Gene Summary

Gene:SEPT5; septin 5
Summary:This gene is a member of the septin gene family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. This gene is mapped to 22q11, the region frequently deleted in DiGeorge and velocardiofacial syndromes. A translocation involving the MLL gene and this gene has also been reported in patients with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. The presence of a non-consensus polyA signal (AACAAT) in this gene also results in read-through transcription into the downstream neighboring gene (GP1BB; platelet glycoprotein Ib), whereby larger, non-coding transcripts are produced. [provided by RefSeq, Dec 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 13 March, 2017

Cancer Overview

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Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SEPT5 (cancer-related)

Igawa T, Sato Y, Kawai H, et al.
Spontaneous regression of plasmablastic lymphoma in an elderly human immunodeficiency virus (HIV)-negative patient.
Diagn Pathol. 2015; 10:183 [PubMed] Free Access to Full Article Related Publications
Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with human immunodeficiency virus (HIV) infection. Herein we describe a rare case of PBL that spontaneously regressed. An 80-year-old man was referred to our hospital owing to an exophytic gingival tumor in the right maxillary second molar region. He had no significant past medical history, and a screening test for HIV was negative. Imaging showed that the tumor measured 26 × 23 × 16 mm and was confined in the alveolar bone. The tumor was histologically comprised of highly proliferative immunoblastic cells positive for CD138 and Epstein-Barr virus (EBV)-encoded RNA. Monoclonal IgH chain gene rearrangement was detected via polymerase chain reaction. After biopsy and diagnosis of PBL, the tumor began to decrease in size and had apparently disappeared at the time of surgery. There was no histological evidence of a residual lesion in the surgical specimen. In conclusion, a minority of immunosenescence-associated PBLs in the elderly should be recognized as a unique clinicopathological entity distinct from common aggressive PBL.

Maugeri G, D'Amico AG, Magro G, et al.
Expression profile of parkin isoforms in human gliomas.
Int J Oncol. 2015; 47(4):1282-92 [PubMed] Related Publications
Mutations of parkin gene are not restricted to familial forms of Parkinsonism but they also occur in a wide variety of malignancies including gliomas. Parkin over-expression reduces glioma cells proliferation and analysis of its expression is predictive for the survival outcome of patients with glioma. To date have been identified 21 parkin alternative splice variants. However, most of the studies have focused their attention exclusively on full-length protein. In the present study, the expression profile of parkin isoforms in different grades of astrocytomas was analyzed for the first time, in order to evaluate their involvement in this malignancy. Furthermore, to investigate their role in cellular processes, their expression in three glioblastoma cell lines was analyzed following treatment with the proteasome inhibitor MG132, or induction of mitophagy with CCCP, or after serum deprivation. Results suggested that H20, H1 and H5 isoforms are always expressed in tumors both in vivo and in vitro models. Therefore, these isoforms might be used as specific biomarkers to develop a prognostic tool for brain tumors.

D'Amico AG, Maugeri G, Magro G, et al.
Expression pattern of parkin isoforms in lung adenocarcinomas.
Tumour Biol. 2015; 36(7):5133-41 [PubMed] Related Publications
The parkin gene has been shown to be genetically altered in a wide variety of human tumors including lung cancer. Although many parkin splice variants have been identified, to date, most of the studies have only been focused on originally cloned isoforms. In this work, for the first time, the expression profile of parkin isoforms in human lung adenocarcinomas has been analyzed to identify their involvement in lung cancer. Their contribution in some biological conditions, such as proteasomal degradation or mitophagy or cell death, has been analyzed in human lung cells. The expression profile of parkin isoforms has been investigated in paraffin-embedded samples of human lung adenocarcinomas by using Western blot analysis. Their expression has also been evaluated in human lung adenocarcinoma and in human normal bronchial epithelial cell lines following treatment with a proteasome inhibitor or mitochondrial depolarizing agent, or in serum starvation. Parkin proteins were detected on blot by using two antibodies, AbI and AbII, which recognize different domains of originally cloned parkin. Furthermore, parkin immunolocalization has been visualized in both cell lines by using immunofluorescence analysis. Results have shown that H1 and/or H5, H14, H4 and/or H8 and/or H17 and H3 and/or H12 isoforms are expressed in human lung adenocarcinomas. Some of them are also present in A549 cell line, whereas they are absent or faintly expressed in BEAS-2B cells. Furthermore, their expression changed after treatment. Human lung adenocarcinomas express different parkin isoforms, which might represent markers of malignancy and could be linked to specific biological functions.

Panagopoulos I, Gorunova L, Bjerkehagen B, Heim S
Novel KAT6B-KANSL1 fusion gene identified by RNA sequencing in retroperitoneal leiomyoma with t(10;17)(q22;q21).
PLoS One. 2015; 10(1):e0117010 [PubMed] Free Access to Full Article Related Publications
Retroperitoneal leiomyoma is a rare type of benign smooth muscle tumor almost exclusively found in women and with histopathological features similar to uterine leiomyomas. The pathogenesis of retroperitoneal leiomyoma is unclear and next to nothing is known about the cytogenetics and molecular genetics of the tumor. Here we present the first cytogenetically analyzed retroperitoneal leiomyoma. It had a t(10;17)(q22;q21) as the sole chromosomal abnormality. Using RNA-Sequencing and the 'grep' command to search the fastq files of the sequence data we found that the translocation resulted in fusion of the genes KAT6B (10q22) with KANSL1 (17q21). RT-PCR together with direct (Sanger) sequencing verified the presence of a KAT6B-KANSL1 fusion transcript. No reciprocal KANSL1-KAT6B transcript was amplified suggesting that it was either absent or unexpressed. The KAT6B-KANSL1 fusion transcript consists of exons 1 to 3 of KAT6B and exons 11 to 15 of KANSL1, is 3667 bp long, has a 1398 bp long open reading frame, and codes for a 466 amino acid residue protein. The corresponding KAT6B-KANSL1 protein contains the NEMM domain (including the linker histone H1/H5, domain H15) of KAT6B and the PEHE domain of KANSL1. The function of the fusion protein might be regulation of transcription with an affinity for chromatin (linker histone H1/H5) and interaction with the HAT domain of KAT8 (PEHE domain). The tumor expressed HMGA2 and HMGA1 even though 12q14-15 and 6p looked normal by G-banding analysis. The tumor also expressed MED12 in the absence of exon 2 mutations. Overall, the data show that the examined retroperitoneal leiomyoma resembles a subset of uterine leiomyomas in terms of histology and genetics.

Janakiram M, Chinai JM, Fineberg S, et al.
Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein.
Clin Cancer Res. 2015; 21(10):2359-66 [PubMed] Free Access to Full Article Related Publications
PURPOSE: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors.
EXPERIMENTAL DESIGN: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors.
RESULTS: HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2.
CONCLUSIONS: Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.

Byers JT, Paniccia A, Kaplan J, et al.
Expression of the Novel Costimulatory Molecule B7-H5 in Pancreatic Cancer.
Ann Surg Oncol. 2015; 22 Suppl 3:S1574-9 [PubMed] Related Publications
BACKGROUND: This study investigated how the B7-H5 protein, a new member of the B7 family, is expressed in normal human pancreas tissues and examined its expression changes in pancreatic cancer.
METHODS: In this analysis, B7-H5 expression was examined by immunohistochemical staining of frozen specimens from patients undergoing pancreatic resection.
RESULTS: Membranous B7-H5 protein was expressed on normal ductal epithelium within the pancreas. Other cell types from the normal pancreas, such as acinar cells and islet cells, did not express B7-H5. In adenocarcinoma, B7-H5 staining was decreased or absent. Interestingly, B7-H5 expression in intraductal papillary mucinous neoplasms varied with grade. No B7-H5 expression was found with other cancer types such as neuroendocrine tumors, but normal ducts adjacent to tumors were highly positive.
CONCLUSIONS: The findings showed that B7-H5 expression was restricted to ductal cells in the normal pancreas and the expression was downregulated in pancreatic adenocarcinomas. In addition, the findings showed that B7-H5 expression changes within different stages of dysplasia. The study suggests that loss of the B7-H5 signal may contribute to immune evasion of pancreatic adenocarcinoma. However future studies are needed.

Conway K, Edmiston SN, May R, et al.
DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival.
Breast Cancer Res. 2014; 16(5):450 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood.
METHODS: A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer.
RESULTS: Consensus clustering using methylation (β) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset.
CONCLUSIONS: This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes.

Kuo IY, Chang JM, Jiang SS, et al.
Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients.
Int J Med Sci. 2014; 11(8):779-87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.
METHODS: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients.
RESULTS: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17.
CONCLUSIONS: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.

Iwatani K, Takata K, Sato Y, et al.
Low-grade B-cell lymphoma presenting primarily in the bone marrow.
Hum Pathol. 2014; 45(7):1379-87 [PubMed] Related Publications
Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma.

Mascarenhas Cdo C, Ferreira da Cunha A, Brugnerotto AF, et al.
Identification of target genes using gene expression profile of granulocytes from patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.
Leuk Lymphoma. 2014; 55(8):1861-9 [PubMed] Related Publications
Differential gene expression analysis by suppression subtractive hybridization with correlation to the metabolic pathways involved in chronic myeloid leukemia (CML) may provide a new insight into the pathogenesis of CML. Among the overexpressed genes found in CML at diagnosis are SEPT5, RUNX1, MIER1, KPNA6 and FLT3, while PAN3, TOB1 and ITCH were decreased when compared to healthy volunteers. Some genes were identified and involved in CML for the first time, including TOB1, which showed a low expression in patients with CML during tyrosine kinase inhibitor treatment with no complete cytogenetic response. In agreement, reduced expression of TOB1 was also observed in resistant patients with CML compared to responsive patients. This might be related to the deregulation of apoptosis and the signaling pathway leading to resistance. Most of the identified genes were related to the regulation of nuclear factor κB (NF-κB), AKT, interferon and interleukin-4 (IL-4) in healthy cells. The results of this study combined with literature data show specific gene pathways that might be explored as markers to assess the evolution and prognosis of CML as well as identify new therapeutic targets.

Launay E, Henry C, Meyer C, et al.
MLL-SEPT5 fusion transcript in infant acute myeloid leukemia with t(11;22)(q23;q11).
Leuk Lymphoma. 2014; 55(3):662-7 [PubMed] Related Publications
Chromosomal rearrangements involving the MLL gene at band 11q23 are the most common genetic alteration encountered in infant acute myeloid leukemia. Reciprocal translocation represents the most frequent form of MLL rearrangement. Currently, more than 60 partner genes have been identified. We report here a case of de novo acute myeloid leukemia with a t(11;22)(q23;q11) in a 23-month-old child. Fluorescence in situ hybridization study revealed that the 3'MLL segment was translocated onto the derivative chromosome 22 and the breakpoint on chromosome 22 was located in or near the SEPT5 gene at 22q11.21. Long distance inverse-polymerase chain reaction was used to identify precisely the MLL partner gene and confirmed the MLL-SEPT5 fusion transcript. Involvement of the SEPT5 gene in MLL rearrangement occurs very rarely. Clinical, cytogenetic and molecular features of acute myeloid leukemia with a MLL-SEPT5 fusion gene are reviewed.

Cerveira N, Bizarro S, Teixeira MR
MLL-SEPTIN gene fusions in hematological malignancies.
Biol Chem. 2011; 392(8-9):713-24 [PubMed] Related Publications
The mixed lineage leukemia (MLL) locus is involved in more than 60 different rearrangements with a remarkably diverse group of fusion partners in approximately 10% of human leukemias. MLL rearrangements include chromosomal translocations, gene internal duplications, chromosome 11q deletions or inversions and MLL gene insertions into other chromosomes, or vice versa. MLL fusion partners can be classified into four distinct categories: nuclear proteins, cytoplasmatic proteins, histone acetyltransferases and septins. Five different septin genes (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been identified as MLL fusion partners, giving rise to chimeric fusion proteins in which the N terminus of MLL is fused, in frame, to almost the entire open reading frame of the septin partner gene. The rearranged alleles result from heterogeneous breaks in distinct introns of both MLL and its septin fusion partner, originating distinct gene fusion variants. MLL-SEPTIN rearrangements have been repeatedly identified in de novo and therapy related myeloid neoplasia in both children and adults, and some clinicopathogenetic associations are being uncovered. The fundamental roles of septins in cytokinesis, membrane remodeling and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton and MLL deregulation could be involved in the pathogenesis of hematological malignancies.

Sun T, Mary LG, Oh WK, et al.
Inherited variants in the chemokine CCL2 gene and prostate cancer aggressiveness in a Caucasian cohort.
Clin Cancer Res. 2011; 17(6):1546-52 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Though C-C chemokine ligand 2 (CCL2) has been shown to play a pivotal role in prostate cancer tumorigenesis and invasion, the role of inherited variation in the CCL2 gene in prostate cancer progression and metastases remains unanswered. This study is aimed to determine the influence of CCL2 germline variants on prostate cancer aggressiveness.
EXPERIMENTAL DESIGN: We performed an association study between six single nucleotide polymorphisms (SNP) in the CCL2 gene and prostate cancer clinicopathologic variables in a large hospital-based Caucasian patient cohort (N = 4,073).
RESULTS: Genetic variation at CCL2 is associated with markers of disease aggressiveness. Three SNPs, each in strong linkage disequilibrium, are associated with a higher (>7) biopsy Gleason score: CCL2 -1811 A/G, -2835 A/C, and +3726 T/C (P = 0.01, 0.03, and 0.04, respectively). The CCL2 -1811 G allele is additionally associated with advanced pathologic stages in patients who underwent radical prostatectomy (P = 0.04). In haplotype analysis, we found that the frequency of a common haplotype, H5, was higher among patients with D'Amico good risk features (P(permutation) = 0.04).
CONCLUSIONS: These results support the influence of CCL2 variants on prostate cancer development and progression.

Cerveira N, Santos J, Teixeira MR
Structural and expression changes of septins in myeloid neoplasia.
Crit Rev Oncog. 2009; 15(1-2):91-115 [PubMed] Related Publications
Septins are an evolutionarily conserved family of GTP-binding proteins that associate with cellular membranes and the actin and microtubule cytoskeletons. Fourteen septin genes have been characterized to date (SEPT1 to SEPT14) in humans. Septins have been reported to be misregulated in various human diseases, including neurological disorders, infection, and neoplasia. In this review, we describe what is known thus far about septin deregulation in myeloid neoplasia. Septin abnormalities in myeloid neoplasia can be divided into two major groups. First, some septins (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been repeatedly identified as in-frame fusion partners of the MLL gene in de novo and therapy-related myeloid neoplasia, in both children and adults. Second, deregulation of the expression of septin family genes in hematological cancers can be observed either with or without the concomitant presence of MLL gene fusions. Although current hypotheses regarding the roles of septins in oncogenesis remain speculative for the most part, the fundamental roles of septins in cytokinesis, membrane remodeling, and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton could be involved in neo-plastic disorders.

Santos J, Cerveira N, Bizarro S, et al.
Expression pattern of the septin gene family in acute myeloid leukemias with and without MLL-SEPT fusion genes.
Leuk Res. 2010; 34(5):615-21 [PubMed] Related Publications
Septins are proteins associated with crucial steps in cell division and cellular integrity. In humans, 14 septin genes have been identified, of which five (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) are known to participate in reciprocal translocations with the MLL gene in myeloid neoplasias. We have recently shown a significant down-regulation of both SEPT2 and MLL in myeloid neoplasias with the MLL-SEPT2 fusion gene. In this study, we examined the expression pattern of the other 13 known septin genes in altogether 67 cases of myeloid neoplasia, including three patients with the MLL-SEPT2 fusion gene, four with MLL-SEPT6 fusion, and three patients with the MLL-SEPT9 fusion gene. When compared with normal controls, a statistically significant down-regulation was observed for the expression of both MLL (6.4-fold; p=0.008) and SEPT6 (1.7-fold; p=0.002) in MLL-SEPT6 leukemia. Significant down-regulation of MLL was also found in MLL-MLLT3 leukemias. In addition, there was a trend for SEPT9 down-regulation in MLL-SEPT9 leukemias (4.6-fold; p=0.077). Using hierarchical clustering analysis to compare acute myeloid leukemia genetic subgroups based on their similarity of septin expression changes, we found that MLL-SEPT2 and MLL-SEPT6 neoplasias cluster together apart from the remaining subgroups and that PML-RARA leukemia presents under-expression of most septin family genes.

Sakakibara T, Hibi K, Koike M, et al.
PAI-1 expression levels in gastric cancers are closely correlated to those in corresponding normal tissues.
Hepatogastroenterology. 2008 Jul-Aug; 55(85):1480-3 [PubMed] Related Publications
BACKGROUND/AIMS: To investigate the mechanism of PAI-1 overexpression in gastric cancers, the PAI-1 expression levels in gastric cancers were compared to those in the corresponding normal tissues.
METHODOLOGY: A quantitative RT-PCR for PAI-1 gene was performed in gastric cancers and corresponding normal tissues, and evaluated the association between the PAI-1 expression levels in gastric cancers and those in corresponding normal tissues.
RESULTS: There was a significant correlation between gastric cancer and corresponding normal PAI-1 expressions with a Spearman's rank correlation coefficient of 0.74 (p < 0.0001). PAI-1 expression levels in corresponding normal tissues increased significantly with tumor stage [stage I, -8.04 +/- 0.72; stage II, -7.71 +/- 0.61: stage III, -6.81 +/- 0.51; stage IV, -4.95 +/- 0.20 (p = 0.0022)).
CONCLUSIONS: Previous studies found that PAI-1 overexpression was significantly associated with malignancy of gastric cancers. Taken together, PAI-1 overexpression in gastric cancers might be originated from higher PAI-1 expression in corresponding normal tissues and result in a malignant phenotype of these cancers.

Marcotte R, Muller WJ
Signal transduction in transgenic mouse models of human breast cancer--implications for human breast cancer.
J Mammary Gland Biol Neoplasia. 2008; 13(3):323-35 [PubMed] Related Publications
The advent of genetically engineered mouse models (GEMs) of human breast cancer, have provided important insight into molecular basis or human breast cancer. This review will focus on two of the most extensively studied mouse models for human breast cancer involving mammary gland specific expression of the polyoma middle T (PyV MT) antigen and of the ErbB2. In addition, this review will discuss past and recent advances in understanding relative contribution of the signaling pathways in tumor induction and metastasis by these potent mammary oncogenes.

Wilson BJ, Giguère V
Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway.
Mol Cancer. 2008; 7:49 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transcription factor GATA3 has recently been shown to be necessary for mammary gland morphogenesis and luminal cell differentiation. There is also an increasing body of data linking GATA3 to the estrogen receptor alpha (ERalpha) pathway. Among these it was shown that GATA3 associates with the promoter of the ERalpha gene and ERalpha can reciprocally associate with the GATA3 gene. GATA3 has also been directly implicated in a differentiated phenotype in mouse models of mammary tumourigenesis. The purpose of our study was to compare coexpressed genes, by meta-analysis, of GATA3 and relate these to a similar analysis for ERalpha to determine the depth of overlap.
RESULTS: We have used a newly described method of meta-analysis of multiple cancer studies within the Oncomine database, focusing here predominantly upon breast cancer studies. We demonstrate that ERalpha and GATA3 reciprocally have the highest overlap with one another. Furthermore, we show that when both coexpression meta-analysis lists for ERalpha and GATA3 are compared there is a significant overlap between both and, like ERalpha, GATA3 coexpresses with ERalpha pathway partners such as pS2 (TFF1), TFF3, FOXA1, BCL2, ERBB4, XBP1, NRIP1, IL6ST, keratin 18(KRT18) and cyclin D1 (CCND1). Moreover, as these data are derived from human tumour samples this adds credence to previous cell-culture or murine based studies.
CONCLUSION: GATA3 is hypothesized to be integral to the ERalpha pathway given the following: (1) The large overlap of coexpressed genes as seen by meta-analysis, between GATA3 and ERalpha, (2) The highest coexpressing gene for GATA3 was ERalpha and vice-versa, (3) GATA3, like ERalpha, coexpresses with many well-known ERalpha pathway partners such as pS2.

McDermott WG, Boissan M, Lacombe ML, et al.
Nm23-H1 homologs suppress tumor cell motility and anchorage independent growth.
Clin Exp Metastasis. 2008; 25(2):131-8 [PubMed] Related Publications
Nm23-H1 suppresses metastasis, as well as in vitro cell motility, invasion and anchorage independent growth, in a variety of cancer models. Eight human homologs of Nm23 have been identified that share 26-88% identity with the prototype Nm23-H1. Here, we examine the potential of its homologs, -H2, DR-, -H4 and -H5, to inhibit in vitro correlates of metastasis in two highly metastatic human cell lines, MDA-MB-435 and MDA-MB-231. The metastatic cells were transfected with mammalian expression constructs containing the genes encoding for Nm23-H1, -H2, DR-, -H4 and -H5 and the resultant transfectants were analyzed by Boyden chamber motility and soft agar colonization assays. Nm23-H1 suppressed motility by 3.3- and 1.5-fold in MDA-MB-435 and MDA-MB-231 cells, respectively and inhibited anchorage independent growth in soft agar by 2.9- and 1.9-fold, respectively. None of the -H1 homologs were capable of suppressing motility in MDA-MB-435 cells, but in MDA-MB-231 cells, -H2 inhibited motility by 3-fold upon overexpression. When anchorage independent growth was assessed, -H2, -H4 and -H5 suppressed growth from 1.2- to 2.0-fold in both cell lines. Given their ability to suppress anchorage independent growth, Nm23-H1 homologs -H2, -H4 and -H5 may have some capacity to suppress metastasis. Motility suppression appears to be cell context dependent, but sequence disparities between -H1/H2 and the other family members may reveal regions critical for this inhibitory phenotype. Similarly, sequence differences between DR-Nm23 and its homologs may be important for anchorage independent growth suppression.

Wilson BJ, Giguère V
Identification of novel pathway partners of p68 and p72 RNA helicases through Oncomine meta-analysis.
BMC Genomics. 2007; 8:419 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The Oncominedatabase is an online collection of microarrays from various sources, usually cancer-related, and contains many "multi-arrays" (collections of analyzed microarrays, in a single study). As there are often many hundreds of tumour samples/microarrays within a single multi-array results from coexpressed genes can be analyzed, and are fully searchable. This gives a potentially significant list of coexpressed genes, which is important to define pathways in which the gene of interest is involved. However, to increase the likelihood of revealing truly significant coexpressed genes we have analyzed their frequency of occurrence over multiple studies (meta-analysis), greatly increasing the significance of results compared to those of a single study.
RESULTS: We have used the DEAD-box proteins p68(Ddx5) and p72(Ddx17) as models for this coexpression frequency analysis as there are defined functions for these proteins in splicing and transcription (known functions which we could use as a basis for quality control). Furthermore, as these proteins are highly similar, interact together, and may be to some degree functionally redundant, we then analyzed the overlap between coexpressed genes of p68 and p72. This final analysis gave us a highly significant list of coexpressed genes, clustering mainly in splicing and transcription (recapitulating their published roles), but also revealing new pathways such as cytoskeleton remodelling and protein folding. We have further tested a predicted pathway partner, RNA helicase A(Dhx9) in a reciprocal meta-analysis that identified p68 and p72 as being coexpressed, and further show a direct interaction of Dhx9 with p68 and p72, attesting to the predictive nature of this technique.
CONCLUSION: In summary we have extended the capabilities of Oncomineby analyzing the frequency of coexpressed genes over multiple studies, and furthermore assessing the overlap with a known pathway partner (in this case p68 with p72). We have shown our predictions corroborate previously published studies on p68 and p72, and that novel predictions can be easily tested. These techniques are widely applicable and should increase the quality of data from future meta-analysis studies.

Sandanaraj E, Jada SR, Shu X, et al.
Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients.
Pharmacogenomics J. 2008; 8(3):174-85 [PubMed] Related Publications
Genetic polymorphisms in hepatically expressed UGT1A1 and UGT1A9 contribute to the interindividual variability i-n irinotecan disposition and toxicity. We screened UGT1A1 (UGT1A1*60, g.-3140G>A, UGT1A1*28 and UGT1A1*6) and UGT1A9 (g.-118(T)(9>10) and I399C>T) genes for polymorphic variants in the promoter and coding regions, and the genotypic effect of UGT1A9 I399C>T polymorphism on irinotecan disposition in Asian cancer patients was investigated. Blood samples were collected from 45 patients after administration of irinotecan as a 90 min intravenous infusion of 375 mg/m(2) once in every 3 weeks. Genotypic-phenotypic correlates showed that cancer patients heterozygous or homozygous for the I399C>T allele had approximately 2-fold lower systemic exposure to SN-38 (P<0.05) and a trend towards a higher relative extent of glucuronidation (REG) of SN-38 (P>0.05). UGT1A1-1A9 diplotype analysis showed that patients harbouring the H1/H2 (TG6GT(10)T/GG6GT(9)C) diplotype had 2.4-fold lower systemic exposure to SN-38 glucuronide (SN-38G) compared with patients harbouring the H1/H5 (TG6GT(10)T/GG6GT(10)C) diplotype (P=0.025). In conclusion, this in vivo study supports the in vitro findings of Girard et al. and suggests that the UGT1A9 I399C>T variant may be an important glucuronidating allele affecting the pharmacokinetics of SN-38 and SN-38G in Asian cancer patients receiving irinotecan chemotherapy.

Yang H, Spitz MR, Stewart DJ, et al.
ATM sequence variants associate with susceptibility to non-small cell lung cancer.
Int J Cancer. 2007; 121(10):2254-9 [PubMed] Free Access to Full Article Related Publications
ATM gene mutations have been implicated in many human cancers. However, the role of ATM polymorphisms in lung carcinogenesis is largely unexplored. We conducted a case-control analysis of 556 Caucasian non-small-cell lung cancer (NSCLC) patients and 556 controls frequency-matched on age, gender and smoking status. We genotyped 11 single nucleotide polymorphisms of the ATM gene and found that compared with the wild-type allele-containing genotypes, the homozygous variant genotypes of ATM08 (rs227060) and ATM10 (rs170548) were associated with elevated NSCLC risk with ORs of 1.55 (95% CI: 1.02-2.35) and 1.51 (0.99-2.31), respectively. ATM haplotypes and diplotypes were inferred using the Expectation-Maximization algorithm. Haplotype H5 was significantly associated with reduced NSCLC risk in former smokers with an OR of 0.47 (0.25-0.96) compared with the common H1 haplotype. Compared with the H1-H2 diplotype, H2-H2 and H3-H4 diplotypes were associated with increased NSCLC risk with ORs of 1.58 (0.99-2.54) and 2.29 (1.05-5.00), respectively. We then evaluated genotype-phenotype correlation in the control group using the comet assay to determine DNA damage and DNA repair capacity. Compared with individuals with at least 1 wild-type allele, the homozygous variant carriers of either ATM08 or ATM10 exhibited significantly increased DNA damage as evidenced by a higher mean value of the radiation-induced olive tail moment (ATM08: 4.86 +/- 2.43 vs. 3.79 +/- 1.51, p = 0.04; ATM10: 5.14 +/- 2.37 vs. 3.79 +/- 1.54, p = 0.01). Our study presents the first epidemiologic evidence that ATM genetic variants may affect NSCLC predisposition, and that the risk-conferring variants might act through down-regulating the functions of ATM in DNA repair activity upon genetic insults such as ionizing radiation.

Brem R, Cox DG, Chapot B, et al.
The XRCC1 -77T->C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage.
Carcinogenesis. 2006; 27(12):2469-74 [PubMed] Related Publications
X-ray repair cross-complementing 1 (XRCC1) is required for single-strand break repair in human cells and several polymorphisms in this gene have been implicated in cancer risk and clinical prognostic factors. We examined the frequency of the 5'-untranslated region (5'-UTR) variant -77T-->C (rs 3213235) in 247 French breast cancer (BC) patients, 66 of whom were adverse radiotherapy responders, and 380 controls and determined the haplotypes based on this and the previously genotyped variants Arg194Trp, Arg280His and Arg399Gln. The -77T-->C variant alone showed no significant association with BC risk or therapeutic radiation sensitivity. The H5 haplotype (variant allele codon 280, wild-type allele other positions) was associated with increased BC risk [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.12-3.23] and the H3 haplotype (wild-type allele all four positions) was inversely associated with therapeutic radiation sensitivity compared with the reference group (H1 haplotype, -77C, wild-type allele codons 194, 280, 399) (OR, 0.39; 95% CI, 0.16-0.92). However given that the global tests for association were not significant these results should be interpreted carefully. Lymphoblastoid cell lines heterozygous for the H1/H3 haplotypes had a significantly higher cell survival (P=0.04) after exposure to ionising radiation (IR) than those with the H1/H1 haplotypes, in agreement with the association study. However no haplotype-specific differences in XRCC1 expression or cell cycle progression were noted in the 24 h following IR exposure. These results suggest that the -77T-->C genotype or another variant in linkage disequilibrium influences the cellular response to DNA damage, although the underlying molecular mechanisms remain to be established.

Capurso G, Crnogorac-Jurcevic T, Milione M, et al.
Peanut-like 1 (septin 5) gene expression in normal and neoplastic human endocrine pancreas.
Neuroendocrinology. 2005; 81(5):311-21 [PubMed] Related Publications
Peanut-like 1 (PNUTL1) is a septin gene which is expressed at high levels in human brain. There it plays a role in the process of membrane fusion during exocytosis by interacting with syntaxin and synaptophysin. As the secretory apparatus of pancreatic islet cells closely resembles that of neurons, we decided to study the expression of PNUTL1 in the human endocrine pancreas, both in normal islets and in pancreatic endocrine tumors (PETs). Normal pancreatic tissue, purified islets, 11 PETs and two cell lines were used to evaluate the presence of PNUTL1 by RT-PCR and Western blot. The expression of the PNUTL1 protein was also evaluated by immunohistochemistry on normal pancreas, additional 26 PETs, eight pancreatic adenocarcinomas, one mixed endocrine-exocrine pancreatic neoplasm, a specimen of solid papillary pseudomucinous tumor, an adult islet cell hyperplasia and a case of neonatal nesidioblastosis. In addition, a tissue array (LandMark High Density Cancer Tissue MicroArray) comprising 280 various tumor and matched normal specimens was utilized. In PETs, the expression of pancreatic hormones, chromogranin-A, synaptophysin and Ki-67 were also evaluated. In the normal pancreas PNUTL1 expression is almost exclusively confined to the islet cells, weak expression was occasionally seen in some acinar cells, while immunoreactivity was completely absent in the ductal epithelia. PNUTL1 expression is maintained at similar high levels in hyperplastic and neoplastic islet cells, but this did not correlate with any of the clinicopathological data nor with proliferation status in PETs. Weak immunoreactivity was also noted in a proportion of exocrine neoplasms. Our findings describe for the first time the high expression levels of PNUTL1 in human pancreatic endocrine cells that suggests a similar role of this protein in islet cells to that demonstrated in neuronal tissues, and warrants further functional studies of this protein.

Cho YL, Bae S, Koo MS, et al.
Array comparative genomic hybridization analysis of uterine leiomyosarcoma.
Gynecol Oncol. 2005; 99(3):545-51 [PubMed] Related Publications
PURPOSE: Using a genome-wide array-based comparative genomic hybridization (array-CGH), DNA copy number changes in uterine leiomyosarcoma were analyzed.
MATERIALS AND METHODS: We analyzed 4 cases of uterine leiomyoma and 7 cases of uterine leiomyosarcoma. The paraffin-fixed tissue samples were microdissected under microscope and DNA was extracted. Array-based CGH and fluorescence in situ hybridization (FISH) were carried out with Genome database (Gene Ontology).
RESULTS: Uterine leiomyoma showed no genetic alterations, while all of 7 cases of uterine leiomyosarcoma showed specific gains and losses. The percentage of average gains and losses were 4.86% and 15.1%, respectively. The regions of high level of gain were 7q36.3, 7q33-q35, 12q13-12q15, and 12q23.3. And the regions of homozygous loss were 1p21.1, 2p22.2, 6p11.2, 9p21.1, 9p21.3, 9p22.1, 14q32.33, and 14q32.33 qter. There were no recurrent regions of gain, but recurrent regions of loss were 1p21.1-p21.2, 1p22.3-p31.1, 9p21.2-p22.2, 10q25-q25.2, 11q24.2-q25, 13q12-q12.13, 14q31.1-q31.3, 14q32.32-q32.33, 15q11-q12, 15q13-q14, 18q12.1-q12.2, 18q22.1-q22.3, 20p12.1, and 21q22.12-q22.13. In the high level of gain regions, BAC clones encoded HMGIC, SAS, MDM2, TIM1 genes. Frequently gained BAC clone-encoded genes were TIM1, PDGFR-beta, REC Q4, VAV2, FGF4, KLK2, PNUTL1, GDNF, FLG, EXT1, WISP1, HER-2, and SOX18. The genes encoded by frequently lost BAC clones were LEU1, ERCC5, THBS1, DCC, MBD2, SCCA1, FVT1, CYB5, and ETS2/E2. A subset of cellular processes from each gene was clustered by Gene Ontology database.
CONCLUSION: Using array-CGH, chromosomal aberrations related to uterine leiomyosarcoma were identified. The high resolution of array-CGH combined with human genome database would give a chance to find out possible target genes present in the gained or lost clones.

Laganière J, Deblois G, Giguère V
Functional genomics identifies a mechanism for estrogen activation of the retinoic acid receptor alpha1 gene in breast cancer cells.
Mol Endocrinol. 2005; 19(6):1584-92 [PubMed] Related Publications
The identification of estrogen receptor (ERalpha) target genes is crucial to our understanding of its predominant role in breast cancer. In this study, we used a chromatin immunoprecipitation (ChIP)-cloning strategy to identify ERalpha-regulatory modules and associated target genes in the human breast cancer cell line MCF-7. We isolated 12 transcriptionally active genomic modules that recruit ERalpha and the coactivator steroid receptor coactivator (SRC)-3 to different intensities in vivo. One of the ERalpha-regulatory modules identified is located 3.7 kb downstream of the first transcriptional start site of the RARA locus, which encodes retinoic acid receptor alpha1 (RARalpha1). This module, which includes an estrogen response element (ERE), is conserved between the human and mouse genomes. Direct binding of ERalpha to the ERE was shown using EMSAs, and transient transfections in MCF-7 cells demonstrated that endogenous ERalpha can induce estrogen-dependent transcriptional activation from the module or the ERE linked to a heterologous promoter. Furthermore, ChIP assays showed that the coregulators SRC-1, SRC-3, and receptor-interacting protein 140 are recruited to this intronic module in an estrogen-dependent manner. As expected from previous studies, the transcription factor Sp1 can be detected at the RARA alpha1 promoter by ChIP. However, treatment with estradiol did not influence Sp1 recruitment nor help recruit ERalpha to the promoter. Finally, ablation of the intronic ERE was sufficient to abrogate the up-regulation of RARA alpha1 promoter activity by estradiol. Thus, this study uncovered a mechanism by which ERalpha significantly activates RARalpha1 expression in breast cancer cells and exemplifies the utility of functional genomics strategies in identifying long-distance regulatory modules for nuclear receptors.

Vais H, Gao GP, Yang M, et al.
Novel adenoviral vectors coding for GFP-tagged wtCFTR and deltaF508-CFTR: characterization of expression and electrophysiological properties in A549 cells.
Pflugers Arch. 2004; 449(3):278-87 [PubMed] Related Publications
E1/E3-deleted adenoviral vectors expressing an N-terminal green fluorescent protein (GFP) reporter gene fused to either wtCFTR (H5.040CMVEGFP-wtCFTR) or deltaF508-CFTR (H5.040CMVEGFP-deltaF508CFTR) were generated. To characterize the expression and activity, A549 cells were infected with vectors expressing GFP-tagged and non-tagged forms of CFTR and deltaF508CFTR. CFTR activity was assayed in cell-attached and excised patches. For H5.040CMVEGFP-wtCFTR, forskolin-dependent outward current was observed in cell-attached patches from 56 of 67 GFP-positive cells. Single-channel conductances, open probability, mean open and mean closed time values for GFP-CFTR and CFTR were not significantly different. After excision, GFP-CFTR activity required ATP and exhibited a linear I-V relationship. For H5.040CMVEGFP-deltaF508CFTR, media were supplemented with 5 mM butyrate 16 h after infection. Forskolin-dependent outward current was observed in cell-attached patches from 21 of 30 butyrate-treated GFP-positive cells and 0 of 8 GFP-positive cells without butyrate. Single-channel conductances, open probability, mean open and mean closed time values for GFP-deltaF508CFTR and deltaF508CFTR were not significantly different. However, the increase in open probability with genistein was significantly smaller for GFP-deltaF508CFTR than for deltaF508CFTR. In excised patches, GFP-deltaF508CFTR activity required ATP and exhibited a linear I-V relationship. Despite the consistent detection of GFP-CFTR and GFP-deltaF508CFTR channels in the plasma membrane by patch clamping, GFP fluorescence was observed only in intracellular regions and was not altered by butyrate. The data show that high levels of functional GFP-tagged CFTR channels can be expressed with these adenoviral vector constructs.

Moore SD, Herrick SR, Ince TA, et al.
Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF.
Cancer Res. 2004; 64(16):5570-7 [PubMed] Related Publications
Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring chromosomal aberration in uterine leiomyomata is rearrangement of 10q22. Chromosome 10 breakpoints were mapped by fluorescence in situ hybridization to intervals ranging from 8.9 to 72.1 kb within the third intron of MORF (monocytic leukemia zinc finger protein-related factor or MYST4) in four uterine leiomyomata tested. Additional Southern hybridization experiments confirmed that the breakpoint lies within the third intron and narrowed the interval to 2.1 kb in one uterine leiomyomata. MORF is a member of the MYST family of histone acetyltransferase and previously has been found rearranged in some types of acute myeloid leukemia (AML). This is the first instance in which disruption of a histone acetyltransferase has been reported in another tumor type. The breakpoints in uterine leiomyomata would fall in the NH2-terminal portion of the protein between a conserved domain found in histones H1 and H5 and the PHD zinc fingers, the CH2CH zinc finger, or the CoA binding site, which is distinct from the breakpoints reported in AML. Mapping of the 17q21 breakpoint by fluorescence in situ hybridization within a specific region in three tumors revealed several positional candidates including GCN5L2, a gene with histone acetyltransferase activity similar to those fused to MORF in AML. Of note, two of three uterine leiomyomata were of the cellular subtype. Involvement of MORF in four uterine leiomyomata with chromosomal rearrangements involving 10q22 and 17q21 suggests a role for this histone acetyltransferase and altered chromatin regulation in uterine mesenchymal neoplasia.

Larisch S
The ARTS connection: role of ARTS in apoptosis and cancer.
Cell Cycle. 2004; 3(8):1021-3 [PubMed] Related Publications
ARTS is an unusual septin that is localized to mitochondria in living cells and promotes apoptosis by antagonizing IAPs. ARTS functions as a tumor suppressor in Acute Lymphoblastic Leukemia (ALL) and is lost in more than 70% of leukemic patients. The loss of ARTS is specific as levels of H5, a closely related non-apoptotic septin protein derived from the same gene, were unaffected. Thus, ARTS, a new member in the mitochondrial pro-apoptotic arsenal, provides a link between mitochondria, apoptosis and cancer.

Cho H, Kim WJ, Lee YM, et al.
N-/C-terminal deleted mutant of human endostatin efficiently acts as an anti-angiogenic and anti-tumorigenic agent.
Oncol Rep. 2004; 11(1):191-5 [PubMed] Related Publications
Non-collagenous (NC-1) fragments at the C-terminus of basement membrane collagen IV, XV and XIII have been implicated as negative regulators of angiogenesis. Endostatin is an endogenous carboxyl-terminal fragment of collagen XVIII/NC-1, suppressing endothelial cell proliferation, migration in vitro and tumor growth in mouse models. Endostatin can bind zinc through N- and C-terminal residues. Here we demonstrate that N-/C-terminal deleted derivative of human endostatin, H5, effectively inhibited the proliferation of human umbilical vein endothelial cells (HUVECs). Also, tube formation in vitro was comparably inhibited either by H5 or endostatin. The anti-angiogenic and anti-tumorigenic activities of H5 and endostatin were confirmed by an in vivo assay using chick chorioallantoic membrane (CAM) and mouse models, respectively. Treatment of 30 ng of H5 inhibited the capillary formation in CAM by 50%. In addition, H5 exhibited more potent anti-tumor activity than wild-type endostatin in in vivo mouse metastasis assay. These results indicate that the N-/C-terminal deletion mutant would be a strong candidate of anti-cancer agent against spontaneous tumor development and growth.

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