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Mehmet Gunduz

Publications and source records attributed to Mehmet Gunduz.

At least 19 recordsLinked to original sources
PubMed2006

Heparanase promotes angiogenesis through Cox-2 and HIF1alpha.

Heparanase has been given attention for its role in the invasion and metastasis of various cancers for years. We have also investigated and reported the role of heparanase in several human cancers, including gastric, esophageal and colon carcinomas. Other than the critical role of heparanase in tumor invasion and metastasis, it is also believed that heparanase is involved in angiogenesis, another feature of tumor progression which is complicatedly mediated by many molecules, including cyclooxygenese-2 (Cox-2). Thus, our recent study elucidated a possible relationship of heparanase with Cox-2 upon tumor angiogenesis. Based upon our study, three major transcription factor binding sites containing NF-kappaB, NF-IL-6 and CRE sites seemed to have a compensative and cooperative role in heparanase-induced Cox-2 upregulation. On the other hand, tumor hypoxia often occurs in most tumors and Cox-2-induced HIF1alpha overexpression has recently been shown in various cancers. Here we believe that heparanase may also be involved in tumor hypoxia through the induction of HIFalpha either directly or indirectly through the Cox-2 pathway. This hypothesis indicates a possible novel function of heparanase and its link to HIF1alpha and Cox-2, and therefore this function would give us a clue about potential new strategies for cancer therapy.

Animals↗
PubMed2006

Fine deletion mapping of chromosome 2q21-37 shows three preferentially deleted regions in oral cancer.

We analysed the loss of heterozygosity (LOH) of long arm of chromosome 2 by using 16 polymorphic microsatellite markers in 39 matched oral normal and cancer tissues, and defined the deletional mapping of the region with putative tumor suppressor genes. LOH was detected at least one location in 33 of 39 (85%) tumor tissues. Frequent deletions were detected at the locations of microsatellite markers, D2S2304 (35%), D2S111 (40%), D2S155 (35%), D2S1327 (29%), D2S164 (29%), D2S125 (68%) and D2S140 (32%). Three preferentially deleted regions at 2q21-24, 2q33-35 and 2q37.3 were observed. Several candidate tumor suppressor genes in these regions such as LRP1B, CASP8, CASP10, BARD1, ILKAP, PPP1R7, and ING5, are located. Further molecular analysis of each gene should be performed to clarify their roles in oral carcinogenesis.

Carcinoma, Squamous Cell↗
PubMed2006

The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach.

Signet-ring cell carcinoma (SRC) of the stomach exhibits diffuse growth and invasion without forming ducts. Destruction of the surrounding basal membrane and angiogenesis appear to be required for SRC to exhibit marked invasion and growth. We recently reported that heparanase (HPA) and cyclooxygenase-2 (COX-2) were strongly correlated with microvessel density, and that COX-2 expression is up-regulated by HPA in esophageal cancer. In this study, we examined the relationship between HPA expression and that of COX-2 in SRC of the stomach. We examined HPA and COX-2 expression in 3 cell lines derived from SRC of the stomach and in 50 SRC lesions of stomach by immunohistochemistry (IHC), in situ hybridization, and reverse transcriptase-polymerase chain reaction (RT-PCR). We also examined the relationships among HPA expression, COX-2 expression, and the clinicopathologic features of SRC, mean age, sex, invasion depth, regional lymph node metastasis, lymphatic invasion, and venous blood vessel invasion. Of the 3 cell lines, 2 exhibited both HPA and COX-2 mRNA expression on RT-PCR. Of the 3 cell lines, 1 exhibited only HPA mRNA expression on RT-PCR. Heparanase expression was confirmed in 23 (46%) of 50 tumor samples by IHC. COX-2 expression was confirmed in 25 (50%) of the 50 tumor samples by IHC. In situ hybridization revealed messenger RNA expression in the same area as in that revealed by IHC. A close correlation was noted between HPA and COX-2 expressions (P < .0001). The present study thus elucidated the biologic features of SRC of the stomach related to growth and angiogenesis.

Adult↗
PubMed2006

Epigenetic alterations of BRG1 leads to cancer development through its nuclear-cytoplasmic shuttling abnormalities.

SWI/SNF is a multiprotein chromatin remodeling complex important for gene regulation. BRG1 and its close relative BRM, have ATPase activity necessary for transcriptional regulation by conformational change of nucleosomes. Due to this role on gene expression, several members of SWI/SNF complex including BRG1 and BRM function as a tumor suppressor or negative regulator of cellular proliferation. On the other hand, the shuttling of proteins between nucleus and cytoplasm is strongly involved in the regulation of cell cycle and proliferation. Many of tumor suppressor gene (TSG)s including p53, BRCA1, ING1 play some of their functions through nucleocytoplasmic shuttling. Abnormalities related with this process abrogate the subcellular localization of the TSGs and lead to cancer development. We recently demonstrated BRG1 as a TSG in oral cancer. Our analysis also revealed an interesting finding that one of the splicing forms of BRG1 is selectively lost in cancer tissue as compared to normal counterparts. Our further analysis revealed a putative nuclear retention signal domain for this splicing form. In this article, we speculate the possible mechanism for the inactivation of BRG1 gene in oral cancer through an abnormality in its subcellular localization.

Active Transport, Cell Nucleus↗
PubMed2006

Efficacy of atelocollagen honeycomb scaffold in bone formation using KUSA/A1 cells.

To induce new bone formation, mesenchymal stem cells were seeded onto atelocollagen honeycomb scaffold. We evaluated the efficacy of this scaffold combined with KUSA/A1 cells in vivo. KUSA/A1 cells alone and with atelocollagen were implanted in the subcutaneous pockets of 4-week-old male SCID mice. The transplants were subjected to radiographical, histological, and immunohistochemical examinations after 2 and 4 weeks of implantation. Radiographically, both KUSA/A1 cells alone and KUSA/A1-atelocollagen showed some radiopaque areas formation but the latter disclosed a larger amount. Histologically, KUSA/A1 cells alone showed few small islands of new bone formation surrounded by a thin layer of cellular proliferation. On the other hand, KUSA/A1-atelocollagen revealed abundant new bone formation as well as cellular proliferation. We also determined the immunolocalization of type I collagen, CD34, osteocalcin, osteopontin, and PCNA in this newly formed bone. Our results indicated that collagen scaffold plays an important role allowing vessel formation and cell anchorage, especially through the proliferation and differentiation process in a confined space. This study supports tissue engineering as an alternative for treating different target diseases, such as trauma or congenital defects, and enhances existing therapeutic applications.

Animals↗
PubMed2006

Immobilized rhBMP-2/succinylated type I atelocollagen gene expression of intracellular signaling molecules on ST2 cells.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) chemically-bonded to succinylated type I atelocollagen, a biomaterial carrier with a porous structure, was reported to augment cellular activity of ST2 cells. The Smad protein family has been suggested to play an important role in the intracellular signaling pathway of BMP by its binding to receptors on target cells. However, there has been no study analyzing the downstream genes of the rhBMP-2 induced intracellular signal transduction pathway. The purpose of this study was to examine the effect of immobilized rhBMP-2 on gene expression of intracellular signaling molecules on ST2 cells. Our study showed two expression patterns of downstream genes of rhBMP-2 intracellular signal transduction pathway. In the first pattern, BMPR-IA, Smad 1, and Smad 5 genes showed high basic expression before the addition of rhBMP, and the high level of gene expression continued for long period and decreased in the late stage when rhBMP-2 was immobilized. In the second pattern, Smad 6, Smad 7, and Smad 8 genes showed low basic expression before the addition of rhBMP-2 and a continuous increase from the beginning was followed by a decrease in the late stage when rhBMP-2 was immobilized. Our results also showed that intracellular signaling continued for prolonged period when rhBMP-2 was immobilized to succinylated type I atelocollagen. This study indicated that immobilizing rhBMP-2 is an efficient method to increase bone induction.

Animals↗
PubMed2006

Microcystic adnexal carcinoma with mandibular bone marrow involvement: a case report with immunohistochemistry.

Microcystic adnexal carcinoma is a rare, locally aggressive cutaneous neoplasm with a high probability of persistence locally but a low probability of metastasis. We report a case of a 69-year-old female patient with an indurated plaque at the mental region. Histologically, the tumor cells invaded the subcutaneous tissue and mandibular bone. The tumor consisted mainly of squamous and basaloid epithelial nests and cords embedded in a desmoplastic stroma. A few keratin-filled microcysts and ductal structures were also observed. Perineural encroachment was also noted but there was no mitosis, cytologic features of malignancy, or metastasis. The epithelial nests were positive to various cytokeratins except for CK20 and the lumina of the ductal structures were positive to carcinoembryonic antigen. Our results indicate that microcystic adnexal carcinoma consists of tumor cells capable of both follicular and eccrine differentiation. It is locally aggressive, extends far beyond its clinical presentation and may involve the bone. It may persist and remain asymptomatic for so many years without metastasis. A lifetime postsurgery monitoring is mandatory to ensure early and proper management.

Aged↗
PubMed2006

COX-2 induction by heparanase in the progression of breast cancer.

Breast cancer confined within the lactiferous duct or lobule, without invading the stroma, is called ductal carcinoma in situ (DCIS), whereas breast cancer that has invaded the stroma through the basal membrane is called invasive cancer. Heparanase, an endo-beta-D-glucuronidase that specifically degrades heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays an important role when breast cancer cells breach the basal membrane. Recently, we have reported that heparanase is involved in angiogenesis through direct induction of cyclo-oxygenase-2 (COX-2). COX-2 induces vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thus involved in neovascularization. The present study was undertaken to analyze surgically resected breast cancer specimens for heparanase and COX-2 expression, using specimens from 59 patients with invasive cancer and 85 patients with DCIS (including 41 cases of DCIS adjacent to invasive cancer). This study yielded the following results: a) the distribution of heparanase within tumor tissue was identical to that of COX-2; b) heparanase expression was more frequent in invasive cancer than in non-invasive cancer; c) a close positive correlation was noted between heparanase and COX-2 expression (this correlation was particularly strong in cases of invasive cancer); and d) COX-2 expression was always seen in cases positive for heparanase expression. Our results indicate that heparanase expression increases during the progression of breast cancer into invasive cancer, and that this change is accompanied by increased COX-2 expression. They also suggest that heparanase may play a novel role for COX-2 mediated tumor angiogenesis in breast-cancer progression.

Adult↗
PubMed2005

Heparanase is involved in angiogenesis in esophageal cancer through induction of cyclooxygenase-2.

PURPOSE: Both heparanase and cyclooxygenase-2 (COX-2) are thought to play critical roles for tumor malignancy, including angiogenesis, although it is unknown about their relationship with each other in cancer progression. We hypothesized that they may link to each other on tumor angiogenesis. EXPERIMENTAL DESIGN: The expressions of heparanase and COX-2 in 77 primary human esophageal cancer tissues were assessed by immunohistochemistry to do statistical analysis for the correlation between their clinicopathologic features, microvessel density, and survival of those clinical cases. Human esophageal cancer cells were transduced with heparanase cDNA and used for reverse transcription-PCR and Western blot to determine the expression of heparanase and COX-2. COX-2 promoter vector and its deletion/mutation constructs were also used along with transduction of heparanase cDNA for luciferase assay. RESULTS: Heparanase and COX-2 protein expression exhibited a similar pattern in esophageal tumor tissues, and their expression correlated with tumor malignancy and poor survival. Their expression also revealed a significant correlation with high intratumoral microvessel density. Up-regulation of COX-2 mRNA and protein was observed in esophageal cancer cells transfected with heparanase cDNA. COX-2 promoter was activated after heparanase cDNA was transduced and the deletion/mutation of three transcription factor (cyclic AMP response element, nuclear factor-kappaB, and nuclear factor-interleukin-6) binding elements in COX-2 promoter strongly suppressed its activity. CONCLUSION: Our results suggest that heparanase may play a novel role for COX-2-mediated tumor angiogenesis.

Adult↗
PubMed2005

Immunolocalization and distribution patterns of type IV collagen alpha chains in oral mucosal melanoma.

The basement membrane (BM) is mainly composed of type IV collagen, which is composed of triple combinations of six distinct alpha (alpha) chains in a tissue-specific manner. The six collagen chain-specific antibodies (alpha1-alpha6) were used to examine the BMs of the oral epithelium (OE) and tumor clusters in oral mucosal melanoma (OMM). Eight OMM cases were examined. Results showed that the alpha1 and alpha2 chains were constantly detected at the BM of the normal OE as well as at the OE with atypical melanocytic proliferation and in invasive melanoma with nodular nests. The alpha1 and alpha2 chains were intermittently detected in in situ OMM, early invasive OMM and advanced invasive OMM with sheet-like nests. Gradual loss of alpha5 and alpha6 from the OE with atypical melanocyte through in situ OMM and early invasive OMM was observed. These findings suggest that changes in the immunolocalization and distribution patterns of type IV collagen alpha chains are associated with the progression of OMM. The distribution pattern of type IV collagen alpha chain varies depending on the architecture of the nest.

Basement Membrane↗
PubMed2005

Effects of immobilized recombinant human bone morphogenetic protein-2/succinylated type I atelocollagen on cellular activity of ST2 cells.

The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce ectopic bone formation requires a carrier. Type I atelocollagen, a biomaterial with a porous structure, excellent operational features, and biocompatibility, is an effective carrier for rhBMP-2. However, the conventionally used lyophilized rhBMP-2/collagen mixture does not necessarily give adequate bone-induction effect. In the present study, we examined the effect of immobilizing rhBMP-2 to type I atelocollagen on the cellular activity of ST2 cells. The following results were obtained: (1) rhBMP-2 was effectively immobilized to succinylated type I atelocollagen, indicating the usefulness of succinylated type I atelocollagen in immobilization; (2) studies of alkaline phosphatase activity confirmed the effectiveness of rhBMP-2 immobilized on succinylated atelocollagen in augmenting cellular activity.

Alkaline Phosphatase↗
PubMed2005

Identification of a candidate tumor suppressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer.

PURPOSE: Aims of the study are to narrow-down the hotspot region on 10q21 defined by previous genome-wide loss of heterozygosity (LOH) analysis in head and neck squamous cell carcinomas (HNSCC) and to define candidate tumor suppressor genes (TSG) concerned with 10q21. MATERIALS AND METHODS: LOH analysis was carried out with ten polymorphic microsatellite markers. Expression analysis was performed by semi-quantitative RT-PCR, and mutation analysis by PCR and direct sequencing. RESULTS: LOH analysis on 10q21 in 52 HNSCC indicated distinctive and frequent allelic loss at D10S589 (42%). Among flanking genes, we found the RHOBTB1 gene as a candidate TSG, since an intragenic marker demonstrated the highest LOH (44%). Expression analysis revealed down-regulation of RHOBTB1 mRNA in 37% of tumors. Interestingly, all the five tumors that showed decreased expression of RHOBTB1 were accompanied with LOH, supporting the haploinsufficiency and class 2 TSG characteristics of RHOBTB1. No pathogenic mutation of RHOBTB1 was found. Furthermore, another gene within the region, EGR2, was also taken under scope. LOH frequencies around the EGR2 gene were relatively low (23 and 33%). Albeit semi-quantitative expression analysis of EGR2 demonstrated downregulation in 45% of tumor samples, no relation was found between the expression levels and LOH status. CONCLUSION: Frequent allelic loss and decreased expression of RHOBTB1 suggested that this gene has a role in tumorigenesis of a subset of HNSCC.

Base Sequence↗
PubMed2005

Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas.

We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer.

Carcinoma, Squamous Cell↗
PubMed2005

Emergence of nuclear heparanase induces differentiation of human mammary cancer cells.

The study of epithelial differentiation touches upon many modern aspects of biology. The epithelium is in constant dialogue with the underlying mesenchyme to control stem cell activity, proliferation in transit-amplifying compartments, lineage commitment, terminal differentiation and, ultimately, cell death. There are spatially distinct compartments dedicated to each of these events. Recently we reported that heparanase is expressed in nucleus as well as in the cytoplasm and that nuclear heparanase seems to be related to cell differentiation. In this study, we investigated the role of nuclear heparanase in differentiation by transducing human mammary epithelial cancer cells with heparanase which was delivered specifically into nucleus. We observed that expression of nuclear heparanase allowed the cells to differentiate with the appearance of lipid droplets. This finding supports the idea that heparanase plays a novel role in epithelial cell differentiation apart from its known enzymatic function.

Breast Neoplasms↗
PubMed2005

Heparanase gene and protein expression in ameloblastoma: possible role in local invasion of tumor cells.

Ameloblastoma is the most common odontogenic neoplasm, particularized by its local invasiveness. Heparanase is the endo-glucuronidase enzyme that specifically cleaves heparan sulfate, the important modulator of extracellular matrix, and related to invasion of tumor cells. In this study, we addressed to show the gene expression and localization of heparanase in ameloblastoma. Immunohistochemistry and in situ hybridization of heparanase were carried out in 23 ameloblastomas. Strong expression of heparanase at both mRNA and protein levels was detected in all ameloblastomas studied. Small tumor nests and budding epithelial branches showed stronger staining pattern and the stromal tissues at the immediate vicinity of the tumor nests with strong heparanase expression were loose and edematous. Cystic areas and squamous metaplastic areas of the tumor showed intense staining with heparanase antibody proposing the implication of heparanase in these processes. These results suggest the possible contribution of heparanase in the local invasiveness and secondary morphologic changes of ameloblastoma.

Ameloblastoma↗