Showing papers by "Sug Hyung Lee published in 2007"
TL;DR: The data indicate that beclin‐1 inactivation by loss of expression may not occur in colorectal and gastric cancers and suggests that neo‐expression of beclIn‐1 may play a role in both coloreCTal and Gastric tumorigenesis.
Abstract: Autophagy plays important roles in both cell death and cell survival. Beclin-1, a key regulator of autophagy formation, has been considered as a haploinsufficient tumor suppressor. Loss of expression or point mutation could serve as a mechanism of loss of beclin-1 tumor suppressor function in cancers. However, our recent study revealed that point mutation of the beclin-1 gene is a rare event in common human cancers. In this study we investigated beclin-1 protein expression in 103 colorectal and 60 gastric carcinoma tissues by immunohistochemistry using a tissue microarray approach. In the cancers, expression of beclin-1 was detected in 95% of the colorectal carcinomas and 83% of the gastric carcinomas. In contrast, normal mucosal cells of both stomach and colon showed no or very weak expression of beclin-1. There was no significant association of beclin-1 expression with clinocopathologic characteristics, including invasion, metastasis and stage. The beclin-1 expression of colorectal and gastric cancers in the present study is quite in contrast to that of the breast cancers in the previous study, which showed a decreased beclin-1 expression in breast cancer cells compared to normal breast cells. Our data indicate that beclin-1 inactivation by loss of expression may not occur in colorectal and gastric cancers. Rather, increased expression of beclin-1 in the malignant colorectal and gastric epithelial cells compared to their normal mucosal epithelial cells suggests that neo-expression of beclin-1 may play a role in both colorectal and gastric tumorigenesis.
189 citations
TL;DR: The data indicate that NOTCH1 is mutated in T‐ALL, but not in other common human cancers, and that notCH2, NOTCH3 and NOTH4 genes are rarely mutated in common human cancer.
Abstract: NOTCH proteins (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) play crucial roles in embryonic development. Also, mounting evidence indicates that NOTCH contributes to the pathogenesis of hematopoietic and solid malignancies. Recent studies reported a high incidence of gain-of-function mutations of the NOTCH1 gene in T-cell acute lymphoblastic leukemias (ALL). To see whether NOTCH1 mutation occurs in other malignancies, we analyzed NOTCH1 for the detection of somatic mutations in 334 malignancies, including 48 lung, 48 breast, 48 colorectal and 48 gastric carcinomas, and 142 acute leukemias (105 acute myelogenous leukemias, 32 B-ALLs and 4 T-ALLs) by single-strand conformation polymorphism assay. Also, to see whether other NOTCH genes harbor somatic mutations, we analyzed NOTCH2, NOTCH3 and NOTCH4 genes in the same tissue samples. Overall, we detected three NOTCH mutations in the cancers, which consisted of one NOTCH1 mutation in the T-ALLs (25.0%), one NOTCH2 mutation in the breast carcinomas (2.1%), and one NOTCH3 mutation in the colorectal carcinomas (2.0%). There was no NOTCH mutation in other malignancies analyzed. Our data indicate that NOTCH1 is mutated in T-ALL, but not in other common human cancers, and that NOTCH2, NOTCH3 and NOTH4 genes are rarely mutated in common human cancers. Despite the importance of NOTCH activation in many types of human cancers, mutation of NOTCH genes, except for NOTCH1 mutation in T-ALL, may not play an important role in the tumorigenesis of common cancers.
81 citations
TL;DR: Gab2 over‐expression is a feature not only of breast cancers, but also of gastric cancers, and increased expression of Gab2 in malignant gastric cells compared with normal epithelial cells suggests that Gab2 expression may play a role in gastric cancer development.
44 citations
TL;DR: The first report on BECN1 gene mutations in human cancer tissues is reported, and the data suggest that point mutations are a rare event in common human cancers and probably do not play a major role in cancer pathogenesis.
Abstract: Evasion of programmed cell death (PCD) is one of the hallmarks of human cancers. It is well known that not only apoptosis, but also autophagy, acts as an action mechanism of PCD. BECN1 protein is a key regulator of autophagic PCD. The BECN1 gene that encodes BECN1 protein acts as a haploinsufficient tumor-suppressor gene. However, to date, data on BECN1 mutation in human cancer tissues are lacking. To explore the possibility that somatic mutation of the BECN1 gene might contribute to the development of human cancers, we analyzed the entire coding region and all splice sites of the human BECN1 gene for detection of somatic mutations in 180 gastric carcinomas, 94 breast carcinomas, 50 acute leukemias, 50 colorectal carcinomas, 50 hepatocellular carcinomas, and 124 non-small cell lung cancers by single-strand conformation polymorphism (SSCP) and DNA sequencing. Overall, we detected 11 somatic mutations of the BECN1 gene, including 3 missense mutations (N8K, P350R and R389C) in coding sequences and 8 mutations in introns. The mutations were observed in five gastric, three colorectal, one lung and one breast carcinoma (s). We expressed the three mutations (N8K, P350R and R389C) in HT1080 cells, and found that two (P350R and R389C) of them showed only slightly decreased cell death activities compared to the wild-type BECN1. This is the first report on BECN1 gene mutations in human cancer tissues, and the data suggest that point mutations are a rare event in common human cancers and probably do not play a major role in cancer pathogenesis.
36 citations
TL;DR: The data indicate that N PM1 exon 12 is mutated in AMLs, but not in other common human cancers, and suggest that the NPM1 mutation may not play a role in the tumorigenesis of common solid cancers.
Abstract: Nucleophosmin is a nucleolar phosphoprotein that shuttles between nucleus and cytoplasm. Recent reports demonstrated that exon 12 of the nucleophosmin 1 (NPM1) gene was frequently mutated in acute myelogenous leukemias (AMLs). To see whether the NPM1 mutation occurs in other malignancies, we analyzed exon 12 of NPM1 for the detection of somatic mutations in 467 carcinomas, including 142 lung, 47 hepatocellular, 93 breast, 103 colorectal and 82 gastric carcinomas, by single-strand conformation polymorphism assay. We also analyzed the NPM1 mutation in 142 acute leukemias, including 105 AMLs. We detected 15 NPM1 mutations in the AMLs (14.3%), but there was no NPM1 mutation in the other malignancies analyzed. Our data indicate that NPM1 exon 12 is mutated in AMLs, but not in other common human cancers, and suggest that the NPM1 mutation may not play a role in the tumorigenesis of common solid cancers.
28 citations
TL;DR: It is demonstrated that the somatic mutation of the PTPRT phosphatase domain rarely occurred in common human cancers, suggesting that alterations of thePTPRT‐mediated signaling pathway by PTPRt phosphatases domain mutation may not play a critical role in the development of common human cancer.
Abstract: A recent report revealed that the protein-tyrosine phosphatase, receptor-type, T (PTPRT) gene is somatically mutated in several types of human cancer, suggesting that the mutated PTPRT gene is a tumor suppressor gene in human cancers. However, because previously the mutational search has focused primarily on colon cancers, data on PTPRT mutations in other types of human cancer have largely been lacking. Here, we performed a mutational analysis of the PTPRT phosphatase domain by polymerase chain reaction-based single-strand conformation polymorphism (PCR-SSCP) assay in 345 cases of common human cancers, including colon carcinomas, hepatocellular carcinomas, acute leukemias, gastric carcinomas, breast carcinomas and non-small cell lung cancers. We detected PTPRT phosphatase domain mutations in 1 of 105 colon carcinomas (1%) and 1 of 48 gastric carcinomas (2%), but none in acute leukemias, hepatocellular carcinomas, breast carcinomas and non-small cell lung cancers. The PTPRT mutation detected in the colon carcinoma was a missense mutation and the mutation in the gastric carcinomas was a splice-site mutation. Contrary to the previous report on the frequent PTPTR phosphatase domain mutations in colon cancers, this study demonstrated that the somatic mutation of the PTPRT phosphatase domain rarely occurred in common human cancers. The data suggested that alterations of the PTPRT-mediated signaling pathway by PTPRT phosphatase domain mutation may not play a critical role in the development of common human cancers.
19 citations
TL;DR: The data indicated that expressions of both PUMA and p-BAD were increased in the colorectal cancer cells, and suggested that the increased expression of these proteins in malignant colOREctal epithelial cells compared to the normal mucosal epithelial Cells may possibly alter the cell death regulation during coloreCTal tumorigenesis.
Abstract: Several lines of evidence indicate that, together with deregulated growth, alteration of apoptosis plays a pivotal role in tumorigenesis. PUMA, a pro-apoptotic member of Bcl-2 family, mediates p53-dependent and -independent apoptosis. BAD is also a pro-apoptotic Bcl-2 family member and phosphorylation of BAD protein inhibits the pro-apoptosis function of BAD. To see whether the alteration of protein expressions of PUMA and phospho-BAD (p-BAD) are characteristics of human colorectal cancers, we analyzed the expression of these proteins in 103 colorectal carcinomas by immunohistochemistry. Also, we analyzed the mutation of the Bcl-2 homology 3 (BH3) domain of PUMA gene, an important domain in the apoptosis function of PUMA, by single-strand conformation polymorphism (SSCP) in 98 colorectal carcinomas. p-BAD immunostaining was detected in 62 cases (60.1%) of the 103 carcinomas, whereas it was not detected in the normal colonic mucosal epithelial cells. PUMA protein expression was detected in both cancer cells and normal mucosal cells in all of the 103 cases. However, the cancer cells showed higher intensities of PUMA immunostaining than the normal cells of the same patients in 50.4% of the cases. There was no association of the p-BAD expression with the PUMA expression. The mutational analysis revealed no PUMA BH3 domain mutation in the cancers. Our data indicated that expressions of both PUMA and p-BAD were increased in the colorectal cancer cells, and suggested that the increased expression of these proteins in malignant colorectal epithelial cells compared to the normal mucosal epithelial cells may possibly alter the cell death regulation during colorectal tumorigenesis.
19 citations
TL;DR: The data showed that the expression of p-FADD in gastric cancers was heterogenous in its location compared to the uniform nuclear expression in normal gastric cells, suggesting that p- FADD functions in the nucleus may be perturbed in the cancers.
Abstract: Fas-associated death domain (FADD) plays a crucial role during death receptor-mediated apoptosis In addition, FADD possesses apoptosis-independent activities, including cell-cycle regulation and cell proliferation regulated by the phosphorylation of FADD at Ser194 The aim of this study was to explore the possibility whether alteration of phosphorylated FADD (p-FADD) expression might be a characteristic of gastric cancer We analyzed the expression of p-FADD protein in 60 gastric adenocarcinomas by immunohistochemistry using a tissue microarray approach In the normal gastric mucosal cells, surface and glandular epithelial cells evenly expressed p-FADD in the nuclei but not in the cytoplasm In the cancers, p-FADD expression was detected in 38 cases (63%) of the gastric carcinomas, but there was no p-FADD immunostaining in the remaining 22 cancers (37%) Of note, p-FADD immunostaining was observed in cytoplasm/nuclei (20 cancers; 33%) and cytoplasm (18 cancers; 30%) There was no significant association of p-FADD expression with clinocopathological characteristics, including invasion, metastasis, and stage Our data showed that the expression of p-FADD in gastric cancers was heterogenous in its location compared to the uniform nuclear expression of p-FADD in normal gastric cells Many of the cancers (67%) were devoid of nuclear p-FADD, suggesting that p-FADD functions in the nucleus may be perturbed in the cancers Also, p-FADD expression in the cytoplasm in a large fraction of the cancers (63%), not seen in the normal cells, suggested that the cell death functions of p-FADD could be altered in the cancer cells
16 citations
TL;DR: In this article, upregulation of cyclooxygenase-2 (COX•2) plays crucial roles in tumorigenesis of gastrointestinal cancers, and administration of COX-2 inhibitors is known to reduce the risk of cancer developm...
13 citations
TL;DR: Results indicate that caspase‐9 is frequently phosphorylated in gastric carcinomas, and that the phosphorylation of caspite‐9 might be an inhibitory mechanism of casing‐9‐mediated apoptosis in gastrics carcinomas.
Abstract: Alterations of caspases, the main executioners of apoptosis, have been described in human cancers. Caspase-9 plays a crucial role in the initiation phase of the intrinsic apoptosis pathway. Caspase-9 is phosphorylated at Thr125 through the mitogen-activated protein kinase (MAPK) pathway, and this phosphorylation is associated with inhibition of caspase-9 activation. The aim of this study was to explore whether phosphorylated caspase-9 (p-caspase-9) expression could be a characteristic of gastric carcinomas. We analyzed expression of p-caspase-9 protein in 60 gastric adenocarcinomas by immunohistochemistry using a tissue microarray approach. p-caspase-9 was detected in 33 of the 60 carcinomas (55%). Both early and advanced gastric carcinomas expressed p-caspase-9. There was no significant association of p-caspase-9 expression with clinocopathological characteristics, including invasion, metastasis and stage. In contrast to gastric cancer cells, epithelial cells in normal gastric mucosa showed no or only weak expression of p-caspase-9. Taken together, these results indicate that caspase-9 is frequently phosphorylated in gastric carcinomas, and that the phosphorylation of caspase-9 might be an inhibitory mechanism of caspase-9-mediated apoptosis in gastric carcinomas. Increased expression of p-caspase-9 in malignant gastric epithelial cells compared to normal mucosal epithelial cells suggests that p-caspase-9 expression might play a role in gastric carcinoma development.
13 citations
TL;DR: In this paper, the expression of BNIP3 protein in 60 gastric adenocarcinomas by immunohistochemistry was analyzed and mutations in the DNA sequences encoding BH3 (Bcl-2 homology3) and TM (transmembrane) domains that are important in the cell death function were found in 48 colorectal, 48 gastric and 48 breast carcinomas, and 48 acute leukemias.
Abstract: Cell death deregulation is a hallmark of human cancers. BNIP3 was initially identified as a pro-apoptotic member of the Bcl-2 family and plays an important role in apoptosis, necrosis and autophagy. The aim of this study was to see whether alterations of BNIP3 protein expression and somatic mutation of the BNIP3 gene are characteristics of human cancers. We analyzed the expression of BNIP3 protein in 60 gastric adenocarcinomas by immunohistochemistry. In addition, we analyzed BNIP3 mutation in the DNA sequences encoding BH3 (Bcl-2 homology3) and TM (transmembrane) domains that are important in the cell death function of BNIP3 by single-strand conformation polymorphism (SSCP) in 48 colorectal, 48 gastric, and 48 breast carcinomas, and 48 acute leukemias. By immunohistochemistry, BNIP3 protein was detected in 40 of the 60 carcinomas (67%). Both early and advanced gastric carcinomas expressed BNIP3. There was no significant association between BNIP3 expression and clinicopathologic characteristics, including invasion, metastasis and stage. In contrast to the cancer cells, epithelial cells in normal gastric mucosa showed no or weak expression of BNIP3. Mutational analysis revealed BNIP3 mutation in neither the BH3 nor the TM domain, suggesting that BNIP3 mutation in these domains is not a direct target of inactivation in gastric, colorectal and breast carcinomas, and acute leukemias. Increased expression of BNIP3 in the malignant gastric epithelial cells compared to the normal mucosal epithelial cells suggests that BNIP3 expression might play a role in gastric carcinoma development.
TL;DR: The data indicate that caspase‐14 gene is rarely mutated in colorectal carcinomas, but not mutated in gastric, lung, breast and hepatocellular carcinoma, and suggest that the casp enzyme‐14 mutation may not be a direct target of inactivation in tumorigenesis of common carcinomas.
TL;DR: The aim of this study was to confirm the presence of MLL3 gene mutations in colorectal carcinomas, and to see whether there exists any significant difference in the frequency of M LL3 mutations between colorective carcinomas in the USA and Korea.
Abstract: A central aim of cancer research has been to identify mutated genes that are causally implicated in tumorigenesis. Mutation in cancer could be categorized either as cancer-specific mutation affecting a key gene in the neoplastic process or as non-functional passenger mutation (1). Analyses of human genes to find functional cancer-specific mutations have focused on a small fraction of genes or domains. However, recently Sjöblom et al. analyzed 13,023 genes (approximately one third of the total number of human genes), a set of protein coding genes termed the consensus coding sequences (2). In 35 breast and 35 colorectal cancer tissues, they identified 189 genes that were mutated at significant frequencies. In addition to genes that had been reported to be mutated in colorectal or breast cancers, such as TP53, APC and KRAS, many other genes were newly found to be mutated in these cancers (2). Of these, myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) was found to be frequently mutated in colorectal carcinomas (6/35; 17.1%). MLL3 has a significant homology with MLL that is frequently fused with other gene products by chromosomal translocations (3). The six mutations identified in the MLL3 gene consisted of five substitution mutations (four missense mutations and one nonsense mutation) and one deletion mutation. The aim of this study was to confirm the presence of MLL3 gene mutations in colorectal carcinomas, and to see whether there exists any significant difference in the frequency of MLL3 mutations between colorectal carcinomas in the USA (2) and Korea. Methacarn-fixed tissues of 104 colorectal carcinomas from Koreans were
TL;DR: The data suggested that the proapoptotic ITGB3 cytoplasmic domain is rarely mutated in common human cancers and may not play an important role in the development of the cancers.
Abstract: Aims: Mounting evidence indicates that deregulation of apoptosis is involved in the mechanisms of cancer development. Integrins are cell adhesion receptors that mediate cell survival and migration. A recent study showed that unligated integrin beta 3 (ITGB3) induced apoptosis by recruitment of caspase-8. The aim of the present study was to explore the possibility that genetic alteration of the ITGB3 gene is involved in the development of human cancers possibly by inactivating the apoptosis function of ITGB3. Methods: We analyzed the coding region of the cytoplasmic domain of the human ITGB3 gene for the detection of somatic mutations in 100 gastric, 90 colorectal, 100 non-small cell lung, 43 urinary bladder and 50 head-neck cancers by a polymerase chain reaction-based, single-strand conformation polymorphism. Results: We found an identical ITGB3 mutation in two unrelated patient samples (one in colorectal and the other in bladder cancer). The ITGB3 mutation was a missense mutation which would substitute an amino acid (E757K). Conclusions: The data suggested that the proapoptotic ITGB3 cytoplasmic domain is rarely mutated in common human cancers and may not play an important role in the development of the cancers.
TL;DR: The data suggest that BAD mutation may not be a direct target of inactivation in gastric tumorigenesis, and decreased expression of p‐BAD in malignant gastric epithelial cells compared to normal mucosal epithelial Cells suggested that loss of p-BAD expression may play a role in gastrics tumorigenisation.
Abstract: Mounting evidence indicates that deregulation of apoptosis contributes to the development of human cancers. BAD, a proapoptotic Bcl-2 family protein, regulates the intrinsic apoptosis pathway. The aim of this study was to explore whether alterations of phospho-BAD (p-BAD) protein that antagonizes apoptosis function of BAD and mutation of BAD gene are characteristics of human gastric cancers. We analyzed expression of p-BAD in 60 gastric adenocarcinomas by immunohistochemistry. Also, we analyzed BAD gene for detection of somatic mutations by single-strand conformation polymorphism (SSCP) assay. p-BAD expression was detected well in normal gastric mucosal epithelial cells, whereas it was detected in only 51% (31 of the 60) of the cancers. There was no somatic mutation of BAD gene in the 60 gastric cancer samples. The decreased expression of p-BAD in malignant gastric epithelial cells compared to normal mucosal epithelial cells suggested that loss of p-BAD expression may play a role in gastric tumorigenesis. The data also suggest that BAD mutation may not be a direct target of inactivation in gastric tumorigenesis.
TL;DR: The data presented here indicate that the pro-apoptotic BNIP3 gene may not be somatically mutated in human NSCLCs, which suggests that mutational events of the BN IP3 gene might not be involved in the mechanisms by whichNSCLCs evade cell death.
Abstract: Purpose: Cell death deregulation is a hallmark of human cancers. BNIP3, which was initially identified as a pro-apoptotic member of the Bcl-2 family, plays an important role in apoptosis, necrosis and autophagy. This study was conducted to explore whether mutation of the BNIP3 gene is a characteristic of human non-small cell lung cancers (NSCLC). Materials and Methods: In the current study, we used polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and DNA sequencing to detect somatic mutations in the DNA sequences encoding the BH3 (Bcl-2 homology3) and TM (transmembrane) domains that are important to the cell death function of BNIP3 in 48 NSCLCs. Results: SSCP analysis revealed no evidence of somatic mutation in the DNA sequences encoding the BH3 and TM domains of the human BNIP3 gene in the 48 NSCLCs evaluated in this study. Conclusion: The data presented here indicate that the pro-apoptotic BNIP3 gene may not be somatically mutated in human NSCLCs, which suggests that mutational events of the BNIP3 gene may not be involved in the mechanisms by which NSCLCs evade cell death. (J Lung Cancer 2007;6(2):74�� 77)
TL;DR: The increased expression of FLASH in the malignant gastric epithelial cells compared to the normal mucosal epithelial Cells suggests that FLASH expression may play a role in gastric tumorigenesis, and the data suggest that somatic mutation of FLash is a rare event in Gastric carcinomas.
Abstract: FLASH was initially identified as a pro-apoptotic protein that transmits an apoptosis signal during death receptor-induced apoptosis. Additionally, diverse biologic roles of FLASH, including TNF-induced NF-κB activation, cell-cycle progression and cell division, have been identified. Although such functions are important in cancer pathogenesis, little is known about the alterations of FLASH gene and FLASH protein expression in human cancers. In this study, we analyzed the expression of FLASH protein in 60 gastric adenocarcinomas by immunohistochemistry. We furthermore analyzed mutation of FLASH in exon 8, where two polyadenine tracts ((A)8 and (A)9) are present, by single-strand conformation polymorphism (SSCP) assay in 184 gastric adenocarcinomas. By immunohistochemistry, FLASH protein expression in cancer cells was detected positively in 42 gastric carcinoma tissues (70%), whereas its expression in epithelial cells of normal gastric mucosa was shown as no or very weak intensity. Mutational analysis detected one FLASH mutation in the gastric carcinomas (0.5%). The increased expression of FLASH in the malignant gastric epithelial cells compared to the normal mucosal epithelial cells suggests that FLASH expression may play a role in gastric tumorigenesis. Also, the data suggest that somatic mutation of FLASH is a rare event in gastric carcinomas.
TL;DR: These studies suggest that gene rearrangements that are causally implicated in oncogenesis may exist in common epithelial cancers but may be masked by the multiple nonspecific chromosomal rearrangement.
Abstract: Cancers only become manifest following accumulation of somatic mutations. One of the most common types of somatic mutation is chromosomal translocations that result in a chimeric transcript or apposition of one gene to regulatory regions of another gene. This mutation type is common in leukaemias, lymphomas and mesenchymal tumors. Although recurrent chromosomal translocations are rare in epithelial neoplasia, several examples have been reported among epithelial neoplasia, including thyroid papillary carcinoma, thyroid follicular carcinoma, renal papillary carcinoma, and breast secretory carcinomas (1). Recent studies demonstrated chromosomal translocations that resulted in fusions of the 5øuntranslated region of transmembrane protease, serine 2 (TMPRSS2) with ERG or ETV1 or ETV4 (ETS transcription factors) in prostate cancer tissues (2, 3). They showed that up to 80% of prostate cancer samples harbored rearrangements in ERG or ETV1 or ETV4. Cell line experiments suggested that the promoter elements of TMPRSS2 mediate overexpression of the ETS family members in prostate cancer (2). These studies suggest that gene rearrangements that are causally implicated in oncogenesis may exist in common epithelial cancers but may be masked by the multiple nonspecific chromosomal rearrangements. Because the ETS transcription factors target multiple genes that may be involved in tumorigenesis and developmental processes, it could be hypothesized that other human carcinomas might possibly harbor the TMPRSS2:ERG or ETV1 fusion. However, to date, such data for common carcinomas besides prostate carcinomas are lacking. To see whether the same types of gene fusion
TL;DR: The data presented here indicate that BH3 domain mutation of the proapoptotic genes Bad, Bmf and Bcl-G is rare in laryngeal squamous cell carcinoma and may not contribute to the apoptosis-resistance mechanisms of larynx squamouscell carcinoma.
Abstract: Aims: There is mounting evidence that deregulation of apoptosis is involved in the mechanisms of cancer development. Somatic mutations of apoptosis-related genes have been reported in many human cancers. The aim of this study was to explore the possibility that mutation of the BH3 domains of the proapoptotic Bcl-2 genes Bad, Bmf and Bcl-G might be involved in the development of laryngeal cancer. Methods: We analyzed the BH3 domains of Bad, Bmf and Bcl-G for the detection of somatic mutations in 33 squamous cell carcinomas of the larynx by a polymerase chain reaction-based single-strand conformation polymorphism assay. Results: There were no somatic mutations of the BH3 domains of Bad, Bmf and Bcl-G in the laryngeal squamous cell carcinoma samples. Conclusions: The data presented here indicate that BH3 domain mutation of the proapoptotic genes Bad, Bmf and Bcl-G is rare in laryngeal squamous cell carcinoma and may not contribute to the apoptosis-resistance mechanisms of laryngeal squamous cell carcinoma.
TL;DR: There was not any evidence of CASP7 or CASP8 mutation in the gastrointestinal NHL samples, which suggests that neither of them may play an important role in the development of gastrointestinal lymphomas.
Abstract: To the Editor: Failure of apoptosis could allow survival of transformed cells that are prone to undergo further genetic damage and play an important role in development of tumors, and inactivation of apoptosis process by mutations of pro-apoptotic genes has been reported in many human cancers (1–3). Caspase-8 activation plays a central role in the initiation phase of apoptosis, and caspase-7 activation involves in the execution phase of apoptosis. Previously, we reported that both CASP7 and CASP8 genes are inactivated by mutations in many types of carcinomas, including gastric and colorectal carcinomas (1–3). Several lines of evidence suggest that loss of apoptosis enhances lymphoid tumor development (4). Thus, it could be hypothesized that lymphomas might harbor CASP7 or CASP8 mutation, which might contribute to tumor development. However, now-a-days, mutation of CASP7 and CASP8 genes in human lymphoma tissues is largely unknown. We selected 41 gastrointestinal non-Hodgkin lymphomas (NHL) from surgical resection for this study. The NHLs consisted of two mucosa-associated lymphoid tissue lymphomas in stomach, 19 diffuse large B-cell lymphomas (DLCLB) in stomach, 10 DLCLBs in small intestine and 10 DLCLBs in colon. Malignant cells and normal cells from formalin-fixed tissues were selectively procured from hematoxylin and eosin-stained slides using a 30G1 ⁄ 2 hypodermic needle as described previously (1–3). Genomic DNA was isolated, and analyzed for potential mutations in the six exons of CASP7 gene and the eight exons of CASP8 gene by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis as described previously (1–3). All of the patients were Asians (Korean). Approval was obtained from the Catholic University of Korea, College of Medicine’s institutional review board for this study. Radioisotope ([P]dCTP) was incorporated into PCR products for detection by autoradiogram. On SSCP autoradiogram, all of the PCR products were clearly seen. However, the SSCP from the lymphoma samples did not reveal any aberrantly migrating band compared with the wild-type band from normal tissues of the same patients, indicating that there was not any evidence of CASP7 or CASP8 mutation in the gastrointestinal NHL samples either. We included carcinoma samples with known CASP7 or CASP8 mutations, and these samples showed aberrant migration in SSCP (data not shown). Several polymorphisms are known within CASP7 and CASP8 genes. In the NHLs analyzed, heterozygosity rates of CASP8 polymorphisms at nucleotides 789A ⁄G, 960A ⁄G and IVS9 –19A ⁄G were 15, 32 and 40, respectively. The heterozygosity rates of CASP7 polymorphisms at nucleotides 633C ⁄G and 648 G ⁄A were 13 and 5%, respectively. We repeated the experiments twice, including tissue micro dissection, PCR, SSCP and direct DNA sequencing analysis to ensure the results, and found that the data was consistent. Because both CASP7 and CASP8 genes were reported to be mutated in many carcinomas, we expected to detect some somatic mutations of CASP7 or CASP8 gene in the gastrointestinal lymphomas. However, we detected no somatic mutation of them in this study. This observation indicates that neither CASP7 nor CASP8 mutation may occur in gastrointestinal lymphomas, and suggests that neither of them may play an important role in the development of gastrointestinal lymphomas. There have been reports on somatic mutations of genes encoding pro-apoptosis proteins, including caspase-10, Fas and TRAIL receptor 2 in NHL (5–7), suggesting such mutations, but neither CASP7 nor CASP8 mutation, contribute to apoptosis resistance in NHL.
TL;DR: 160 acute leukemia samples were selected and FBXW7 gene was found to be somatically mutated in several human tumors, including endometrial, colorectal and ovarian tumors, and CCRF-CEM, a cell line derived from T-ALL, contains a FBXw7 mutation (R465C) , suggesting that FBxW7 mutation may play a role in the pathogenesis of T-all.
Abstract: sisted of 105 cases of AML, 54 cases of ALL (43 B-ALL and 11 T-ALL) and 1 undifferentiated acute leukemia. The AML samples included 8 cases of AML minimally differentiated, 15 cases of AML without maturation, 21 cases of AML with maturation, 7 acute myelomonocytic leukemia samples, 7 acute monoblastic and monocytic leukemia samples, 2 acute erythroid leukemia samples, 15 cases of AML with t(8; 21)(q22;q22), 6 cases of AML with abnormal bone marrow eosinophils Inv(16) (p13; q22), 12 acute promyelocytic leukemia samples [AML with t(q22;q12)], 11 AML samples with multilineage dysplasia and 1 AML and myelodysplastic syndrome, therapy-related according to the WHO classification. The acute leukemia DNA samples were extracted from bone marrows of acute leukemia patients (age range 20–80 years). All of the patients were Asians (Korean). Approval for this study was obtained from the institutional review board, College of Medicine, Catholic University of Korea. Most of the FBXW7 mutations have been reported within the exon 8–9 [3] . Thus, we analyzed FBXW7 gene in these 2 exons. Genomic DNA was isolated and analyzed for potential mutations in the FBXW7 exon 8–9 by polymerase chain reaction (PCR) with primer pairs ( table 1 ). Radioisotope ( 32 P-dCTP) was incorporated into PCR products for detection by autoradiogram. The PCR products were subsequently analyzed by a single-strand conformation polymorphism (SSCP) analysis, as described previously [10, 11] . On SSCP autoradiogram, all of the PCR products were clearly seen. However, the SSCP from the acute leukemia Cell cycle deregulation is important in the pathogenesis of human cancers. Cyclin E couples with Cdk2 and is involved in the G1 progression of the cell cycle. Degradation of cyclin E depends on ubiquitin-mediated proteolysis by the SCF ubiquitin ligase complex. FBXW7 (also known as hCDC4) is a component of the SCF complex [1, 2] . Inactivation of FBXW7 causes an increased expression of cyclin E and chromosomal instability of the affected cells [2, 3] . In a mouse model, the loss of 1 FBXW7 allele promoted tumor transformation, suggesting that FBXW7 gene may be a haploinsufficient tumor suppressor gene [4] . FBXW7 gene was found to be somatically mutated in several human tumors, including endometrial, colorectal and ovarian tumors (2.9–16% of the endometrial carcinomas, 13% of the colorectal tumors and 2% of the ovarian carcinomas) [1, 3, 5, 6] . Mutational analyses of FBXW7 have been performed in acute leukemia samples [7–9] . FBXW7 mutation was detected in both pediatric and adult T cell acute lymphoblastic leukemia (T-ALL), but neither in B-ALL nor in acute myelogenous leukemia (AML) [7–9] . Additionally, CCRF-CEM, a cell line derived from T-ALL, contains a FBXW7 mutation (R465C) [1] , suggesting that FBXW7 mutation may play a role in the pathogenesis of T-ALL. However, because all of the FBXW7 mutational analyses were performed in Western countries, we would like to know whether the pattern of FBXW7 mutation in acute leukemia in an Asian country is similar to that in Western countries. In this study, we selected 160 acute leukemia samples and analyzed the FBXW7 mutation. The samples conReceived: July 17, 2007 Accepted after revision: August 30, 2007 Published online: November 9, 2007
01 Jan 2007
TL;DR: The data indicate that EN PP2 is occasionally mutated in breast carcinomas, and suggest that ENPP2 mutation may contribute to the tumor development in some breast carcinoma.
Abstract: ENPP2, a 125 kDa secreted lysophopholipase D which originally identified as a tumor-motogen, Autotaxin, enhances cellular locomotion, cell proliferation, angiogenesis and cell survival by generating the signal molecule lysophosphatic acid or sphingosine-1-phosphate. Previous studies have suggested that expression of Autotaxin is associated with invasive phenotype in advanced breast carcinomas. Thus, to determine whether genetic alterations of ENPP2 gene are involved in the development or progression of breast cancer, we analyzed its somatic mutation in 85 breast carcinomas by single-stranded conformational polymorphism and sequencing. Overall, six ENPP2 mutations were found (7.0%), comprising five missense and one nonsense mutation (s). To our knowledge, this is the first report on ENPP2 mutation in breast carcinoma, and the data indicate that ENPP2 is occasionally mutated in breast carcinomas, and suggest that ENPP2 mutation may contribute to the tumor development in some breast carcinomas.
Journal Article•
TL;DR: It is suggested that GAs may subclassify as intestinal and diffused type of GA by their characteristic molecular expression, and this may facilitate to understand different molecular carcinogenesis of gastric cancer.
Abstract: Gastric adenocarcinoma (GA) is a major tumor type of gastric cancers and subdivides into several different tumors such as papillary, tubular mucinous, signet-ring cell and adenosquamous carcinoma according to histopatholigical determination. In other hand, GA is also subdivided into intestinal and diffuse type of adenocarcinoma by the Lauren’s classification. In this study, we have examined differential gene expression pattern analysis of three histologically different GAs of 24 samples by using DNA microarray containing approximately 19000 genetic elements. The hierarchical clustering analysis of 24 gastric adenocarcinomas (12 of intestinal type, 7 of diffuse type and 5 of mixed type) resulted in two major subgroup on dendrogram, and two subgroups included most of intestinal and diffused type of GAs respectively. Supervised analysis of 19 intestinal and diffuse type GAs by using Wilcoxon rank T-test (P⁄ 0.01) resulted in 100 outlier genes which exactly separated intestinal and diffuse type of GA by differential gene expression. In conclusion, genome-wide analysis of gene expression of GAs suggested that GAs may subclassify as intestinal and diffused type of GA by their characteristic molecular expression. Our results also provide large-scale genetic elements which reflect molecular differences of intestinal and diffuse type of GAs, and this may facilitate to understand different molecular carcinogenesis of gastric cancer.