166 results on '"Nakamura, Y."'
Search Results
2. Abstract OT3-01-01: A phase II study of PD-L1 and CTLA-4 inhibition and immunopharmcogenomics in metastatic breast cancer
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Santa-Maria, CA, primary, Jain, S, additional, Flaum, L, additional, Park, J-H, additional, Kato, T, additional, Gross, L, additional, Uthe, R, additional, Tellez, C, additional, Stein, R, additional, Rademaker, A, additional, Gradishar, WJ, additional, Nakamura, Y, additional, Giles, FJ, additional, and Cristofanilli, M, additional
- Published
- 2017
- Full Text
- View/download PDF
3. Abstract P6-07-10: Cytogenetic analysis of squamous cell carcinoma of the breast reveals inter- and intra-tumoral heterogeneity
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Oikawa, M, primary, Igawa, A, additional, Ishida, M, additional, Nakamura, Y, additional, Nishimura, S, additional, Koga, C, additional, Akiyoshi, S, additional, Koi, Y, additional, Taguchi, K, additional, Ohno, S, additional, and Tokunaga, E, additional
- Published
- 2016
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4. Abstract P5-08-47: Clinical outcome of pathological T1N0 breast cancer according to the hormone receptor and HER2 status and adjuvant therapy
- Author
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Tokunaga, E, primary, Akiyoshi, S, additional, Koga, C, additional, Nakamura, Y, additional, Taguchi, K, additional, Ishida, M, additional, and Ohno, S, additional
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- 2016
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5. Abstract P1-13-15: Risk of late recurrence of hormone receptor positive breast cancer in cases with no recurrent disease at five years after surgery
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Ohno, S, primary, Koui, Y, additional, Oikawa, M, additional, Akiyoshi, S, additional, Koga, C, additional, Igawa, A, additional, Saruwatari, A, additional, Nishimura, S, additional, Nakamura, Y, additional, Taguchi, K, additional, and Ishida, M, additional
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- 2013
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6. Abstract P5-14-18: Indication of post-mastectomy radiation associated with risk of local recurrence in breast cancer patients with 1-3 lymph node metastasis
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Saruwatari, A, primary, Ishida, M, additional, Koi, Y, additional, Akiyoshi, S, additional, Igawa, A, additional, Oikawa, M, additional, Koga, C, additional, Nishimura, S, additional, Nakamura, Y, additional, and Ohno, S, additional
- Published
- 2013
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7. Up-regulation of the ectodermal-neural cortex 1 (ENC1) gene, a downstream target of the beta-catenin/T-cell factor complex, in colorectal carcinomas
- Author
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Fujita M, Furukawa Y, Tsunoda T, Toshihiro Tanaka, Ogawa M, and Nakamura Y
- Subjects
Microfilament Proteins ,Neuropeptides ,Nuclear Proteins ,Proteins ,Cell Differentiation ,Transfection ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,Butyrates ,Cytoskeletal Proteins ,Axin Protein ,Transduction, Genetic ,Colonic Neoplasms ,Trans-Activators ,Tumor Cells, Cultured ,Humans ,Promoter Regions, Genetic ,TCF Transcription Factors ,HT29 Cells ,Transcription Factor 7-Like 2 Protein ,Cell Division ,beta Catenin ,HeLa Cells ,Transcription Factors - Abstract
To clarify the molecular mechanisms of human carcinogenesis associated with abnormal Wnt/wingless signaling, we searched for genes the expression of which was significantly altered by introduction of wild-type AXIN1 into LoVo colon cancer cells. By means of a cDNA microarray, we compared expression profiles of LoVo cells infected with either adenoviruses expressing wild-type AXIN1 (Ad-Axin) or those expressing a control gene (Ad-LacZ). Among the genes showing altered expression, the ectodermal-neural cortex 1 (ENC1) gene was down-regulated in response to Ad-Axin. The promoter activity of ENC1 was elevated approximately 3-fold by transfection of an activated form of beta-catenin together with wild-type T-cell factor (Tcf)4 in HeLa cells. Semiquantitative reverse transcription-PCR experiments revealed that expression of ENC1 was increased in more than two-thirds of 24 primary colon cancer tissues that we examined compared with corresponding noncancerous mucosae. Introduction of exogenous ENC1 increased the growth rate of HCT116 colon cancer cells in serum-depleted medium. In other experiments, overexpression of ENC1 in HT-29 colon cancer cells suppressed the usual increase of two differentiation markers, in response to treatment with sodium butyrate, a differentiation-inducible agent. These data suggest that ENC1 is regulated by the beta-catenin/Tcf pathway and that its altered expression may contribute to colorectal carcinogenesis by suppressing differentiation of colonic cells.
- Published
- 2001
8. Identification of AF17 as a downstream gene of the beta-catenin/T-cell factor pathway and its involvement in colorectal carcinogenesis
- Author
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Ym, Lin, Ono K, Satoh S, Ishiguro H, Fujita M, Miwa N, Toshihiro Tanaka, Tsunoda T, Kc, Yang, Nakamura Y, and Furukawa Y
- Subjects
Transcriptional Activation ,Transcription, Genetic ,Lymphoid Enhancer-Binding Factor 1 ,Cell Cycle ,3T3 Cells ,Transfection ,Neoplasm Proteins ,DNA-Binding Proteins ,Cytoskeletal Proteins ,Mice ,COS Cells ,Chlorocebus aethiops ,Trans-Activators ,Tumor Cells, Cultured ,Animals ,Humans ,Colorectal Neoplasms ,Cell Division ,beta Catenin ,Oligonucleotide Array Sequence Analysis ,Signal Transduction ,Transcription Factors - Abstract
To elucidate the molecular mechanism of colorectal carcinogenesis, we have been attempting to isolate genes involved in the beta-catenin/T-cell factor pathway. In the experiments reported here, analysis by cDNA microarray indicated that AF17, a fusion partner of the MLL gene in acute leukemias with t(11;17)(q23;q21), was transactivated according to accumulation of beta-catenin. Expression of AF17 was significantly enhanced in 8 of the 12 colorectal cancer tissues examined. Introduction of a plasmid designed to express AF17 stimulated growth of NIH3T3 cells, and fluorescence-activated cell sorter analysis indicated that the AF17 regulation of cell-cycle progression was occurring mainly at the G(2)-M transition. Our results suggest that the AF17 gene product is likely to be involved in the beta-catenin-T-cell factor/lymphoid enhancer factor signaling pathway and to function as a growth-promoting, oncogenic protein. These findings should aid development of new strategies for diagnosis, treatment, and prevention of colon cancers and acute leukemias by clarifying the pathogenesis of these conditions.
- Published
- 2001
9. Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN
- Author
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Matsushima-Nishiu M, Motoko Unoki, Ono K, Tsunoda T, Minaguchi T, Kuramoto H, Nishida M, Satoh T, Tanaka T, and Nakamura Y
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Gene Expression Profiling ,Tumor Suppressor Proteins ,Cell Cycle ,PTEN Phosphohydrolase ,Gene Expression ,Apoptosis ,Transfection ,Phosphoric Monoester Hydrolases ,Adenoviridae ,Endometrial Neoplasms ,Gene Expression Regulation, Neoplastic ,Tumor Cells, Cultured ,Humans ,Female ,Cell Division ,Oligonucleotide Array Sequence Analysis ,Signal Transduction - Abstract
The PTEN tumor suppressor gene encodes a multifunctional phosphatase that plays an important role in inhibiting the phosphatidylinositol-3-kinase pathway and downstream functions that include activation of Akt/protein kinase B, cell survival, and cell proliferation. Enforced expression of PTEN in various cancer cell lines decreases cell proliferation through arrest of the cell cycle, accompanied in some cases by induction of apoptosis. We used cDNA microarrays containing 4009 cDNAs to examine changes in gene-expression profiles when exogenous PTEN was induced in PTEN-defective cells. The microarrays and subsequent semi-quantitative reverse transcription-PCR analysis revealed transcriptional stimulation of 99 genes and repression of 72 genes. Some of the differentially expressed genes already had been implicated in cell proliferation, differentiation, apoptosis, or cell cycle control, e.g., overexpression of PTEN-induced transactivation of cyclin-dependent inhibitor 1B (p27Kip1) and 2B (p15INK4B), members of the TNF receptor family, tumor necrosis factor-associated genes, and members of the Notch-signaling and Mad families. To our knowledge this is the first report of transactivation of those genes by PTEN. The genes differentially expressed in our experiments also included many whose correlation with cancer development had not been recognized before. Our data should contribute to a greater understanding of the broad spectrum of ways in which PTEN affects intracellular signaling pathways. Analysis of expression profiles with microarrays appears to be a powerful approach for identifying anticancer genes and/or disease-specific targets for cancer therapy.
- Published
- 2001
10. Identification by cDNA microarray of genes involved in ovarian carcinogenesis
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Ono, K., Tanaka, T., Tatsuhiko Tsunoda, Kitahara, O., Kihara, C., Okamoto, A., Ochiai, K., Takagi, T., and Nakamura, Y.
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Gene Expression Regulation, Neoplastic ,Ovarian Neoplasms ,DNA, Complementary ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Down-Regulation ,Humans ,Female ,DNA, Neoplasm ,RNA, Neoplasm ,Adenocarcinoma, Mucinous ,Cystadenocarcinoma, Serous ,Up-Regulation - Abstract
To identify genes involved in the development or progression of ovarian cancer, we analyzed gene expression profiles of nine ovarian tumors using a DNA microarray consisting of 9121 genes. Comparison of expression patterns between carcinomas and the corresponding normal ovarian tissues enabled us to identify 55 genes that were commonly up-regulated and 48 genes that were down-regulated in the cancer specimens. When the five serous adenocarcinomas were analyzed separately from the four mucinous adenocarcinomas, we identified 115 genes that were expressed differently between the two types of tumor. Investigation of these genes should help to disclose the molecular mechanism(s) of ovarian carcinogenesis and define molecular separation of the two most common histological types of ovarian cancer.
- Published
- 2000
11. Isolation and characterization of a novel human lung-specific gene homologous to lysosomal membrane glycoproteins 1 and 2: significantly increased expression in cancers of various tissues
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Kouichi Ozaki, Nagata M, Suzuki M, Fujiwara T, Ueda K, Miyoshi Y, Takahashi E, and Nakamura Y
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Membrane Glycoproteins ,Base Sequence ,Molecular Sequence Data ,Chromosome Mapping ,Lysosome-Associated Membrane Glycoproteins ,Neoplasm Proteins ,Up-Regulation ,Antigens, CD ,Neoplasms ,Humans ,Amino Acid Sequence ,Chromosomes, Human, Pair 3 ,RNA, Messenger ,Lung - Abstract
We have isolated and characterized a novel human lung-specific gene and observed its increased expression in cancers arising from various tissues. The cDNA, designated TSC403, contained an open reading frame of 1248 nucleotides encoding 416 amino acids; the deduced amino acid sequence showed significant similarities to lysosomal membrane glycoproteins (lamps) 1 and 2. We localized the gene to chromosomal band 3q27, a genomic region that is often amplified in human cancers of several tissue types. We detected a high level of the TSC403 transcript in primary cancers of the esophagus, colon, fallopian tube, ovary, breast, and liver, although expression of this gene was barely detectable in corresponding normal tissues. These findings indicated that up-regulation of the TSC403 transcript may be related to the development and/or progression of cancer in humans.
- Published
- 1998
12. Isolation of murine and human homologues of the fission-yeast dis3+ gene encoding a mitotic-control protein and its overexpression in cancer cells with progressive phenotype
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Lim J, Kuroki T, Kouichi Ozaki, Kohsaki H, Yamori T, Tsuruo T, Nakamori S, Imaoka S, Endo M, and Nakamura Y
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Exosome Multienzyme Ribonuclease Complex ,Sequence Homology, Amino Acid ,Molecular Sequence Data ,Mitosis ,Adenocarcinoma ,Neoplasm Proteins ,Fungal Proteins ,Gene Expression Regulation, Neoplastic ,Mice ,Exoribonucleases ,Tumor Cells, Cultured ,Animals ,Humans ,Amino Acid Sequence ,RNA, Neoplasm ,Schizosaccharomyces pombe Proteins ,Cloning, Molecular ,Neoplasm Metastasis ,Colorectal Neoplasms ,Sequence Alignment - Abstract
To investigate genes involved in metastasis, we used a differential display method to compare the levels of gene expression in three cell lines derived from murine colon-adenocarcinoma 26 that show different metastatic potentials. The results, and subsequent Northern analyses, confirmed that one gene was expressed most strongly in NL17, the cell line with the highest experimentally metastatic potential to the lung; strongly in NL22, the line with moderately metastatic potential; and very weakly in NL4, which has no metastatic potential in recipient mice. Using this fragment as a probe, we isolated the murine cDNA as well as its human homologue and determined their DNA sequences. The cDNA sequences from both species contained open reading frames of 2874 nucleotides, encoding peptides of 958 amino acids with calculated molecular weights of approximately 109,000; the murine and human nucleotide sequences were 90% identical. The deduced amino acid sequences of these cDNAs revealed significant homology (45% identity) to the dis3+ gene product of Schizosaccharomyces pombe, a protein thought to be essential for mitotic control in the yeast. We therefore termed the murine and human genes hmc (homologue to the mitotic-control gene) and HMC, respectively. In 7 of 13 patients with colorectal cancers and liver metastases, expression of HMC was increased up to 38-fold in primary tumors and metastatic foci as compared to adjacent normal colorectal mucosa. An increase in expression of HMC, its novel product likely to belong to a structurally distinct family of mitotic-control proteins, may be associated with malignant phenotypes of some colorectal cancers.
- Published
- 1997
13. Abstract P3-06-26: Serum anti-p53 antibody titers predict pathological response to preoperative chemotherapy in women with HER2 positive or triple negative breast cancer.
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Yoshiyama, T, primary, Nakamura, Y, additional, Igawa, A, additional, Saruwatari, A, additional, Shigechi, T, additional, Ueda, N, additional, Kuba, S, additional, Ishida, M, additional, Nishimura, S, additional, Nishiyama, K, additional, and Ohno, S, additional
- Published
- 2012
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14. Abstract P6-05-14: Estrogen-induced genes in ductal carcinoma in situ(DCIS): their comparison with invasive ductal carcinoma.
- Author
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Ebata, A, primary, Suzuki, T, additional, Takagi, K, additional, Miki, Y, additional, Onodera, Y, additional, Nakamura, Y, additional, Fujishima, F, additional, Ishida, K, additional, Watanabe, M, additional, Tamaki, K, additional, Ishida, T, additional, Ohuchi, N, additional, and Sasano, H, additional
- Published
- 2012
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15. P5-13-21: Japanese Patients with Discordance in Estrogen Receptor between Primary Breast Cancer and Recurrent Tumor Have a Poorer Outcome.
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Tanaka, K, primary, Kawaguchi, H, additional, Kuba, S, additional, Koga, C, additional, Nishimura, S, additional, Yoshiyama, T, additional, Ishida, M, additional, Nakamura, Y, additional, and Ohno, S, additional
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- 2011
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16. Abstract P3-14-12: High Risk of Recurrence in Japanese Patients with HER2-Positive T1N0 Breast Cancer
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Tanaka, K, primary, Kawaguchi, H, additional, Koga, C, additional, Nishimura, S, additional, Yoshiyama, T, additional, Yamaguchi, H, additional, Nakamura, Y, additional, and Ohno, S., additional
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- 2010
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17. Abstract PD05-02: Genome-Wide Associations of Breast Events and Functional Genomic Studies in High-Risk Women Receiving Tamoxifen or Raloxifene on NSABP P1 and P2 Prevention Trials. A Pharmacogenomics Research Network-RIKEN-NSABP Collaboration
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Ingle, JN, primary, Liu, M, additional, Wickerham, DL, additional, Schaid, DJ, additional, Mushiroda, T, additional, Kubo, M, additional, Costantino, JP, additional, Goetz, MP, additional, Ames, MM, additional, Wang, L, additional, Vogel, VG, additional, Paik, S, additional, Batzler, A, additional, Flockhart, DA, additional, Wolmark, N, additional, Nakamura, Y, additional, and Weinshilboum, R., additional
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- 2010
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18. A Genome-Wide Association Study in Patients Experiencing Musculoskeletal Adverse Events on Aromatase Inhibitors as Adjuvant Therapy in Early Breast Cancer Entered on NCIC CTG Trial MA.27. A Pharmacogenetics Research Network-RIKEN Collaboration.
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Ingle, J., primary, Schaid, D., additional, Goss, P., additional, Mushiroda, T., additional, Chapman, J., additional, Kubo, M., additional, Jenkins, G., additional, Batzler, A., additional, Liu, M., additional, Shepherd, L., additional, Ellis, M., additional, Flockhart, D., additional, Nakamura, Y., additional, and Weinshilboum, R., additional
- Published
- 2009
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19. EGF-dependent enhancement of invasive ability in squamous cell carcinoma of the breast.
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Kimura, F, primary, Iwaya, K, additional, Kawaguchi, T, additional, Yamada, K, additional, Ogata, A, additional, Kaise, H, additional, Komatsu, S, additional, Nakamura, Y, additional, Ueda, N, additional, Mukai, K, additional, and Kohno, N, additional
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- 2009
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20. Serum anti-p53 antibody titers predict pathological response to preoperative chemotherapy in women with HER2 positive or triple negative breast cancer.
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Yoshiyama, T., Nakamura, Y., Igawa, A., Saruwatari, A., Shigechi, T., Ueda, N., Kuba, S., Ishida, M., Nishimura, S., Nishiyama, K., and Ohno, S.
- Subjects
- *
BREAST cancer research , *HER2 gene , *BREAST cancer surgery , *DOCETAXEL , *ANTINEOPLASTIC agents - Abstract
Background: In SABCS 2009, we reported that the high level of serum anti-p53 antibody titers was associated with response to preoperative chemotherapy in cases with primary breast cancer (SABCS 2009). Prognostic meaning of pathological complete response (pCR) after preoperative chemotherapy differs among various subtype, and there is a close relationship between pCR and prognosis in cases with HER2 positive or triple negative disease. The aim of this study is to evaluate the association between the high level of serum anti-p53 antibody titers and pCR in patients with HER2-positive or triple negative breast cancer. Patients and Methods: In this study, we analyzed 196 women with operable early stage breast cancer (T1-T3, N0-1) treated with preoperative chemotherapy and definitive curative surgery since 2002 to 2011. All of the patients received four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w). The serum anti-p53 antibody titers were assessed by ELISA with the anti-p53 EIA Kit II (MESACUP anti-53 Test: MBL) in the pre-treatment serum samples. The test's cut-off value was determined to be 1.3 IU/ml based on reference distribution in healthy control individuals. The association between serum anti-p53 antibody titers and pCR was analyzed. Results: The subtype of tumors of 196 patients were classified to 86 of ER+/HER2-, 24 of ER+/HER2+, 29 of ER-/HER2+ and 57 of ER-/HER2-. The pCR was achieved 49 of 196 patients (25%). The pCR rate were 7%(6/86), 33%(8/24), 48%(14/29) and 37%(21/57) in the subtype of ER+/HER2-, ER+/HER2+, ER-/HER2+ and ER-/HER2- respectively. The range of serum anti-p53 antibody titers in the serum samples of 196 patients was between 0.40 and 5610 (the median was 0.40 and the average was 85.2). Excluding 86 cases with ER+/HER2-, relationship between serum anti-p53 antibody titers and pCR was evaluated. According to serum anti-p53 antibody titers with the patients of pCR, cut-off value of serum anti-p53 antibody titers was set to be 6 IU/ml. The pCR was observed in nine of 12 cases (75%) with high serum anti-p53 antibody titers, which was significantly higher than those with low titers (35%: 34/98; p = 0.01). Multivariate analysis showed that the only high anti- p53 antibody titer was an independent predictive factor for pCR due to preoperative chemotherapy (p = 0.01). Conclusion: p53 mutation analysis using serum anti-p53 antibody titers might be a useful predictive test for response to preoperative chemotherapy in patients especially with HER2 positive or triple negative breast cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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21. Estrogen-induced genes in ductal carcinoma in situ (DCIS): their comparison with invasive ductal carcinoma.
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Ebata, A., Suzuki, T., Takagi, K., Miki, Y., Onodera, Y., Nakamura, Y., Fujishima, F., Ishida, K., Watanabe, M., Tamaki, K., Ishida, T., Ohuchi, N., and Sasano, H.
- Subjects
- *
ESTROGEN , *DUCTAL carcinoma , *BREAST cancer , *GENE expression , *ESTROGEN receptors - Abstract
It is well known that estrogens play important roles in both the pathogenesis and development of invasive ductal carcinoma (IDC) of human breast. However, molecular features of estrogen actions have remained largely unclear in pure ductal carcinoma in situ (pDCIS), regarded as a precursor lesion of many IDCs. This is partly due to the fact that gene expression profiles of estrogen-responsive genes have not been examined in pDCIS. Therefore, we first examined the profiles of estrogen-induced genes in estrogen receptor (ER)-positive pDCIS and DCIS (DCIS-c) and IDC (IDC-c) components of IDC cases (n = 4, respectively) by microarray analysis. Estrogen-induced genes identified in this study were tentatively classified into three different groups in the hierarchical clustering analysis, and 33% of the genes were predominantly expressed in pDCIS rather than DCIS-c or IDC-c cases. Among these genes, the status of MYB (c-MYB), RBBP7 (RbAp46) and BIRC5 (survivin) expression in carcinoma cells was significantly higher in ER-positive pDCIS(n = 53) than that in ER-positive DCIS-c (n = 27) or IDC-c (n = 27) by subsequent immunohistochemical analysis of the corresponding genes (P < 0.0001, P = 0.03 and P = 0.0003, respectively). In particular, the status of c-MYB immunoreactivity was inversely (P = 0.006) correlated with Ki-67 in the pDCIS cases. These results suggest that expression profiles of estrogen-induced genes in pDCIS may be different from those in IDC, and c-MYB, RbAp46 and survivin may play particularly important roles among estrogen induced genes in ER-positive pDCIS. [ABSTRACT FROM AUTHOR]
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- 2012
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22. CD106 in Tumor-Specific Exhausted CD8+ T Cells Mediates Immunosuppression by Inhibiting TCR Signaling.
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Naoi Y, Morinaga T, Nagasaki J, Ariyasu R, Ueda Y, Yamashita K, Zhou W, Kawashima S, Kawase K, Honobe-Tabuchi A, Ohnuma T, Kawamura T, Umeda Y, Kawahara Y, Nakamura Y, Kiniwa Y, Yamasaki O, Fukushima S, Kawazu M, Suzuki Y, Nishikawa H, Hanazawa T, Ando M, Inozume T, and Togashi Y
- Subjects
- Animals, Mice, Humans, Mice, Inbred C57BL, Antigens, CD immunology, Antigens, CD metabolism, Antigens, CD genetics, Female, Neoplasms immunology, Neoplasms pathology, Immunosuppression Therapy, Immune Tolerance immunology, Cell Line, Tumor, Immunotherapy methods, CD8-Positive T-Lymphocytes immunology, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell genetics, Tumor Microenvironment immunology, Signal Transduction immunology
- Abstract
T-cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T-cell exhaustion, such as programmed death 1, can reinvigorate tumor-specific T cells and activate antitumor immunity in various types of cancer. In this study, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed antitumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to programmed death 1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy. Significance: CD106 is specifically expressed in tumor-specific exhausted CD8+ T cells and inhibits the TCR signaling pathway by reducing surface expression of the TCR/CD3 complex to suppress antitumor immunity., (©2024 American Association for Cancer Research.)
- Published
- 2024
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23. α 1 -Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages.
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Matsusaka K, Fujiwara Y, Pan C, Esumi S, Saito Y, Bi J, Nakamura Y, Mukunoki A, Takeo T, Nakagata N, Yoshii D, Fukuda R, Nagasaki T, Tanaka R, Komori H, Maeda H, Watanabe H, Tamada K, Komohara Y, and Maruyama T
- Subjects
- Animals, Carcinogenesis, Cell Proliferation, Disease Progression, Enhancer Elements, Genetic, Hepatocytes metabolism, Immunosuppression Therapy, Interferon-gamma metabolism, Macrophages cytology, Membrane Proteins, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Monocytes cytology, Orosomucoid genetics, Signal Transduction, Toll-Like Receptor 4 metabolism, B7-H1 Antigen metabolism, Macrophages metabolism, Orosomucoid metabolism, Tumor-Associated Macrophages metabolism
- Abstract
Blood levels of acute-phase protein α
1 -acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell-derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte-derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL6 production from macrophages, which stimulated proliferation in tumor cells by IL6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages (TAM) on tumor progression. AGP decreased IFNγ secretion from T cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL6 production in macrophages by binding with CD14, a coreceptor for Toll-like receptor 4 (TLR4), and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with TAMs and that AGP might be a target molecule for anticancer therapy. SIGNIFICANCE: AGP-mediated suppression of antitumor immunity contributes to tumor progression by inducing PD-L1 expression and IL6 production in TAMs., (©2021 American Association for Cancer Research.)- Published
- 2021
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24. A rare polymorphic variant of NBS1 reduces DNA repair activity and elevates chromosomal instability.
- Author
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Yamamoto Y, Miyamoto M, Tatsuda D, Kubo M, Nakagama H, Nakamura Y, Satoh H, Matsuda K, Watanabe T, and Ohta T
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- Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Breast Neoplasms genetics, Cell Cycle Proteins chemistry, Cell Line, Tumor, DNA Breaks, Double-Stranded, Female, Humans, Molecular Sequence Data, Multiprotein Complexes metabolism, Nuclear Proteins chemistry, Nuclear Proteins metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Protein Binding, Protein Transport, Sequence Alignment, Trans-Activators metabolism, Cell Cycle Proteins genetics, Chromosomal Instability, DNA Repair, Nuclear Proteins genetics, Polymorphism, Genetic
- Abstract
Failure to expeditiously repair DNA at sites of double-strand breaks (DSB) ultimately is an important etiologic factor in cancer development. NBS1 plays an important role in the cellular response to DSB damage. A rare polymorphic variant of NBS1 that resulted in an isoleucine to valine substitution at amino acid position 171 (I171V) was first identified in childhood acute lymphoblastic leukemia. This polymorphic variant is located in the N-terminal region that interacts with other DNA repair factors. In earlier work, we had identified a remarkable number of structural chromosomal aberrations in a patient with pediatric aplastic anemia with a homozygous polymorphic variant of NBS1-I171V; however, it was unclear whether this variant affected DSB repair activity or chromosomal instability. In this report, we demonstrate that NBS1-I171V reduces DSB repair activity through a loss of association with the DNA repair factor MDC1. Furthermore, we found that heterozygosity in this polymorphic variant was associated with breast cancer risk. Finally, we showed that this variant exerted a dominant-negative effect on wild-type NBS1, attenuating DSB repair efficiency and elevating chromosomal instability. Our findings offer evidence that the failure of DNA repair leading to chromosomal instability has a causal impact on the risk of breast cancer development., (©2014 American Association for Cancer Research.)
- Published
- 2014
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25. Midkine promotes neuroblastoma through Notch2 signaling.
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Kishida S, Mu P, Miyakawa S, Fujiwara M, Abe T, Sakamoto K, Onishi A, Nakamura Y, and Kadomatsu K
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- Animals, Aptamers, Nucleotide genetics, Aptamers, Nucleotide metabolism, Aptamers, Nucleotide pharmacology, Blotting, Western, Cell Line, Tumor, Cytokines metabolism, Ganglia, Sympathetic metabolism, Ganglia, Sympathetic pathology, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Immunohistochemistry, Mice, Mice, 129 Strain, Mice, Knockout, Mice, Nude, Mice, Transgenic, Midkine, Neuroblastoma pathology, Neuroblastoma prevention & control, Protein Binding, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Receptor, Notch2 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Cytokines genetics, Neuroblastoma genetics, Receptor, Notch2 genetics, Signal Transduction
- Abstract
Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma.
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- 2013
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26. DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through its interaction with NPM1 in renal cell carcinomas.
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Fukawa T, Ono M, Matsuo T, Uehara H, Miki T, Nakamura Y, Kanayama HO, and Katagiri T
- Subjects
- Animals, COS Cells, Carcinoma, Renal Cell metabolism, Cell Nucleolus genetics, Cell Nucleolus metabolism, DEAD-box RNA Helicases biosynthesis, DEAD-box RNA Helicases metabolism, HEK293 Cells, Humans, Immunohistochemistry, Kidney Neoplasms metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Nucleophosmin, Prognosis, Proto-Oncogene Proteins c-mdm2 genetics, Signal Transduction, Transcription, Genetic, Transfection, Tumor Suppressor Protein p53 genetics, Up-Regulation, Carcinoma, Renal Cell genetics, DEAD-box RNA Helicases genetics, Kidney Neoplasms genetics, Proto-Oncogene Proteins c-mdm2 metabolism, RNA, Ribosomal genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Studies of renal cell carcinoma (RCC) have led to the development of new molecular-targeted drugs but its oncogenic origins remain poorly understood. Here, we report the identification and critical roles in renal carcinogenesis for DDX31, a novel nucleolar protein upregulated in the vast majority of human RCC. Immunohistochemical overexpression of DDX31 was an independent prognostic factor for patients with RCC. RNA interference (RNAi)-mediated attenuation of DDX31 in RCC cells significantly suppressed outgrowth, whereas ectopic DDX31 overexpression in human 293 kidney cells drove their proliferation. Endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1) in the nucleoli of RCC cells, and attenuation of DDX31 or NPM1 expression decreased pre-ribosomal RNA biogenesis. Notably, in DDX31-attenuated cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm where it bound to HDM2. As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G(1) phase cell-cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31-NPM1 complex is likely to play critical roles in renal carcinogenesis., (©2012 AACR.)
- Published
- 2012
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27. NLRR1 enhances EGF-mediated MYCN induction in neuroblastoma and accelerates tumor growth in vivo.
- Author
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Hossain S, Takatori A, Nakamura Y, Suenaga Y, Kamijo T, and Nakagawara A
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Enzyme Activation drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression, Gene Expression Regulation, Neoplastic drug effects, Humans, Insulin-Like Growth Factor I pharmacology, Male, Membrane Proteins genetics, Mice, Mice, Inbred BALB C, Mice, Nude, N-Myc Proto-Oncogene Protein, Neoplasm Proteins genetics, Nerve Tissue Proteins, Neuroblastoma mortality, Promoter Regions, Genetic, Sp1 Transcription Factor metabolism, Transcription, Genetic drug effects, Epidermal Growth Factor pharmacology, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Neuroblastoma genetics, Neuroblastoma metabolism, Nuclear Proteins genetics, Oncogene Proteins genetics
- Abstract
Neuronal leucine-rich repeat protein-1 (NLRR1), a type-1 transmembrane protein highly expressed in unfavorable neuroblastoma, is a target gene of MYCN that is predominately expressed in primary neuroblastomas with MYCN amplification. However, the precise biological role of NLRR1 in cell proliferation and tumor progression remains unknown. To investigate its functional importance, we examined the role of NLRR1 in EGF and insulin growth factor-1 (IGF-1)-mediated cell viability. We found that NLRR1 positively regulated cell proliferation through activation of extracellular signal-regulated kinase mediated by EGF and IGF-1. Interestingly, EGF stimulation induced endogenous MYCN expression through Sp1 recruitment to the MYCN promoter region, which was accelerated in NLRR1-expressing cells. The Sp1-binding site was identified on the promoter region for MYCN induction, and phosphorylation of Sp1 was important for EGF-mediated MYCN regulation. In vivo studies confirmed the proliferation-promoting activity of NLRR1 and established an association between NLRR1 expression and poor prognosis in neuroblastoma. Together, our findings indicate that NLRR1 plays an important role in the development of neuroblastoma and therefore may represent an attractive therapeutic target for cancer treatment., (©2012 AACR.)
- Published
- 2012
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28. Critical function for nuclear envelope protein TMEM209 in human pulmonary carcinogenesis.
- Author
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Fujitomo T, Daigo Y, Matsuda K, Ueda K, and Nakamura Y
- Subjects
- Cell Growth Processes physiology, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Membrane Proteins genetics, Membrane Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Proto-Oncogene Proteins c-myc metabolism, RNA, Small Interfering administration & dosage, RNA, Small Interfering genetics, Transfection, Cell Transformation, Neoplastic metabolism, Lung Neoplasms metabolism, Membrane Proteins biosynthesis, Nuclear Envelope metabolism, Nuclear Proteins biosynthesis
- Abstract
Therapeutic targets for more effective and less toxic treatments of lung cancer remain important. Here we report the identification of the integral nuclear envelope protein TMEM209 as a critical driver of human lung cancer growth and survival. TMEM209 expression was normally limited to testis, but we found that it was widely expressed in lung cancer, in which it localized to the nuclear envelope, Golgi apparatus, and the cytoplasm of lung cancer cells. Ectopic overexpression of TMEM209 promoted cell growth, whereas TMEM209 attenuation was sufficient to block growth. Mass spectrometric analysis identified the nucleoporin protein NUP205 as a TMEM209-interacting protein, stabilizing NUP205 and increasing the level of c-Myc in the nucleus. Taken together, our findings indicate that TMEM209 overexpression and TMEM209-NUP205 interaction are critical drivers of lung cancer proliferation, suggesting a promising new target for lung cancer therapy., (©2012 AACR.)
- Published
- 2012
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29. Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression.
- Author
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Takawa M, Cho HS, Hayami S, Toyokawa G, Kogure M, Yamane Y, Iwai Y, Maejima K, Ueda K, Masuda A, Dohmae N, Field HI, Tsunoda T, Kobayashi T, Akasu T, Sugiyama M, Ohnuma S, Atomi Y, Ponder BA, Nakamura Y, and Hamamoto R
- Subjects
- Aged, Cell Line, Tumor, DNA Damage, DNA Replication, Female, Histone-Lysine N-Methyltransferase genetics, Humans, Lysine metabolism, Male, Methylation, Middle Aged, Proliferating Cell Nuclear Antigen chemistry, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Cell Transformation, Neoplastic, Histone-Lysine N-Methyltransferase physiology, Proliferating Cell Nuclear Antigen metabolism
- Abstract
Although the physiologic significance of lysine methylation of histones is well known, whether lysine methylation plays a role in the regulation of nonhistone proteins has not yet been examined. The histone lysine methyltransferase SETD8 is overexpressed in various types of cancer and seems to play a crucial role in S-phase progression. Here, we show that SETD8 regulates the function of proliferating cell nuclear antigen (PCNA) protein through lysine methylation. We found that SETD8 methylated PCNA on lysine 248, and either depletion of SETD8 or substitution of lysine 248 destabilized PCNA expression. Mechanistically, lysine methylation significantly enhanced the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retarded the maturation of Okazaki fragments, slowed DNA replication, and induced DNA damage, and cells expressing a methylation-inactive PCNA mutant were more susceptible to DNA damage. An increase of methylated PCNA was found in cancer cells, and the expression levels of SETD8 and PCNA were correlated in cancer tissue samples. Together, our findings reveal a function for lysine methylation on a nonhistone protein and suggest that aberrant lysine methylation of PCNA may play a role in human carcinogenesis., (©2012 AACR.)
- Published
- 2012
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30. YB-1 bridges neural stem cells and brain tumor-initiating cells via its roles in differentiation and cell growth.
- Author
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Fotovati A, Abu-Ali S, Wang PS, Deleyrolle LP, Lee C, Triscott J, Chen JY, Franciosi S, Nakamura Y, Sugita Y, Uchiumi T, Kuwano M, Leavitt BR, Singh SK, Jury A, Jones C, Wakimoto H, Reynolds BA, Pallen CJ, and Dunn SE
- Subjects
- Animals, Base Sequence, Cell Line, Tumor, Immunohistochemistry, Mice, Mice, Knockout, RNA, Small Interfering, Brain Neoplasms pathology, Cell Differentiation physiology, Cell Division physiology, Glioblastoma pathology, Neural Stem Cells cytology, Transcription Factors physiology
- Abstract
The Y-box binding protein 1 (YB-1) is upregulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here, we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knockout mice had reduced Sox-2, nestin, and musashi-1 expression in the SVZ. Although primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Glial tumors often express NSC markers and tend to loose the cellular control that governs differentiation; therefore, we addressed whether YB-1 served a similar role in cancer cells. YB-1, Sox-2, musashi-1, Bmi-1, and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary brain tumor-initiating cells (BTIC). Silencing YB-1 with siRNA attenuated the expression of these NSC markers, reduced neurosphere growth, and triggered differentiation via coordinate loss of GSK3-β. Furthermore, differentiation of BTIC with 1% serum or bone morphogenetic protein-4 suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 expression increased with tumor grade (n = 49 cases). YB-1 was also coexpressed with Bmi-1 (Spearmans 0.80, P > 0.001) and Sox-2 (Spearmans 0.66, P > 0.001) based on the analysis of 282 cases of high-grade gliomas. These proteins were highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 correlatively expresses with NSC markers where it functions to promote cell growth and inhibit differentiation.
- Published
- 2011
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31. Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells.
- Author
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Cho HS, Suzuki T, Dohmae N, Hayami S, Unoki M, Yoshimatsu M, Toyokawa G, Takawa M, Chen T, Kurash JK, Field HI, Ponder BA, Nakamura Y, and Hamamoto R
- Subjects
- Animals, Cell Cycle physiology, Humans, Methylation, Mice, Retinoblastoma Protein metabolism, Histone Demethylases metabolism, Myosin-Light-Chain Kinase metabolism, Myosin-Light-Chain Phosphatase metabolism, Neoplasms enzymology, Neoplasms pathology, Oxidoreductases, N-Demethylating metabolism
- Abstract
Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by histone lysine methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis.
- Published
- 2011
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32. Expression of snail in epidermal keratinocytes promotes cutaneous inflammation and hyperplasia conducive to tumor formation.
- Author
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Du F, Nakamura Y, Tan TL, Lee P, Lee R, Yu B, and Jamora C
- Subjects
- Animals, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Dermatitis genetics, Dermatitis pathology, Hyperplasia, Interleukin-17 metabolism, Interleukin-6 metabolism, Keratinocytes pathology, Keratinocytes physiology, Macrophages pathology, Mice, Mice, Transgenic, STAT3 Transcription Factor metabolism, Signal Transduction, Skin metabolism, Skin pathology, Skin Neoplasms genetics, Skin Neoplasms pathology, Snail Family Transcription Factors, Transcription Factors genetics, Cell Transformation, Neoplastic metabolism, Dermatitis metabolism, Keratinocytes metabolism, Skin Neoplasms metabolism, Transcription Factors biosynthesis
- Abstract
Although metastasis is the most lethal consequence of tumor progression, comparatively little is known regarding the molecular machinery governing this process. In many carcinomas, there is a robust correlation between the expression of the transcription factor Snail and a poor prognosis, but the contribution of this protein to the metastatic process remains unresolved. Interestingly, the prolonged expression of Snail in epidermal keratinocytes is sufficient to recapitulate early features of metastasis. However, it does so without inducing a complete epithelial-mesenchymal transition (EMT), a developmental phenomenon mediated by Snail that is extensively invoked as the mechanism fueling tumorigenesis. Instead, we found that the local invasiveness of keratinocytes is the consequence of the recruitment and activity of macrophages. Moreover, keratinocyte proliferation is the product of an IL-17/IL-6/Stat3 signaling module initiated by activated resident γδT cells in the transgenic skin. Together, these phenotypes prime the transgenic skin for the formation and metastasis of tumors in response to chemically induced carcinogenesis. Thus, the contribution of Snail to the progression of carcinomas is largely through the creation of a hyperproliferative and inflammatory niche that facilitates tumor development and dissemination., (©2010 AACR.)
- Published
- 2010
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33. Cell-permeable peptide DEPDC1-ZNF224 interferes with transcriptional repression and oncogenicity in bladder cancer cells.
- Author
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Harada Y, Kanehira M, Fujisawa Y, Takata R, Shuin T, Miki T, Fujioka T, Nakamura Y, and Katagiri T
- Subjects
- Animals, COS Cells, Cell Growth Processes physiology, Cell Line, Tumor, Cell Membrane Permeability physiology, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Chlorocebus aethiops, GTPase-Activating Proteins antagonists & inhibitors, GTPase-Activating Proteins genetics, Gene Expression Regulation, Neoplastic, Guanine Nucleotide Exchange Factors, Humans, Mice, Repressor Proteins antagonists & inhibitors, Repressor Proteins genetics, Transcriptional Activation, Urinary Bladder Neoplasms pathology, Zinc Fingers genetics, GTPase-Activating Proteins metabolism, Repressor Proteins metabolism, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms metabolism
- Abstract
Bladder cancer is the second most common genitourinary cancer worldwide, yet its oncogenic origins remain poorly understood. The cancer-testis antigen DEPDC1 was shown recently to contribute to bladder cancer oncogenesis. In this study, we examined the biological functions of DEPDC1 and defined a potential therapeutic strategy to target this molecule. Coimmunoprecipitation and immunocytochemistry revealed that DEPDC1 interacted and colocalized with zinc finger transcription factor ZNF224, a known transcriptional repressor. Inhibiting this interaction with a cell-permeable peptide corresponding to the ZNF224-interacting domain in DEPDC1 induced apoptosis of bladder cancer cells in vitro and in vivo. By inhibiting DEPDC1-ZNF224 complex formation, this peptide triggered transcriptional activation of A20, a potent inhibitor of the NF-kappaB signaling pathway. Our findings indicate that the DEPDC1-ZNF224 complex is likely to play a critical role in bladder carcinogenesis., ((c)2010 AACR.)
- Published
- 2010
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34. Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis.
- Author
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Nguyen MH, Koinuma J, Ueda K, Ito T, Tsuchiya E, Nakamura Y, and Daigo Y
- Subjects
- Adaptor Proteins, Signal Transducing biosynthesis, Adaptor Proteins, Signal Transducing genetics, Amino Acid Sequence, Animals, COS Cells, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Small Cell drug therapy, Carcinoma, Small Cell genetics, Carcinoma, Small Cell metabolism, Carcinoma, Small Cell pathology, Cell Cycle Proteins biosynthesis, Cell Cycle Proteins genetics, Cell Growth Processes drug effects, Cell Growth Processes physiology, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Chlorocebus aethiops, Epidermal Growth Factor metabolism, Epidermal Growth Factor pharmacology, Gene Expression Profiling, Gene Knockdown Techniques, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, MAP Kinase Signaling System, Molecular Sequence Data, Peptides chemical synthesis, Peptides pharmacology, Phosphorylation, RNA, Small Interfering genetics, Transcriptional Activation, Adaptor Proteins, Signal Transducing metabolism, Cell Cycle Proteins metabolism, Cell Transformation, Neoplastic metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Lung Neoplasms metabolism
- Abstract
We analyzed the gene expression profiles of clinical lung carcinomas using a cDNA microarray containing 27,648 genes or expressed sequence tags, and identified CDCA5 (cell division cycle associated 5) to be upregulated in the majority of lung cancers. Tumor tissue microarray analysis of 262 non-small cell lung cancer patients revealed that CDCA5 positivity was an independent prognostic factor for lung cancer patients. Suppression of CDCA5 expression with siRNAs inhibited the growth of lung cancer cells; concordantly, induction of exogenous expression of CDCA5 conferred growth-promoting activity in mammalian cells. We also found that extracellular signal-regulated kinase (ERK) kinase phosphorylated CDCA5 at Ser79 and Ser209 in vivo. Exogenous expression of phospho-mimicking CDCA5 protein whose Ser209 residue was replaced with glutamine acid further enhanced the growth of cancer cells. In addition, functional inhibition of the interaction between CDCA5 and ERK kinase by a cell-permeable peptide corresponding to a 20-amino-acid sequence part of CDCA5, which included the Ser209 phosphorylation site by ERK, significantly reduced phosphorylation of CDCA5 and resulted in growth suppression of lung cancer cells. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy., (Copyright 2010 AACR.)
- Published
- 2010
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35. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy.
- Author
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Sato N, Yamabuki T, Takano A, Koinuma J, Aragaki M, Masuda K, Ishikawa N, Kohno N, Ito H, Miyamoto M, Nakayama H, Miyagi Y, Tsuchiya E, Kondo S, Nakamura Y, and Daigo Y
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Antibodies, Neutralizing immunology, Biomarkers, Tumor immunology, Case-Control Studies, Cell Growth Processes physiology, Cell Line, Tumor, Female, Humans, Intercellular Signaling Peptides and Proteins biosynthesis, Intercellular Signaling Peptides and Proteins genetics, Male, Mice, Mice, Inbred BALB C, Middle Aged, NIH 3T3 Cells, Neoplasms blood, Neoplasms pathology, Wnt Proteins antagonists & inhibitors, Antibodies, Neutralizing pharmacology, Biomarkers, Tumor blood, Immunization, Passive methods, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins immunology, Neoplasms therapy
- Abstract
Dickkopf-1 (DKK1) is an inhibitor of Wnt/beta-catenin signaling that is overexpressed in most lung and esophageal cancers. Here, we show its utility as a serum biomarker for a wide range of human cancers, and we offer evidence favoring the potential application of anti-DKK1 antibodies for cancer treatment. Using an original ELISA system, high levels of DKK1 protein were found in serologic samples from 906 patients with cancers of the pancreas, stomach, liver, bile duct, breast, and cervix, which also showed elevated expression levels of DKK1. Additionally, anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice. Our findings suggest DKK1 as a serum biomarker for screening against a variety of cancers, and anti-DKK1 antibodies as potential theranostic tools for diagnosis and treatment of cancer., (Copyright 2010 AACR.)
- Published
- 2010
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36. Involvement of the tubulin tyrosine ligase-like family member 4 polyglutamylase in PELP1 polyglutamylation and chromatin remodeling in pancreatic cancer cells.
- Author
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Kashiwaya K, Nakagawa H, Hosokawa M, Mochizuki Y, Ueda K, Piao L, Chung S, Hamamoto R, Eguchi H, Ohigashi H, Ishikawa O, Janke C, Shinomura Y, and Nakamura Y
- Subjects
- Blotting, Northern, Blotting, Western, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Cell Proliferation, Chromatography, Liquid, Co-Repressor Proteins, Histones genetics, Histones metabolism, Humans, Immunoenzyme Techniques, Immunoprecipitation, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Protein Processing, Post-Translational, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Trans-Activators genetics, Transcription Factors, Tumor Cells, Cultured, Carcinoma, Pancreatic Ductal metabolism, Chromatin Assembly and Disassembly physiology, Gene Expression Regulation physiology, Pancreatic Neoplasms metabolism, Peptide Synthases genetics, Polyglutamic Acid metabolism, Trans-Activators metabolism
- Abstract
Polyglutamylation is a new class of posttranslational modification in which glutamate side chains are formed in proteins, although its biological significance is not well known. Through our genome-wide gene expression profile analyses of pancreatic ductal adenocarcinoma (PDAC) cells, we identified the overexpression of tubulin tyrosine ligase-like family member 4 (TTLL4) in PDAC cells. Subsequent reverse transcription-PCR and Northern blot analyses confirmed its upregulation in several PDACs. TTLL4 belongs to the TTLL family which was reported to have polyglutamylase activity. Knockdown of TTLL4 by short hairpin RNA in PDAC cells attenuated the growth of PDAC cells and exogenous introduction of TTLL4 enhanced cell growth. We also found that TTLL4 expression was correlated with polyglutamylation levels of a glutamate stretch region of the proline, glutamate, and leucine-rich protein 1 (PELP1) that was shown to interact with various proteins such as histone H3, and was involved in several signaling pathways through its function as a scaffold protein. PELP1 polyglutamylation could influence its interaction with histone H3 and affect histone H3 acetylation. We also identified the interaction of PELP1 with LAS1L and SENP3, components of the MLL1-WDR5 supercomplex involving chromatin remodeling. Our findings imply that TTLL4 could play important roles in pancreatic carcinogenesis through its polyglutamylase activity and subsequent coordination of chromatin remodeling, and might be a good molecular candidate for the development of new therapeutic strategies for pancreatic cancer., ((c)2010 AACR.)
- Published
- 2010
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37. Critical roles of mucin 1 glycosylation by transactivated polypeptide N-acetylgalactosaminyltransferase 6 in mammary carcinogenesis.
- Author
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Park JH, Nishidate T, Kijima K, Ohashi T, Takegawa K, Fujikane T, Hirata K, Nakamura Y, and Katagiri T
- Subjects
- Breast Neoplasms enzymology, Breast Neoplasms genetics, Cell Line, Tumor, Gene Expression Profiling, Glycosylation, HeLa Cells, Humans, N-Acetylgalactosaminyltransferases genetics, Transcriptional Activation, Transfection, Up-Regulation, Breast Neoplasms metabolism, Mucin-1 metabolism, N-Acetylgalactosaminyltransferases metabolism
- Abstract
The structure of O-glycosylated proteins is altered in breast cancer cells, but the mechanisms of such an aberrant modification have been largely unknown. We here report critical roles of a novel druggable target, polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6), which is upregulated in a great majority of breast cancers and encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Knockdown of GALNT6 by small interfering RNA significantly enhanced cell adhesion function and suppressed the growth of breast cancer cells. Western blot and immunostaining analyses indicated that wild-type GALNT6 protein could glycosylate and stabilize an oncoprotein mucin 1 (MUC1), which was upregulated with GALNT6 in breast cancer specimens. Furthermore, knockdown of GALNT6 or MUC1 led to similar morphologic changes of cancer cells accompanied by the increase of cell adhesion molecules beta-catenin and E-cadherin. Our findings implied that overexpression of GALNT6 might contribute to mammary carcinogenesis through aberrant glycosylation and stabilization of MUC1 and that screening of GALNT6 inhibitors would be valuable for the development of novel therapeutic modalities against breast cancer.
- Published
- 2010
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38. Lipid rafts and caveolin-1 are required for invadopodia formation and extracellular matrix degradation by human breast cancer cells.
- Author
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Yamaguchi H, Takeo Y, Yoshida S, Kouchi Z, Nakamura Y, and Fukami K
- Subjects
- Breast Neoplasms metabolism, Cell Line, Cell Line, Tumor, Extracellular Matrix pathology, Female, Fluorescent Antibody Technique, Humans, Immunoblotting, Matrix Metalloproteinase 14 metabolism, Neoplasm Invasiveness pathology, Protein Transport physiology, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Breast Neoplasms pathology, Caveolin 1 metabolism, Cell Surface Extensions metabolism, Extracellular Matrix metabolism, Membrane Microdomains metabolism
- Abstract
Invadopodia are ventral membrane protrusions through which invasive cancer cells degrade the extracellular matrix. They are thought to function in the migration of cancer cells through tissue barriers, which is necessary for cancer invasion and metastasis. Although many protein components of invadopodia have been identified, the organization and the role of membrane lipids in invadopodia are not well understood. In this study, the role of lipid rafts, which are cholesterol-enriched membrane microdomains, in the assembly and function of invadopodia in human breast cancer cells was investigated. Lipid rafts are enriched, internalized, and dynamically trafficked at invadopodia sites. Perturbation of lipid raft formation due to depleting or sequestering membrane cholesterol blocked the invadopodia-mediated degradation of the gelatin matrix. Caveolin-1 (Cav-1), a resident protein of lipid rafts and caveolae, accumulates at invadopodia and colocalizes with the internalized lipid raft membranes. Membrane type 1 matrix metalloproteinase (MT1-MMP), a matrix proteinase associated with invadopodia, is localized at lipid raft-enriched membrane fractions and cotrafficked and colocalized with Cav-1 at invadopodia. The small interfering RNA-mediated silencing of Cav-1 inhibited the invadopodia-mediated and MT1-MMP-dependent degradation of the gelatin matrix. Furthermore, Cav-1 and MT1-MMP are coexpressed in invasive human breast cancer cell lines that have an ability to form invadopodia. These results indicate that invadopodia are the sites where enrichment and trafficking of lipid rafts occur and that Cav-1 is an essential regulator of MT1-MMP function and invadopodia-mediated breast cancer cell invasion.
- Published
- 2009
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39. Regulation of protein Citrullination through p53/PADI4 network in DNA damage response.
- Author
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Tanikawa C, Ueda K, Nakagawa H, Yoshida N, Nakamura Y, and Matsuda K
- Subjects
- Blotting, Western, Cell Line, Citrulline metabolism, Humans, Immunoprecipitation, Mass Spectrometry, Nuclear Proteins metabolism, Nucleophosmin, Oligonucleotide Array Sequence Analysis, Protein Transport physiology, Protein-Arginine Deiminase Type 4, Protein-Arginine Deiminases, Reverse Transcriptase Polymerase Chain Reaction, Transfection, DNA Damage physiology, Hydrolases metabolism, Protein Processing, Post-Translational physiology, Signal Transduction physiology, Tumor Suppressor Protein p53 metabolism
- Abstract
Upon a wide range of cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes related to apoptosis, cell cycle arrest, and DNA repair. However, its involvement in posttranslational modifications of proteins has not yet been well characterized. Here, we report the novel role of p53 in the regulation of protein citrullination. p53 transactivated peptidylarginine deiminase type 4 (PADI4) through an intronic p53-binding site. The PADI4 gene encodes an enzyme catalyzing the citrullination of arginine residues in proteins, and ectopic expression of p53 or PADI4 induced protein citrullination. In addition, various proteins were citrullinated in response to DNA damage, but knockdown of PADI4 or p53 remarkably inhibited their citrullination, indicating the regulation of protein citrullination in a p53/PADI4-dependent manner. We found that PADI4 citrullinated the histone chaperone protein, nucleophosmin (NPM1), at the arginine 197 residue in vivo under physiologic conditions. Citrullination of NPM1 by PADI4 resulted in its translocation from the nucleoli to the nucleoplasm, whereas PADI4 did not alter the localization of mutant NPM1 (R197K). Furthermore, ectopic expression of PADI4 inhibited tumor cell growth, and concordantly, the knockdown of PADI4 attenuated p53-mediated growth-inhibitory activity, demonstrating the significance of PADI4-mediated protein citrullination in the p53 signaling pathway
- Published
- 2009
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40. Ubiquitination and downregulation of BRCA1 by ubiquitin-conjugating enzyme E2T overexpression in human breast cancer cells.
- Author
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Ueki T, Park JH, Nishidate T, Kijima K, Hirata K, Nakamura Y, and Katagiri T
- Subjects
- Blotting, Northern, Blotting, Western, Breast Neoplasms genetics, Cell Line, Tumor, Down-Regulation, Female, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Ubiquitin-Conjugating Enzymes genetics, Ubiquitin-Protein Ligases genetics, Breast Neoplasms metabolism, Ubiquitin-Conjugating Enzymes metabolism, Ubiquitin-Protein Ligases metabolism, Ubiquitination physiology
- Abstract
Breast cancer is generated through a multistep genetic and epigenetic process including activations of oncogenes and inactivations of tumor suppressor genes. Here, we report a critical role of ubiquitin-conjugating enzyme E2T (UBE2T), an E2 ubiquitin-conjugating enzyme, in mammary carcinogenesis. Immunocytochemical staining and in vitro binding assay revealed that UBE2T interacted and colocalized with the BRCA1/BRCA1-associated RING domain protein (BARD1) complex. Knocking down of UBE2T expression with small interfering RNA drastically suppressed the growth of breast cancer cells. Interestingly, in vivo ubiquitination assay indicated BRCA1 to be polyubiquitinated by incubation with wild-type UBE2T protein, but not with C86A-UBE2T protein, an E2 activity-dead mutant, in which the 86th residue of cysteine was replaced with alanine. Furthermore, knocking down of UBE2T protein induced upregulation of BRCA1 protein in breast cancer cells, whereas its overexpression caused the decrease of the BRCA1 protein. Our data imply a critical role of UBE2T in development and/or progression of breast cancer through the interaction with and the regulation of the BRCA1/BARD1 complex.
- Published
- 2009
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41. Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism.
- Author
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Tamura K, Makino A, Hullin-Matsuda F, Kobayashi T, Furihata M, Chung S, Ashida S, Miki T, Fujioka T, Shuin T, Nakamura Y, and Nakagawa H
- Subjects
- Androgens pharmacology, Animals, Biomarkers, Tumor, Blotting, Northern, Chromatography, Liquid, Dietary Fats, Fatty Acid Elongases, Gas Chromatography-Mass Spectrometry, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin G immunology, Lipid Metabolism, Male, Mice, Mice, Nude, Molecular Sequence Data, Neoplasms, Hormone-Dependent metabolism, Oligonucleotide Array Sequence Analysis, Peptide Fragments metabolism, Prostatic Neoplasms metabolism, Rabbits, Sterol Regulatory Element Binding Protein 1 genetics, Sterol Regulatory Element Binding Protein 1 metabolism, Tandem Mass Spectrometry, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Acetyltransferases physiology, Fatty Acids metabolism, Neoplasms, Hormone-Dependent pathology, Prostatic Neoplasms pathology
- Abstract
A number of epidemiologic studies have indicated a strong association between dietary fat intake and prostate cancer development, suggesting that lipid metabolism plays some important roles in prostate carcinogenesis and its progression. In this study, through our genome-wide gene expression analysis of clinical prostate cancer cells, we identified a novel lipogenic gene, ELOVL7, coding a possible long-chain fatty acid elongase, as overexpressed in prostate cancer cells. ELOVL7 expression is regulated by the androgen pathway through SREBP1, as well as other lipogenic enzymes. Knockdown of ELOVL7 resulted in drastic attenuation of prostate cancer cell growth, and it is notable that high-fat diet promoted the growth of in vivo tumors of ELOVL7-expressed prostate cancer. In vitro fatty acid elongation assay and fatty acid composition analysis indicated that ELOVL7 was preferentially involved in fatty acid elongation of saturated very-long-chain fatty acids (SVLFA, C20:0 approximately ). Lipid profiles showed that knockdown of ELOVL7 in prostate cancer cells affected SVLFAs in the phospholipids and the neutral lipids, such as cholesterol ester. Focusing on cholesterol ester as a source of de novo steroid synthesis, we show that ELOVL7 affected de novo androgen synthesis in prostate cancer cells. These findings suggest that EVOLV7 could be involved in prostate cancer growth and survival through the metabolism of SVLFAs and their derivatives, could be a key molecule to elucidate the association between fat dietary intake and prostate carcinogenesis, and could also be a promising molecular target for development of new therapeutic or preventive strategies for prostate cancers.
- Published
- 2009
- Full Text
- View/download PDF
42. Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer.
- Author
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Takano A, Ishikawa N, Nishino R, Masuda K, Yasui W, Inai K, Nishimura H, Ito H, Nakayama H, Miyagi Y, Tsuchiya E, Kohno N, Nakamura Y, and Daigo Y
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Biomarkers, Tumor blood, COS Cells, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung genetics, Cell Adhesion Molecules antagonists & inhibitors, Cell Adhesion Molecules blood, Cell Adhesion Molecules genetics, Chlorocebus aethiops, Drug Delivery Systems, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms blood, Lung Neoplasms genetics, Male, Mice, Middle Aged, NIH 3T3 Cells, Oncogene Proteins antagonists & inhibitors, Oncogene Proteins blood, Oncogene Proteins genetics, Oncogene Proteins physiology, RNA, Small Interfering pharmacology, RNA, Small Interfering therapeutic use, Tumor Cells, Cultured, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung drug therapy, Cell Adhesion Molecules physiology, Lung Neoplasms diagnosis, Lung Neoplasms drug therapy
- Abstract
Gene expression profile analysis of lung cancers revealed the transactivation of an immunoglobulin-like molecule Nectin-4 in the majority of non-small cell lung cancers (NSCLC). Immunohistochemical staining of 422 NSCLCs showed that a high level of Nectin-4 expression was associated with poor prognosis for NSCLC patients (P < 0.0001), and multivariate analysis confirmed its independent prognostic value (P < 0.0001). We established an ELISA to measure serum Nectin-4 and found that serum Nectin-4 levels were significantly higher in NSCLC patients than in healthy volunteers. The proportion of the serum Nectin-4-positive cases was 88 of 164 (53.7%) NSCLCs, whereas only 3 of 131 (2.3%) healthy volunteers were falsely diagnosed as positive, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA21-1) in sensitivity and specificity. A combined ELISA for both Nectin-4 and CEA increased sensitivity and classified 65.0% of lung adenocarcinomas as positive with false-positive rate of 4.6%. The use of both Nectin-4 and CYFRA21-1 classified 68.3% of lung squamous cell carcinomas as positive with false-positive rate of 6.1%. Treatment of lung cancer cells with small interfering RNAs against Nectin-4 suppressed its expression and cell growth. In addition, exogenous expression of Nectin-4 increased the lamellipodia formation and the invasive ability of mammalian cells through activation of small GTPase Rac1. Nectin-4 might play a significant role in lung carcinogenesis, and it should be a new candidate serum and tissue biomarker, as well as a therapeutic target.
- Published
- 2009
- Full Text
- View/download PDF
43. Cancer-testis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas.
- Author
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Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, Ito H, Miyagi Y, Nakayama H, Fujita M, Hosokawa M, Tsuchiya E, Kohno N, Nakamura Y, and Daigo Y
- Subjects
- Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Squamous Cell blood, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cell Line, Tumor, Esophageal Neoplasms blood, Esophageal Neoplasms genetics, GPI-Linked Proteins, Gene Expression Profiling, Humans, Lung Neoplasms blood, Lung Neoplasms genetics, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Antigens, Ly analysis, Antigens, Neoplasm genetics, Biomarkers, Tumor analysis, Carcinoma, Non-Small-Cell Lung pathology, Esophageal Neoplasms pathology, Lung Neoplasms pathology, Neoplasm Proteins genetics
- Abstract
Gene expression profile analyses of non-small cell lung carcinomas (NSCLC) and esophageal squamous cell carcinomas (ESCC) revealed that lymphocyte antigen 6 complex locus K (LY6K) was specifically expressed in testis and transactivated in a majority of NSCLCs and ESCCs. Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035). We established an ELISA to measure serum LY6K and found that the proportion of the serum LY6K-positive cases was 38 of 112 (33.9%) NSCLC and 26 of 81 (32.1%) ESCC, whereas only 3 of 74 (4.1%) healthy volunteers were falsely diagnosed. In most cases, there was no correlation between serum LY6K and conventional tumor markers of carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA 21-1) values. A combined ELISA for both LY6K and CEA classified 64.7% of lung adenocarcinoma patients as positive, and the use of both LY6K and CYFRA 21-1 increased sensitivity in the detection of lung squamous cell carcinomas and ESCCs up to 70.4% and 52.5%, respectively, whereas the false positive rate was 6.8% to 9.5%. In addition, knocked down of LY6K expression with small interfering RNAs resulted in growth suppression of the lung and esophageal cancer cells. Our data imply that a cancer-testis antigen, LY6K, should be useful as a new type of tumor biomarker and probably as a target for the development of new molecular therapies for cancer treatment.
- Published
- 2007
- Full Text
- View/download PDF
44. The lysine 831 of vascular endothelial growth factor receptor 1 is a novel target of methylation by SMYD3.
- Author
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Kunizaki M, Hamamoto R, Silva FP, Yamaguchi K, Nagayasu T, Shibuya M, Nakamura Y, and Furukawa Y
- Subjects
- Cell Line, Cell Line, Tumor, Cell Proliferation, Histone Methyltransferases, Humans, Methylation, Models, Biological, Phosphorylation, Plasmids metabolism, Protein Methyltransferases, Serine chemistry, DNA Methylation, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Lysine chemistry, Vascular Endothelial Growth Factor Receptor-1 genetics, Vascular Endothelial Growth Factor Receptor-1 metabolism
- Abstract
We previously identified SMYD3 as a histone methyltransferase and showed that its expression was elevated in colorectal, hepatocellular, and breast carcinomas. In the investigation of methyltransferase activity of SMYD3, we have found that vascular endothelial growth factor receptor 1 (VEGFR1) was also methylated by SMYD3. We further identified the methylated residue at VEGFR1 lysine 831, which is located in the kinase domain and is conserved among VEGFR1 orthologues. We also found that the lysine is followed by serine, which is conserved among some of the methylation targets of histone methyltransferases. Furthermore, methylation of VEGFR1 enhanced its kinase activity in cells. These data should be helpful for the profound understanding of the biological role of SMYD3 and regulatory mechanisms of VEGFR1. Additionally our finding may facilitate the development of strategies that may inhibit the progression of cancer cells.
- Published
- 2007
- Full Text
- View/download PDF
45. Gamma-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor pi subunit.
- Author
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Takehara A, Hosokawa M, Eguchi H, Ohigashi H, Ishikawa O, Nakamura Y, and Nakagawa H
- Subjects
- Calcium metabolism, Carcinoma, Pancreatic Ductal genetics, Cell Growth Processes drug effects, Cell Growth Processes physiology, Cell Line, Tumor, Humans, MAP Kinase Signaling System drug effects, Pancreatic Neoplasms genetics, RNA, Small Interfering genetics, Receptors, GABA-A genetics, Receptors, GABA-A metabolism, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, GABA Agents pharmacology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Receptors, GABA-A biosynthesis, gamma-Aminobutyric Acid pharmacology
- Abstract
Gamma-aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter in the mature central nervous system, and GABA/GABA receptors are also present in nonneural tissues, including cancer, but their precise function in nonneuronal or cancerous cells has thus far been poorly defined. Through the genome-wide cDNA microarray analysis of pancreatic ductal adenocarcinoma (PDAC) cells as well as subsequent reverse transcription-PCR and Northern blot analyses, we identified the overexpression of GABA receptor pi subunit (GABRP) in PDAC cells. We also found the expression of this peripheral type GABAA receptor subunit in few adult human organs. Knockdown of endogenous GABRP expression in PDAC cells by small interfering RNA attenuated PDAC cell growth, suggesting its essential role in PDAC cell viability. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRP-expressing PDAC cells, but not GABRP-negative cells, and GABAA receptor antagonists inhibited this growth-promoting effect by GABA. The HEK293 cells constitutively expressing exogenous GABRP revealed the growth-promoting effect of GABA treatment. Furthermore, GABA treatment in GABRP-positive cells increased intracellular Ca2+ levels and activated the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) cascade. Clinical PDAC tissues contained a higher level of GABA than normal pancreas tissues due to the up-regulation of glutamate decarboxylase 1 expression, suggesting their autocrine/paracrine growth-promoting effect in PDACs. These findings imply that GABA and GABRP could play important roles in PDAC development and progression, and that this pathway can be a promising molecular target for the development of new therapeutic strategies for PDAC.
- Published
- 2007
- Full Text
- View/download PDF
46. Helper function of memory CD8+ T cells: heterologous CD8+ T cells support the induction of therapeutic cancer immunity.
- Author
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Nakamura Y, Watchmaker P, Urban J, Sheridan B, Giermasz A, Nishimura F, Sasaki K, Cumberland R, Muthuswamy R, Mailliard RB, Larregina AT, Falo LD, Gooding W, Storkus WJ, Okada H, Hendricks RL, and Kalinski P
- Subjects
- Adenocarcinoma therapy, Animals, Cancer Vaccines pharmacology, Colonic Neoplasms therapy, Female, Immunologic Memory immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Cytotoxic immunology, Adenocarcinoma immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines immunology, Colonic Neoplasms immunology, Dendritic Cells immunology, Immunotherapy, Adoptive methods, T-Lymphocytes, Helper-Inducer immunology
- Abstract
In contrast to the well-established efficacy of preventive vaccines, the effectiveness of therapeutic vaccines remains limited. To develop effective vaccination regimens against cancer, we have analyzed the effect of effector and memory CD8+ T cells on the ability of dendritic cells to mediate the immunologic and antitumor effects of vaccination. We show that in contrast to effector CD8+ T cells that kill antigen-carrying dendritic cells, IFNgamma-producing memory CD8+ T cells act as "helper" cells, supporting the ability of dendritic cells to produce interleukin-12 (IL-12) p70. Promoting the interaction of tumor antigen-carrying dendritic cells with memory-type "heterologous" (tumor-irrelevant) CD8+ T cells strongly enhances the IL-12p70-dependent immunogenic and therapeutic effects of vaccination in the animals bearing established tumors. Our data show that the suppressive and helper functions of CD8+ T cells are differentially expressed at different phases of CD8+ T-cell responses. Selective performance of helper functions by memory (in contrast to effector) CD8+ T cells helps to explain the phenomenon of immune memory and facilitates the design of effective therapeutic vaccines against cancer and chronic infections.
- Published
- 2007
- Full Text
- View/download PDF
47. Activation of Holliday junction recognizing protein involved in the chromosomal stability and immortality of cancer cells.
- Author
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Kato T, Sato N, Hayama S, Yamabuki T, Ito T, Miyamoto M, Kondo S, Nakamura Y, and Daigo Y
- Subjects
- Amino Acid Sequence, Ataxia Telangiectasia Mutated Proteins, Base Sequence, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cellular Senescence genetics, DNA Damage, DNA, Ribosomal genetics, DNA, Ribosomal metabolism, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins metabolism, Gene Expression Regulation, Neoplastic, Humans, Immunoprecipitation, Molecular Sequence Data, Neoplasms metabolism, Neoplasms pathology, Protein Serine-Threonine Kinases metabolism, Signal Transduction, Tumor Suppressor Proteins metabolism, Chromosomal Instability genetics, DNA-Binding Proteins genetics, Neoplasms genetics
- Abstract
We identified a novel gene HJURP (Holliday junction-recognizing protein) whose activation seemed to play a pivotal role in the immortality of cancer cells. HJURP was considered a possible downstream target for ataxia telangiectasia mutated signaling, and its expression was increased by DNA double-strand breaks (DSB). HJURP was involved in the homologous recombination pathway in the DSB repair process through interaction with hMSH5 and NBS1, which is a part of the MRN protein complex. HJURP formed nuclear foci in cells at S phase and those subjected to DNA damage. In vitro assays implied that HJURP bound directly to the Holliday junction and rDNA arrays. Treatment of cancer cells with small interfering RNA (siRNA) against HJURP caused abnormal chromosomal fusions and led to genomic instability and senescence. In addition, HJURP overexpression was observed in a majority of lung cancers and was associated with poor prognosis as well. We suggest that HJURP is an indispensable factor for chromosomal stability in immortalized cancer cells and is a potential novel therapeutic target for the development of anticancer drugs.
- Published
- 2007
- Full Text
- View/download PDF
48. Molecular features of hormone-refractory prostate cancer cells by genome-wide gene expression profiles.
- Author
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Tamura K, Furihata M, Tsunoda T, Ashida S, Takata R, Obara W, Yoshioka H, Daigo Y, Nasu Y, Kumon H, Konaka H, Namiki M, Tozawa K, Kohri K, Tanji N, Yokoyama M, Shimazui T, Akaza H, Mizutani Y, Miki T, Fujioka T, Shuin T, Nakamura Y, and Nakagawa H
- Subjects
- Autoantigens biosynthesis, Autoantigens genetics, Cell Growth Processes genetics, Cluster Analysis, Disease Progression, Gene Expression Profiling, Genome, Human, Humans, Male, Microfilament Proteins biosynthesis, Microfilament Proteins genetics, Neoplasms, Hormone-Dependent genetics, Neoplasms, Hormone-Dependent metabolism, Neoplasms, Hormone-Dependent pathology, Oligonucleotide Array Sequence Analysis, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Receptors, Androgen biosynthesis, Receptors, Androgen genetics, Ribonucleoproteins, Small Nuclear biosynthesis, Ribonucleoproteins, Small Nuclear genetics, snRNP Core Proteins, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms genetics
- Abstract
One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgen-independent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference > 1.5; P < 0.0001). We observed overexpression of AR, ANLN, and SNRPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment.
- Published
- 2007
- Full Text
- View/download PDF
49. Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis.
- Author
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Hayama S, Daigo Y, Yamabuki T, Hirata D, Kato T, Miyamoto M, Ito T, Tsuchiya E, Kondo S, and Nakamura Y
- Subjects
- Amino Acid Sequence, Aurora Kinase B, Aurora Kinases, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins genetics, Cell Growth Processes physiology, Cell Line, Tumor, Cell Membrane Permeability, E2F1 Transcription Factor metabolism, Humans, Lung Neoplasms enzymology, Molecular Sequence Data, Peptides pharmacokinetics, Peptides pharmacology, Phosphorylation, Prognosis, Protein Serine-Threonine Kinases antagonists & inhibitors, RNA, Small Interfering genetics, Cell Cycle Proteins metabolism, Lung Neoplasms metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Through genome-wide gene expression analysis of lung carcinomas, we detected in the great majority of lung cancer samples cotransactivation of cell division cycle associated 8 (CDCA8) and aurora kinase B (AURKB), which were considered to be components of the vertebrate chromosomal passenger complex. Immunohistochemical analysis of lung cancer tissue microarrays showed that overexpression of CDCA8 and AURKB was significantly associated with poor prognosis of lung cancer patients. AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells. Suppression of CDCA8 expression with small interfering RNA against CDCA8 significantly suppressed the growth of lung cancer cells. In addition, functional inhibition of interaction between CDCA8 and AURKB by a cell-permeable peptide corresponding to 20-amino acid sequence of a part of CDCA8 (11R-CDCA8(261-280)), which included two phosphorylation sites by AURKB, significantly reduced phosphorylation of CDCA8 and resulted in growth suppression of lung cancer cells. Our data imply that selective suppression of the CDCA8-AURKB pathway could be a promising therapeutic strategy for treatment of lung cancer patients.
- Published
- 2007
- Full Text
- View/download PDF
50. Oncogenic role of MPHOSPH1, a cancer-testis antigen specific to human bladder cancer.
- Author
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Kanehira M, Katagiri T, Shimo A, Takata R, Shuin T, Miki T, Fujioka T, and Nakamura Y
- Subjects
- Animals, COS Cells, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins immunology, Cell Cycle Proteins metabolism, Cell Line, Tumor, Chlorocebus aethiops, Humans, Kinesins, Mice, NIH 3T3 Cells, Oncogenes, Phosphoproteins antagonists & inhibitors, Phosphoproteins immunology, Phosphoproteins metabolism, RNA Interference, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Subcellular Fractions metabolism, Transfection, Up-Regulation, Urinary Bladder Neoplasms immunology, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms therapy, Cell Cycle Proteins genetics, Phosphoproteins genetics, Urinary Bladder Neoplasms genetics
- Abstract
To disclose the molecular mechanism of bladder cancer, the second most common genitourinary tumor, we had previously done genome-wide expression profile analysis of 26 bladder cancers by means of cDNA microarray representing 27,648 genes. Among genes that were significantly up-regulated in the majority of bladder cancers, we here report identification of M-phase phosphoprotein 1 (MPHOSPH1) as a candidate molecule for drug development for bladder cancer. Northern blot analyses using mRNAs of normal human organs and cancer cell lines indicated this molecule to be a novel cancer-testis antigen. Introduction of MPHOSPH1 into NIH3T3 cells significantly enhanced cell growth at in vitro and in vivo conditions. We subsequently found an interaction between MPHOSPH1 and protein regulator of cytokinesis 1 (PRC1), which was also up-regulated in bladder cancer cells. Immunocytochemical analysis revealed colocalization of endogenous MPHOSPH1 and PRC1 proteins in bladder cancer cells. Interestingly, knockdown of either MPHOSPH1 or PRC1 expression with specific small interfering RNAs caused a significant increase of multinuclear cells and subsequent cell death of bladder cancer cells. Our results imply that the MPHOSPH1/PRC1 complex is likely to play a crucial role in bladder carcinogenesis and that inhibition of the MPHOSPH1/PRC1 expression or their interaction should be novel therapeutic targets for bladder cancers.
- Published
- 2007
- Full Text
- View/download PDF
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