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Haruhiko Sugimura

Publications and source records attributed to Haruhiko Sugimura.

At least 19 recordsLinked to original sources
PubMed2026

Hereditary Diffuse Gastric Cancer With Poorly Differentiated Gallbladder Adenocarcinoma: A Case Report Suggesting Carcinogenesis in the Stomach and Gallbladder Caused by a Pathogenic Germline Variant in CDH1.

BACKGROUND/AIM: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome primarily characterized by a high lifetime risk of diffuse gastric cancer and lobular breast cancer. It is predominantly caused by inactivating germline variants in the tumor suppressor gene CDH1. While the association between HDGC and these two specific malignancies is well-established, the co-occurrence of extra-gastric malignancies in other organs remains exceptionally rare. In particular, the clinical and genetic relationship between HDGC and gallbladder adenocarcinoma has not been previously clarified. CASE REPORT: We present the case of a 67-year-old female initially referred for surgical management of gallbladder cancer (GBC) following an initial cholecystectomy for progressive wall thickening. Pathological examination of the gallbladder revealed a de novo, poorly differentiated adenocarcinoma invading the subserosal layer with reduced E-cadherin expression. Given the atypical histopathology and a significant family history-her father and brother both died of gastric cancer at young ages-a preoperative gastric endoscopy was performed. The endoscopy identified multiple faded mucosal lesions, which biopsy confirmed as signet-ring cell carcinoma. The patient subsequently underwent total gastrectomy and gallbladder bed resection. Postoperative pathology identified 22 distinct malignant gastric lesions, predominantly signet-ring cell carcinoma (pT1a), showing variable or lost E-cadherin expression. Germline genetic testing via direct sequencing identified a pathogenic frameshift mutation in exon 5 of the CDH1 gene. CONCLUSION: This represents the first reported case of synchronous HDGC and primary gallbladder adenocarcinoma associated with a germline CDH1 mutation. Our findings suggest that pathogenic CDH1 variants may contribute to the carcinogenesis of poorly differentiated gallbladder adenocarcinoma. Clinicians should consider the possibility of extra-gastric malignancies in HDGC patients.

Humans↗
PubMed2004

Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation.

Retinoblastoma gene product (pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB. pRB was efficiently ubiquitinated by wild-type Mdm2 in vivo as well as in vitro, but other RB family proteins were not. Mutant Mdm2 with a substitution in the RING finger domain showed dominant-negative stabilization of pRB. Both knockout and knockdown of Mdm2 caused accumulation of pRB. Moreover, Mdm2 inhibited pRB-mediated flat formation of Saos-2 cells. Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers. These results suggest that Mdm2 regulates function of pRB via ubiquitin-dependent degradation of pRB.

Animals↗
PubMed2004

Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer.

Oxidized DNA base lesions, such as thymine glycol (Tg) and 8-hydroxyguanine, are often toxic and mutagenic and have been implicated in carcinogenesis. To clarify whether NEIL1 protein, which exhibits excision repair activity towards such base lesions, is involved in gastric carcinogenesis, we examined 71 primary gastric cancers from Japanese patients and four gastric cancer cell lines for mutations and genetic polymorphisms of the NEIL1 gene. We also examined 20 blood samples from Chinese patients for NEIL1 genetic polymorphisms. Three mutations (c.82_84delGAG:p.Glu28del, c.936G > A and c.1000A > G:p.Arg334Gly) and two genetic polymorphisms were identified. When the excision repair activity towards double-stranded oligonucleotide containing a Tg:A base pair was compared among six types of recombinant NEIL1 proteins, p.Glu28del-type NEIL1, found in a primary case, was found to exhibit an extremely low activity level. Moreover, c.936G > A, located in the last nucleotide of exon 10 and detected in the KATO-III cell line, was shown to be associated with a splicing abnormality using an in vivo splicing assay. An immunofluorescence analysis showed that the wild-type NEIL1 protein, but not the truncated protein encoded by the abnormal transcript arising from the c.936G > A mutation, was localized in the nucleus, suggesting that the truncated protein is unlikely to be capable of repairing nuclear DNA. An expression analysis revealed that NEIL1 mRNA expression was reduced in six of 13 (46%) primary gastric cancer specimens that were examined. These results suggest that low NEIL1 activities arising from mutations and reduced expression may be involved in the pathogenesis in a subset of gastric cancers.

Alternative Splicing↗
PubMed2004

Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.

Arylamine N-Acetyltransferase↗
PubMed2004

A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus.

The MYH gene encodes a DNA glycosylase involved in the excision repair of adenines paired with 8-hydroxyguanines, a major component of oxidative DNA damage, and bi-allelic germline MYH mutations have been reported to predispose individuals to multiple colorectal adenomas and carcinoma. To determine whether the MYH gene is involved in gastric carcinogenesis, we examined blood specimens from 20 Japanese familial gastric cancer (GC) patients for MYH mutations by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis followed by direct sequencing. Bi-allelic germline MYH mutations were not found in any of the specimens, but in addition to four known variants, a novel splice-site variant, IVS10-2A > G (c.892-2A > G), was found in two patients as its heterozygote. Reverse transcription-PCR analysis revealed that the IVS10-2A > G variant caused the production of an aberrant mRNA transcript encoding a truncated MYH protein. Immunofluorescence analysis showed that the wild-type MYH protein, but not the variant-type, is localized in the nucleus. We then searched for the IVS10-2A > G variant in 128 digestive tract cancer patients by PCR with confronting two-pair primers, and eight cancers from six patients with the IVS10-2A/G genotype were identified. However, no other germline MYH mutations or inactivation of the remaining wild-type allele was detected. We next tested the presumed correlation of the IVS10-2G allele with GC risk in a case-control study of 148 GC cases and 292 controls, but no significant difference in the distribution of the IVS10-2A > G variant was found between the cases and controls. Interestingly, the homozygote for the IVS10-2G allele was found in one GC case, but not in any controls. These results suggested that the ability to repair 8-hydroxyguanine in nuclear DNA may differ among Japanese individuals due to the splicing abnormality based on the MYH IVS10-2A > G variant, and that the bi-allelic IVS10-2A > G variation may be responsible for the occurrence of GC.

Adult↗
PubMed2004

Three-dimensional microarray compared with PCR-single-strand conformation polymorphism analysis/DNA sequencing for mutation analysis of K-ras codons 12 and 13.

BACKGROUND: We developed a rapid, precise, and accurate microarray-based method that uses a three-dimensional platform for detection of mutations. METHODS: We used the PamChip microarray to detect mutations in codons 12 and 13 of K-ras in 15 cell lines and 81 gastric or colorectal cancer tissues. Fluorescein isothiocyanate-labeled PCR products were analyzed with the microarray. We confirmed the microarray results with PCR-single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. RESULTS: We could correctly identify wild-type, heterozygous, and homozygous mutant genotypes with the PamChip microarray in <3.5 h. The array data were consistent with those of PCR-SSCP analysis and DNA sequencing. All 15 cell lines and 80 of 81 clinical cancer specimens (98.8%; 95% confidence interval, 96.4-100%) were genotyped accurately with the microarray, a rate better than that of direct DNA sequencing (38.9%) or SSCP (93.8%). Only one clinical specimen was misdiagnosed as homozygous for the wild-type allele. Densitometric analysis of SSCP bands indicated that the content of the mutant allele in the specimen was approximately 16%. The PamChip microarray could detect mutant alleles representing more than 25% of the SSCP band proportions. Therefore, the limit for detection of mutant alleles by the PamChip microarray was estimated to be 16-25% of the total DNA. CONCLUSIONS: The PamChip microarray is a novel three-dimensional microarray system and can be used to analyze K-ras mutations quickly and accurately. The mutation detection rate was nearly 100% and was similar to that of PCR-SSCP together with sequencing analysis, but the microarray analysis was faster and easier.

Cell Line, Tumor↗
PubMed2004

Identification of genes whose expression is upregulated in lung adenocarcinoma cells in comparison with type II alveolar cells and bronchiolar epithelial cells in vivo.

To identify genes whose expression is upregulated in lung adenocarcinoma (AdC) cells in comparison with noncancerous peripheral lung epithelial cells, type II alveolar cells and bronchiolar epithelial cells, as well as AdC cells, were isolated by laser capture microdissection, and subjected to cDNA microarray analysis of 637 human cancer-related genes. Each of the component cells was obtained from several different individuals and analysed independently. As a comparison, two lung AdC cell lines and two primarily cultured normal lung epithelial cell lines were also subjected to cDNA microarray analysis. Four genes, TOP2A, MMP15, MX2 and KOC1, were commonly upregulated in microdissected AdC cells in comparison with microdissected epithelial cells. Hierarchical clustering analysis revealed that differences in gene-expression profiles were more evident between cultured and uncultured cells than between cancerous and noncancerous cells. To further identify the common molecular targets of AdC cells in vivo, quantitative real-time RT-PCR was performed against the four genes upregulated by cDNA microarray analysis. The TOP2A, MMP15, MX2 and KOC1 genes were overexpressed in 10/10 (100%), 8/10 (80%), 5/10 (50%) and 3/10 (30%) microdissected AdC cell samples, respectively, in comparison with any of nine independently microdissected noncancerous epithelial cell samples. The TOP2A gene was commonly overexpressed in lung AdC cells, as previously reported. In addition, the MMP15 and MX2 genes were identified, for the first time, as being commonly overexpressed in lung AdC cells. These results strongly indicate that the MMP15 and MX2 genes could be novel markers for molecular diagnosis and therapy of lung AdC.

Adenocarcinoma↗
PubMed2004

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2.

Bidirectional signals mediated by Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, play pivotal roles in the formation of neural networks by induction of both collapse and elongation of neurites. However, the downstream molecular modules to deliver these cues are largely unknown. We report here that the interaction of a Rac1-specific guanine nucleotide-exchanging factor, Tiam1, with ephrin-B1 and EphA2 mediates neurite outgrowth. In cells coexpressing Tiam1 and ephrin-B1, Rac1 is activated by the extracellular stimulation of clustered soluble EphB2 receptors. Similarly, soluble ephrin-A1 activates Rac1 in cells coexpressing Tiam1 and EphA2. Cortical neurons from the E14 mouse embryos and neuroblastoma cells significantly extend neurites when placed on surfaces coated with the extracellular domain of EphB2 or ephrin-A1, which were abolished by the forced expression of the dominant-negative mutant of ephrin-B1 or EphA2. Furthermore, the introduction of a dominant-negative form of Tiam1 also inhibits neurite outgrowth induced by the ephrin-B1 and EphA2 signals. These results indicate that Tiam1 is required for neurite outgrowth induced by both ephrin-B1-mediated reverse signaling and EphA2-mediated forward signaling.

Animals↗
PubMed2004

Splice-site genetic polymorphism of the human kallikrein 12 (KLK12) gene correlates with no substantial expression of KLK12 protein having serine protease activity.

The human kallikrein 12 (KLK12) gene is a new member of the KLK gene family, some members of which are implicated in the initiation and progression of cancer. In this study, we examined 50 non-cancerous tissues from Japanese patients with primary gastric cancer to determine the presence of genetic polymorphisms in the KLK12 gene using polymerase chain reaction (PCR)-single-strand conformation polymorphism and sequencing. Four different types of genetic polymorphisms were identified: one at a splice-donor site of intron 4 (c.457+2T>C), two in exon 6 (c.618_619delTG:p.Cys206fsX72 and c.735G>A:p.Met245Ile), and one in intron 3. The c.457+2T>C polymorphism was observed at a high frequency (allele frequency:0.63), compared to the frequencies of the two polymorphisms in exon 6 (allele frequency:0.01). Reverse transcriptase (RT)-PCR and Western blot analyses revealed that the c.457+2T>C polymorphism was associated with a splicing abnormality and that the expression of the human KLK12 protein (hK12), corresponding to the putative serine protease, was absent in individuals with a c.457+2C/C genotype but not in individuals with the T/T or T/C genotypes. We also found that recombinant His6-tagged hK12 has activity that cleaves chromogenic substrate (H-D-Pro-L-Phe-L-Arg-p-nitroaniline dihydrochloride), that is, serine protease activity. These results indicate that individuals with the c.457+2C/C genotype have no substantial expression of hK12 serine protease.

Carcinoma↗
PubMed2004

Amplicons on human chromosome 11q are located in the early/late-switch regions of replication timing.

Amplicons are frequently found in human tumor genomes, but the mechanism of their generation is still poorly understood. We previously measured the replication timing of the genes along the entire length of human chromosomes 11q and 21q and found that many "disease-related" genes are located in timing-transition regions. In this study, further scrutiny of the updated replication-timing map of human chromosome 11q revealed that both amplicons on human chromosomal bands 11q13 and 11q22 are located in the early/late-switch regions of replication timing in two human cell lines (THP-1 and Jurkat). Moreover, examination of synteny in the human and mouse genomes revealed that synteny breakage in both genomes occurred primarily at the early/late-switch regions of replication timing that we had identified. In conclusion, we found that the early/late-switch regions of replication timing coincided with "unstable" regions of the genome.

Animals↗
PubMed2004

Polymorphism of interleukin-1beta affects the eradication rates of Helicobacter pylori by triple therapy.

BACKGROUND AND AIMS: Polymorphism in interleukin-1beta (IL-1beta) is associated with intragastric pH levels in Helicobacter pylori-positive subjects. Intragastric pH levels affect the activity of antibiotics against H. pylori in the stomach. The aim of this study was to investigate whether IL-1beta polymorphism is associated with eradication rates of H. pylori by triple therapy with a proton pump inhibitor (PPI), amoxicillin, and clarithromycin. METHODS: Three hundred thirty-six patients infected with H. pylori completed treatment with omeprazole, 20 mg, or lansoprazole, 30 mg twice daily; clarithromycin, 200 mg 3 times daily; and amoxicillin, 500 mg 3 times daily, for 1 week. IL-1beta-511 and CYP2C19 genotypes of patients and sensitivity of H. pylori to clarithromycin and amoxicillin were determined. RESULTS: Logistic regression analysis showed that the IL-1beta-511 polymorphism, as well as CYP2C19 genotype of patients and clarithromycin-resistance of H. pylori, was associated with successful eradication. Eradication rates for H. pylori were 77.3% (75 of 97; 95% confidence interval, 67.5-84.6), 89.6% (147 of 164; 95% confidence interval, 83.9-93.1), and 94.7% (95% confidence interval, 86.9-98.5) in patients with the C/C, C/T, and T/T genotypes of IL-1beta-511, respectively (P = 0.0014). CONCLUSIONS: IL-1beta-511 polymorphism is one of the determinants of successful eradication of H. pylori using triple therapy with a PPI, amoxicillin, and clarithromycin, together with CYP2C19 genotype and bacterial resistance to clarithromycin.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2004

Potential usefulness of detecting cyclooxygenase 2 messenger RNA in feces for colorectal cancer screening.

BACKGROUND & AIMS: Cyclooxygenase 2 (COX-2) is overexpressed frequently in aerodigestive tumors, especially in colorectal tumors. Therefore, it may be a suitable biomarker for colorectal cancer (CRC) screening. We performed a pilot study of whether detecting COX-2 expression in fecal RNA enables us to discriminate between patients with and without CRC. METHODS: The study cohort included 29 patients with CRC, and 22 control patients without neoplastic disease of the colon or rectum. RNA was isolated from routinely collected stool samples using a modified method. The expression levels of carcinoembryonic antigen (CEA) and COX-2 were determined by nested reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: The sensitivity and the specificity of fecal COX-2 assay for CRC were 90% (95% confidence interval [CI], 73%-98%) and 100% (95% CI, 85%-100%), respectively, whereas those of the fecal CEA assay for CRC were 100% (95% CI, 88%-100%) and 5% (95% CI, 2%-23%), respectively. COX-2 messenger RNA (mRNA) was detected in 3 of 4 patients with Dukes' stage A, 13 of 14 patients with Dukes' stage B, and 10 of 11 patients with Dukes' stage C or D. COX-2 mRNA was detected in 5 of 7 patients with proximal cancer and in 21 of 22 patients with distal cancer. The COX-2 assay was superior to the CEA assay for detecting CRC in terms of specificity, although both assays had high sensitivity. CONCLUSIONS: This fecal COX-2 assay had high sensitivity and high specificity for detecting CRC. These results suggest that it would be a promising approach for detecting CRC, although a larger study is necessary to assess the sensitivity and the specificity.

Adult↗
PubMed2004

Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer.

Evidence suggests that the erythropoietin-producing hepatocellular (EPH) receptor tyrosine kinases (RTKs) and their ephrin (EFN) ligands are involved in human carcinogenesis. Expression of two of them, EFNA1 ligand and its receptor, EPHA2, has been proposed to contribute to tumor-induced neovascularization. Colorectal cancers were examined for expressions of EPHA2 and its ligand EFNA1 by semi-quantitative RT-PCR, and double-immunostained for EPHA2 and CD34. Microvessels in the tumors were counted. Double-staining was also performed in 25 cases of adenoma with focal cancer for comparison. Trends of overexpression of both EPHA2 and EFNA1 was found in tumor tissue compared to the corresponding normal tissue in the same specimen [22/37 (59.5%) and 25/37 (67.5%), respectively; P = 0.100 for EPHA2 and P = 0.009 for EFNA1]. Overexpression of EPHA2 and EFNA1 was noted more frequently in the early stage than in the late stage [EPHA2, 15/21 (71.4%) vs. 7/16 (43.8%), P = 0.007; EFNA1, 15/21 (71.4%) vs. 10/16 (62.5%), P = 0.007]. Both EPHA2 and EFNA1 were more frequently overexpressed in smaller tumors (less than 5 cm) than in larger tumors [EPHA2, 15/21 (71.4%) vs. 7/16 (43.8%), P = 0.017; EFNA1, 16/21 (76.2%) vs. 8/16 (50%), P = 0.001]. Tumors less than 5 cm in diameter and in stages I and II were significantly more likely to overexpress EPHA2 and EFNA1 (P = 0.001 for EPHA2, P = 0.001 for EFNA1). Microvessel counts (MVCs) after immunostaining for CD34 were significantly correlated (r = 0.343, P = 0.037) with overexpression of EPHA2. EPHA2-expressing focal cancer also surrounded microvessels in adenomas with focal cancers. These findings suggest an involvement of EPHA2 in colon carcinogenesis, mainly in stages I and II, and probably through their effect on microvessel induction.

Aged↗
PubMed2004

JAM4 enhances hepatocyte growth factor-mediated branching and scattering of Madin-Darby canine kidney cells.

Junctional adhesion molecule (JAM) 4 is a member of immunoglobulin superfamily that interacts with MAGI-1, a membrane-associated guanylate kinase protein at tight junctions in epithelial cells. We prepared Madin-Darby canine kidney II (MDCK) cells expressing JAM4 (MDCK-JAM4) and compared them with wild MDCK cells. The treatment of hepatocyte growth factor (HGF) induced more prominent branching and scattering in MDCK-JAM4 cells. Subsequently we attempted to identify signalling pathways modified by JAM4. The over-expression of JAM4 induced the formation of protrusions in COS-7 cells. Although those protrusions were different from typical lamellipodia, the dominant negative mutant of Rac suppressed them. The pull-down assay using CDC42 and Rac interactive binding domain of PAK also supports that Rac is activated in COS-7 cells expressing JAM4. Taken together, JAM4 itself activates Rac and may augment Rac activation by HGF, resulting in the enhancement of branching and scattering.

Animals↗
PubMed2004

[A case of gastric GIST treated preoperatively by imatinib mesylate].

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, is thought to originate from the interstitial cells of Cajal. The mutation of c-kit, cording KIT, is essential in the development of GIST. Imatinib mesylate (IM), an agent for chronic myeloid leukemia, was reported to inhibit tyrosine kinase activity of KIT and to be highly effective for GIST. We report, here, a case of huge gastric GIST who underwent neoadjuvant therapy followed by surgical resection. The patient was a 62-year-old man with GIST in cardia (KIT+, CD34+, mitotic rate 5/50 HPF), whose chief complaint was general fatigue. Because the huge tumor, 7.5 cm in size, directly invaded the pancreas, total gastrectomy with distal pancreatosplenectomy was necessary for curative resection. IM was administered (400 mg/body/day) as a neoadjuvant treatment for down-staging of the tumor. Leucopenia (grade 2) and diarrhea (grade 1) were observed as the adverse effects of IM. Partial response was obtained. He underwent proximal gastrectomy without pancreatosplenectomy since CT no longer showed direct invasion to the pancreas. Histological examination of the resected specimen revealed the extensive degeneration of the tumor, in which tumor cells containing condensed nuclei had decreased remarkably. Interestingly, mitotic rate decreased to 0/50 HPF in the effective area of the resected specimen, indicating that recurrent risk might be decreased. A part of the viable tumor cells, however, had the same feature to that in the biopsied specimen before treatment. The results suggest that the heterogeneity of GIST induces different sensitivity to IM. The postoperative course was uneventful and no sign of recurrence was observed 3 months after surgery. Neoadjuvant therapy with IM may become a useful strategy for GIST, as it reduces the tumor size and decreases the recurrence rate.

Antigens, CD34↗
PubMed2004

[Two cases of postoperative recurrence of gastric GIST treated by imatinib].

We report two cases of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor imatinib mesylate (IM), and discuss some important items. Case 1: This 63-year-old Japanese man received a partial gastrectomy for leiomyosarcoma in 1993. Partial hepatectomy and proximal gastrectomy were performed for liver metastasis and local recurrence in 2001. However, 5 months after surgery, a CT scan showed multiple tumors in the liver, lung and thyroid. The patient was treated with 300 mg of IM once daily with transient grade 2 neutropenia and intestinal bleeding. Though the response to treatment was SD-PR initially, a CT scan 15 months after initial treatment demonstrated the regrowth of the tumor in his liver. Case 2: A 63-year-old Japanese woman was treated with 200 mg of IM once daily for multiple liver metastases after gastrectomy for GIST with grade 3 neutropenia and edema of legs. The response to treatment was SD, and continued for 12 months. IM is the treatment of choice for unresectable recurrence of GIST. However, some problems remained. Both basic and clinical research is necessary to increase the therapeutic efficacy of IM.

Antineoplastic Agents↗
PubMed2003

A novel secretory factor, Neurogenesin-1, provides neurogenic environmental cues for neural stem cells in the adult hippocampus.

Neurogenesis occurs in restricted regions in the adult mammalian brain, among which the neurogenesis in the hippocampal dentate gyrus plays the crucial role in learning and memory. To date, little is known about neurogenic cues, which result in the neuronal fate adoption of neural stem cells residing in neurogenic regions, especially neurogenic cues in adult hippocampal neurogenesis. In the present study, we show that hippocampal astrocytes and also dentate granule cells adjacent to neural stem cells secrete a newly cloned novel secretory factor, Neurogenesin-1. This protein contains three cysteine-rich domains and a unique sequence and contributes to neuronal differentiation of neural stem cells in the adult brain by preventing the adoption of a glial fate. Furthermore, the neurogenic activity detected in the hippocampal culture medium was markedly suppressed by the administration of an anti-Neurogenesin-1 antibody. These findings suggest endogenous mechanisms that induce adult hippocampal neurogenesis and propose an innovative treatment for the neurodegenerative diseases that cause loss of hippocampal neurons.

Amino Acid Sequence↗