is associated with various signaling pathways related to cell growth and viability, cytoskeletal organization, cell migration, and anti-apoptosis. Accumulated evidence suggests that aberrant regulation of EphA3 and its genetic alterations are implicated in the development and progression of various cancers. However, despite a high incidence of EphA3 over-expression, no such investigation has been performed in hepatocellular carcinoma. Thus, we investigated genetic alterations of the EphA3 gene in 73 cases of hepatocellular carcinoma by single-strand conformational polymorphism and sequencing. One novel D219V missense mutation was found in the extracellular domain of EphA3, and two genetic alterations in the intracellular sterile-alpha-motif (SAM) domain of EphA3 appeared to be polymorphisms. Although the functional assessments of this mutant are incomplete, it is believed that this novel EphA3 mutation may contribute to the development of hepatocellular carcinoma.

The Glu346Lys polymorphism and frameshift mutations of the Methyl-CpG Binding Domain 4 gene in gastrointestinal cancer.

MBD4 (Methyl-CpG Binding Domain 4) is a human DNA repair protein that may be involved in DNA mismatch repair. The polymorphisms and frameshift mutations in MBD4 may influence cancer susceptibility and the development of cancer. The specific aim of this study was to investigate whether frameshift mutations of the MBD4 gene and the codon 346 polymorphism were associated with microsatellite instability (MSI) and the risk for gastrointestinal cancer. We examined the MSI, frameshift mutations and polymorphisms of the MBD4 gene in 84 patients with gastric cancers, 82 colorectal cancers and 299 healthy controls. MSI was found in 19 (22.6%) and 26 (31.7%) of the gastric and colorectal cancer samples, respectively. The mutation analysis revealed no frameshift mutations in the MBD4 gene among the gastrointestinal cancers. The frequencies of genotypes: Glu/Glu, Glu/Lys and Lys/Lys were 41.7% (35/84), 41.7% (35/84) and 16.6% (14/84), respectively, in the gastric cancer cases, and 42.7% (35/82), 36.6% (30/82) and 20.7% (17/82), respectively, in the colorectal cancers. MSI was not associated with the MBD4 codon 346 polymorphism and there was no significant difference in the frequency of the genotypes between healthy controls and gastric cancer patients (P=0.2748). However, the MBD4 codon 346 polymorphism was significantly associated with the risk of colorectal cancer (P=0.0315). Our findings suggest that microsatellite instability may not be associated with frameshift mutations in the MBD4 gene, and that the MBD4 codon 346 polymorphism may play arole in colorectal cancer susceptibility in the Korean population.

Effect of epidural saline washout on regression of sensory and motor block after epidural anaesthesia with 2% lidocaine and fentanyl in elderly patients.

Seventy elderly males received lumbar epidural anaesthesia with 12 ml of 2% lidocaine containing fentanyl 50 mug. At the end of transurethral surgery, the washout group (n = 33) received an epidural bolus of 30 ml saline while the control group (n = 34) did not. Mean (SD) times to 1-grade (17.2 (11.9) vs 32.7 (11.3) min) and 2-grade regression (23.8 (12.2) vs 56.0 (23.9) min) of motor block, 3-dermatomal sensory regression (31.4 (11.6) vs 42.2 (14.4) min for cold and 30.8 (15.6) vs 40.6 (14.2) min for pinprick), and regression to S1 (57.7 (16.1) vs 76.2 (20.2) min for cold and 56.8 (17.3) vs 69.2 (16.2) min for pinprick) were significantly shorter in the washout group than the control group. There were no differences in postoperative pain scores and side effects between the two groups. We concluded that epidural washout facilitates regression of both motor and sensory block following epidural anaesthesia without reducing the postoperative analgesic benefit.

The p53 codon 72 polymorphism and susceptibility to colorectal cancer in Korean patients.

UNLABELLED: TP53 is a major gene involved in the determination of proliferation or growth arrest at the cellular level. The polymorphism of p53 at codon 72 has been widely studied; this variation has been associated with cancer susceptibility and disease outcome. The specific aim of this study was to investigate whether the p53 codon 72 polymorphism is associated with individual susceptibility to colorectal cancer in Korean patients. The frequency of the polymorphism was examined in 156 patients with colorectal cancer and in 293 healthy controls. The polymorphism analysis was performed by amplifying exon 4 of p53 and digesting the products with restriction enzyme. The frequencies of genotypes: Arg/Arg, Arg/Pro and Pro/Pro were 34.6% (54/156), 43.0% (67/156) and 22.4% (35/156), respectively, in the cases with colorectal cancer, and 28.9% (114/293), 47.8% (140/293) and 13.3% (39/293), respectively, in the healthy controls. Statistically, there was a significant difference in the frequency of the genotypes when the healthy controls were compared to the patients with colorectal cancer (p=0.0459). The specific allele frequencies showed borderline significance (p=0.0502). Our findings suggest that the p53 Pro72 variant is associated with an increased risk for colorectal cancer in the Korean population. KEYWORDS: p53, colorectal cancer, polymorphism, susceptibility, metastasis.

Overexpression of Wnt-2 in colorectal cancers.

UNLABELLED: The binding of the Wnt ligand to its receptor Frizzled, activates the Wnt canonical signaling pathway in carcinogenesis as well as many cellular processes, including cellular proliferation and differentiation. Wnt-2, one of 19 members of the Wnt gene family, is frequently overexpressed in malignant tissues. Here, in order to investigate the role of Wnt-2 in colorectal carcinogenesis, we examined the expression of the Wnt-2 protein in 120 colorectal cancers by immunohistochemistry. Wnt-2 protein was expressed in the cell membrane and cytoplasm and up-regulated in 74 (61.7%) of 120 colorectal cancers. Statistically, overexpression of Wnt-2 protein was not associated with the clinical and pathological parameters studied, including tumor location, tumor size, clinical stage, lymph node metastasis, and 5-year survival (P > 0.05). These results indicate that up-regulation of the Wnt-2 protein might play a role in the development of colorectal cancers, as an early event of carcinogenesis. KEYWORDS: Wnt-2 protein, expression, immunohistochemistry, tissue microarray, colon cancer.

Mutational analysis of JAK1 gene in human hepatocellular carcinoma.

UNLABELLED: The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that is noncovalently associated with a variety of cytokine receptors and plays a nonredundant role in cell proliferation, survival, and differentiation. The mutated forms of JAK1 often altered the activation of JAK1 and then changed the activation of JAK1/STAT pathways, and this may contribute to cancer development and progression. Thus, to investigate whether genetic mutations of JAK1 gene are associated in hepatocellular carcinoma (HCC) progression, we analyzed genetic alterations of JAK1 gene in 84 human HCCs by single-strand conformational polymorphism (SSCP) and direct sequencing. Of 24 exons of JAK1 gene, 12 exons were previously reported to have mutations, we searched genetic alteration of JAK1 in these exons. Overall, one missense mutation (1.2%) was found. In addition, 12 cases (14%) were found to have single nucleotide polymorphism (14%) in exon 14. Taken together, we found one novel missense mutation of JAK1 gene in hepatocellular carcinomas with some polymorphisms. Although the functional assessment of this novel mutant remains to be completed, JAK1 mutation may contribute to the tumor development in liver cancer. KEYWORDS: JAK1 gene, hepatocellular carcinoma, mutation.

Down-regulation of ATBF1 is a major inactivating mechanism in hepatocellular carcinoma.

AIMS: alpha-Fetoprotein (AFP) is frequently detected in hepatocellular carcinomas (HCCs) and AT motif binding factor 1 (ATBF1) down-regulates AFP gene expression in hepatic cells. The ATBF1 gene also inhibits cell growth and differentiation, and altered gene expression is associated with malignant transformation. The aim was to investigate the potential role of the ATBF1 gene in HCCs. METHODS AND RESULTS: Somatic mutations, allelic loss and hypermethylation of the ATBF1 gene were analysed in 76 sporadic HCCs. The level of ATBF-1 mRNA expression was analysed using quantitative real-time reverse transcriptase-polymerase chain reaction. Genetic studies of the ATBF1 gene revealed absence of somatic mutation in the hotspot region and 15 (25%) of 60 informative cases showed allelic loss at the ATBF1 locus. Hypermethylation in the intron 1 region of the ATBF1 gene was detected in only one case. Interestingly, ATBF1 mRNA expression in HCCs was significantly reduced in 55 (72.4%) samples compared with the corresponding surrounding liver tissues. Reduced expression was not statistically associated with clinicopathological parameters including stage, histological grade, infective virus type, and serum alpha-fetoprotein level. CONCLUSIONS: The ATBF1 gene may contribute to the development of HCCs via transcriptional down-regulation of mRNA expression, but not by genetic or epigenetic alterations.

No association of MDM2 T309G polymorphism with susceptibility to Korean gastric cancer patients.

Mouse double minute 2 (Mdm2) acts as a negative regulator of p53 by binding to the amino-terminus of p53. The common T309G polymorphism of Mdm2 has been the most frequently investigated, which can influence in cancer susceptibility and disease outcome. The specific aim of this study is to investigate whether the T309G polymorphism of Mdm2 was associated with individual susceptibility to gastric cancer in Korea. The frequency of the polymorphism was examined in 239 gastric cancer patients and 299 healthy controls. Polymorphism analysis was performed by amplifying the first intron of the Mdm2 and digesting with restriction enzyme and sequencing the products. The frequencies of genotypes: T/T, T/G and G/G were 26.8% (64/239), 46.0% (110/239) and 27.2% (65/239), respectively, in gastric cancer cases and 20.4% (61/299), 50.8% (152/ 299) and 28.8% (86/299), respectively, in healthy controls. Statistically, there was no significant difference in the frequency of genotype and allele between healthy control and gastric cancer patients. Finally, the polymorphism was not associated with increased risk of gastric cancer in this population. When stratified by histological subtype of gastric cancer, the risk was also not statistically significant. Our findings suggested that the T309G polymorphism of Mdm2 was not associated with an increased risk for gastric cancer in Korean population.

KLF6 IVS1 -27G/A polymorphism with susceptibility to gastric cancers in Korean.

KLF6 is a key cell cycle regulator that is downregulated in several kinds of human cancers, including gastric cancer. The IVS1 -27G/A polymorphism of KLF6 has been investigated, which can influence susceptibility to gastric cancer and disease outcome. In order to investigate whether the IVS1 -27G/A polymorphism of KLF6 is associated with individual susceptibility to gastric cancer in Korea, the frequency of the polymorphism was examined in 264 gastric cancer patients and 299 healthy controls. Single nucleotide polymorphism (SNP) analysis was performed by amplifying intron 1 of KLF6 and sequencing the products. The frequencies of genotypes: G/G, G/A and A/A were 91.7% (242/264), 5.7% (15/264) and 2.6%, respectively, in gastric cancer cases and 91.9%, 7.0% and 1.1%, respectively, in healthy controls. Genotype frequencies in Korean population were very similar to those of Caucasian population. Interestingly, the male gastric cancer patients showed a significantly higher proportion of the G allele (Chi-Square test, P=0.005) compared to female gastric cancer patients. However, the polymorphism was statistically not associated with increased risk of gastric cancer in Korea. When stratified by histological subtype of gastric cancer, the risk was also not statistically significant. Thus, our results suggested that the IVS1 -27G/A polymorphism of KLF6 is not associated with an increased risk for gastric cancer in Korean population.

Association of cyclin D1 G870A polymorphism with susceptibility to gastric cancers in Korean male patients.

Cyclin D1 is a key cell cycle regulator that is upregulated in gastric cancer. The common G870A polymorphism of cyclin D1 which can influence cancer susceptibility and disease outcome has been the most frequently investigated. The specific aim of this study is to investigate whether the G870A polymorphism of cyclin D1 was associated with individual susceptibility to gastric cancer in Korea. The frequency of the polymorphism was examined in 253 gastric cancer patients and 442 healthy controls. Polymorphism analysis was performed by amplifying exon 4 of cyclin D1 and sequencing the products. The frequencies of genotypes: G/G, G/A and A/A were 28.1% (71/253), 49.4% (125/253) and 22.5% (57/253), respectively, in gastric cancer cases, and 23.1%, 51.1% and 25.8%, respectively, in healthy controls. Statistically, the polymorphism was not associated with increased risk of gastric cancer. When stratified by histological subtype of gastric cancer, the risk was also not statistically significant. However, the male gastric cancer patients showed a significantly higher proportion of the homozygous G/G genotype and the G allele (Chi-Square test, P = 0.0242 & P = 0.0307) compared to males in the control group. Thus, our findings suggested that the G870A polymorphism of cyclin D1 was not associated with an increased risk for gastric cancer in this population, however, it may contribute to susceptibility to gastric cancer in men.

Chk1 frameshift mutation in sporadic and hereditary non-polyposis colorectal cancers with microsatellite instability.

AIM: Protein kinase Chk1 (hChk1) is essential in human cells for cell cycle arrest in response to DNA damage, and has been shown to play an important role in the G2/M checkpoint. The BRAF mutations have been suggested to be linked with defective mismatch repair in colorectal cancers. The aim of this study was to investigate whether a frameshift mutation within the Chk1 gene contribute to the development or progression of eastern sporadic and hereditary non-polyposis colorectal cancer (HNPCC) with microsatellite instability (MSI). METHODS: We analyzed MSI using the 6 microsatellite markers and a frameshift mutation in the BRAF gene and in poly(A)9 within the Chk1 gene in 51 sporadic colorectal cancer and 14 HNPCC specimens. RESULTS: Eleven of the 51 sporadic colorectal cancers and all of the 14 HNPCCs were MSI-positive. Chk1 frameshift mutations were observed in 2 and 3 sporadic colon cancers and HNPCC, respectively, whereas no BRAF mutations were detected in these samples. Interestingly, all cases with the Chk1 frameshift mutation had high-frequency MSI. CONCLUSION: These results suggest that the Chk1 gene is a target of genomic instability in MSI-positive colorectal cancers and that the Chk1 framshift mutations might be involved in colorectal tumourigenesis through a defect in response to DNA damage in a subset of sporadic colorectal cancers and HNPCCs.

Mutational analysis of the hCDC4 gene in gastric carcinomas.

hCDC4, a ubiquitin ligase, plays a role in the control of cell cycle and chromosome stability. The hCDC4 gene is considered a tumour suppressor gene and is mutated in several human neoplasias, including colorectal and endometrial tumours. Data on the hCDC4 mutation in gastric cancer is, however, lacking. This study explored the possibility that hCDC4 mutation is involved in the development of gastric cancer. The hCDC4 gene in 162 gastric adenocarcinoma tissues was analysed for somatic mutations using a polymerase chain reaction-single strand conformation polymorphism assay. Overall, six hCDC4 mutations were found (3.7%), comprising four missense, one frameshift deletion and one nonsense mutation(s). It is notable that the hCDC4 mutations were found in early as well as in advanced gastric carcinomas. These data indicate that hCDC4 mutation occasionally occurs in gastric carcinomas and suggest that it might play a role in the development of some gastric carcinomas.