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  • American Association for Cancer Research (AACR)  (6)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1843-1843
    Abstract: INTRODUCTION: Peritoneal dissemination (PD) is highly frequent and incurable metastasis in gastric cancer (GC). The mechanism causing PD is still poorly understood. In this study, we aimed to identify the genes responsible for PD using several large-scale public microarray databases. MATERIALS AND METHODS: First, we identified the candidate genes, which satisfied the all-4 outlines using microarray data as follow: 1) overexpressed in GC cell lines with high potential of PD; 2) overexpressed in GC patients with PD in Singapore from Duke-NUS Graduate Medical School; 3) overexpressed in tumor tissues in GC from TCGA database; 4) poor prognostic factor in GC from TCGA database. Next, we measured the expression of candidate genes by Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and performed clinicopathological studies of the expression in 146 Japanese GC patients who underwent surgery in our hospital. Finally, we performed gene set enrichment analysis (GSEA) with TCGA database to elucidate the correlation between candidate genes and gene sets that are associated with tumorigenesis or tumor progression in GC. Then, we examined the correlation between the candidate genes and one of the gene sets that were identified through GSEA by qRT-PCR in 5 GC cell lines (MKN7, KATO3, AGS, HSC39, 39As). RESULTS: 1. We identified Arl4c (ADP-ribosylation factor-like 4c) as a PD candidate gene by above our screening system. 2. The expression of Arl4c was significantly higher in tumor tissues than in corresponding normal tissues in Japanese GC patients (p & lt;0.0002). In clinicopathological analysis, the high expression group of Arl4c was significantly associated with depth of invasion (p & lt;0.01) and PD (p & lt;0.05). Multivariate analysis indicated that high expression of Arl4c was an independent prognostic factor (hazard ratio 2.20; 95% CI 1.06-4.97; p & lt; 0.03) among all clinicalpathological factors in GC. 3. GSEA revealed that the expression of Arl4c positively correlated with epithelial-mesenchymal transformation (EMT) gene set. In the 5 GC cell lines, the expression of Arl4c negatively correlated with the expression of cdh1, which was well known as a down-regulated gene in EMT. CONCLUSION: Arl4c is a member of the ADP-ribosylation factor family of GTP-binding proteins and plays a role in cholesterol transport. Recent study revealed that Arl4c regulates YAP/TAZ pathway that is well known to induce EMT and promotes tumorigenesis in lung or colorectal cancer. Our results suggest that Arl4c should be involved in PD via EMT induced by the YAP/TAZ pathway, resulting in a poor prognostic marker in GC. Arl4c may be a novel biomarker and a therapeutic target for PD in GC. Citation Format: Qingjiang Hu, Shiya Kidogami, Sho Nambara, Hisateru Komatsu, Kuniaki Sato, Yushi Ogawa, Tomoko Saito, Shotaro Sakimura, Hidenari Hirata, Ryutaro Uchi, Naoki Hayashi, Tomohiro Iguchi, Takaaki Masda, Shuhei Ito, Hidetoshi Eguchi, Yoshihiko Maehara, Koshi Mimori. Identification of peritoneal dissemination-related genes in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1843.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1972-1972
    Abstract: Background Colorectal cancer (CRC) is one of the most prevalent types of cancer. The high mortality rate of CRC is a serious problem. Hence it is urgently necessary to identify novel molecular target to improve the mortality rate. Amplification of chromosome 7p is frequent in CRC, and it has been considered to harbor driver genes that promote tumorigenesis or tumor progression by the gain of function. The aim of this study is to identify novel candidate driver genes on chromosome 7p and to clarify the clinical significance of their expression in CRC. Material and Methods 1. We selected the candidate genes that satisfied the following criteria using CRC data from The Cancer Genome Atlas (TCGA). 1) The DNA copy number and mRNA expression is positively correlated with each other, 2) overexpressed in the tumor tissues compared to the normal tissues. 2. The mRNA expression of the candidate genes was measured in 108 surgically-resected CRC tissues and the paired normal tissues in our hospital by quantitative RT-PCR. The differences of mRNA expression between CRC tissues and normal tissues were analyzed by Mann Whitney U-test. 3. Survival analysis between high and low expression group of the candidate genes was performed by Kaplan-Meier method. Correlation between the mRNA expression of the candidate genes and the clinicopathological factors were analyzed by Fisher’s exact test. 4. We performed Gene Set Enrichment Analysis (GSEA) in CRC data from TCGA to clarify the correlation between the candidate genes and gene sets that are associated with tumorigenesis or tumor progression. Results DEAD Box Helicase56 (DDX56), ATP-dependent RNA helicases involved in several aspects of RNA metabolism including mRNA splicing and transport, transcription, translation and remodeling of ribonucleoprotein complexes, was satisfied with the criteria. The expression of DDX56 was significantly higher in CRC tissues than in normal colon tissues (p & lt;0.005), and it correlated with lymphatic invasion (p=0.02), and distant metastasis (p=0.03). The high DDX56 expression group had a significantly poorer prognosis than the low expression group (p=0.03). On multivariate analysis, high DDX56 expression was an independent prognostic factor affecting OS (p=0.013) with hazard ratios (95% CI) of 2.32 (1.20-4.48) among clinicopathological factors. GSEA showed that DDX56 expression was positively correlated with mitotic cell cycle progression and spliceosome. Conclusions We identified DDX56 as a promising driver gene of CRC on chromosome 7p. DDX56 expression was positively associated with lymphatic invasion and distant metastasis, and was an independent poor prognostic factor. Furthermore, DDX56 may be involved in tumor progression through stimulating cell-cycle. DDX56 could be a therapeutic target as well as a poor prognostic biomarker in CRC. Note: This abstract was not presented at the meeting. Citation Format: Yuta Kouyama, Yushi Ogawa, Takaaki Masuda, Yukihiro Yoshikawa, Miwa Noda, Hiroaki Wakiyama, Kuniaki Sato, Sho Nambara, Qingjiang Hu, Shinya Kidogami, Tomoko Saito, Shotaro Sakimura, Naoki Hayashi, Yohsuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Koshi Mimori. Identification of novel candidate driver genes of colorectal cancer on chromosome 7p [abstract]. In: Proceedings of the American Association for Cancer Research Annual Me eting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1972. doi:10.1158/1538-7445.AM2017-1972
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 410466-3
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 6 ( 2008-03-15), p. 1881-1888
    Abstract: ErbB2-negative breast tumors represent a significant therapeutic hurdle because of a lack of effective molecular targets. Although NOTCH proteins are known to be involved in mammary tumorigenesis, the functional significance of these proteins in ErbB2-negative breast tumors is not clear. In the present study, we examined the expression of activated NOTCH receptors in human breast cancer cell lines, including ErbB2-negative and ErbB2-positive cell lines. Activated NOTCH1 and NOTCH3 proteins generated by γ-secretase were detected in most of the cell lines tested, and both proteins activated CSL-mediated transcription. Down-regulation of NOTCH1 by RNA interference had little or no suppressive effect on the proliferation of either ErbB2-positive or ErbB2-negative cell lines. In contrast, down-regulation of NOTCH3 significantly suppressed proliferation and promoted apoptosis of the ErbB2-negative tumor cell lines. Down-regulation of NOTCH3 did not have a significant effect on the ErbB2-positive tumor cell lines. Down-regulation of CSL also suppressed the proliferation of ErbB2-negative breast tumor cell lines, indicating that the NOTCH-CSL signaling axis is involved in cell proliferation. Finally, NOTCH3 gene amplification was detected in a breast tumor cell line and one breast cancer tissue specimen even though the frequency of NOTCH3 gene amplification was low ( & lt;1%). Taken together, these findings indicate that NOTCH3-mediated signaling rather than NOTCH1-mediated signaling plays an important role in the proliferation of ErbB2-negative breast tumor cells and that targeted suppression of this signaling pathway may be a promising strategy for the treatment of ErbB2-negative breast cancers. [Cancer Res 2008;68(6):1881–8]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 502-502
    Abstract: Distant metastasis is the leading cause of mortality in patients with malignant tumor including colorectal cancer (CRC). A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis by communicating with host cells. However, little is known about the communicating mechanism is known. Understanding this mechanism should uncover a new field of cancer therapy through the targeting of the interaction between tumor and host. In this study, we focused on circulating microRNAs (miRs) as the communication tool between host and tumor cells that were mainly carried by exosomes in circulation. As a result of gene expression microarray and gene set enrichment analysis, we identified miR-203 as a putative signaling molecule between tumors and monocytes in metastatic CRC patients. The level of miR-203 expression was significantly upregulated in a TNM stage-dependent manner. High exosomal miR-203 expression in serum was significantly associated with poor DFS and OS (P & lt; 0.01), and was an independent poor prognostic factor. Additionally, high exosomal miR-203 was associated with distant metastasis (P & lt; 0.01). We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 promoted the expression of M2 markers such as CD163 and STAT3 in vitro. It suggested that serum exosomal miR-203 released from CRC cells promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs) which facilitated premetastatic niche and distant metastasis. Co-injection of miR-203-transfected CRC cells and monocyte increased a ratio of liver metastasis in vivo compared with only control CRC cells or only miR-203-transfected CRC cells injection. On the other hand, overexpression of miR-203 did not increase the proliferation, invasion and migration capacity of CRC cells. This results indicated that serum exosomal miR-203 might create a premetastatic niche whereas did not affect to malignant phenotype of CRC cells. Our study indicated that serum exosomal miR-203 expression could be a novel and feasible biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Citation Format: Dai Shimizu, Takaaki Masuda, Yuki Takano, Hisae Imamura, Rui Yamaguchi, Kuniaki Sato, Taro Tobo, Hidenari Hirata, Yosuke Kuroda, Sho Nambara, Naoki Hayashi, Tomohiro Iguchi, Shuhei Ito, Hidetoshi Eguchi, Takahiro Ochiya, Katsuhiko Yanaga, Satoru Miyano, Koshi Mimori. Circulating exosomal miR-203 is associated with metastasis via inducing tumor-associated macrophages in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 502.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4927-4927
    Abstract: Background Colorectal cancer(CRC) is one of the most common types of cancer worldwide. Its high mortality rate is serious problems. Hence it is urgently necessary to identify novel molecular target to improve it. Gain of chromosome 7 is frequently found in CRC, and it has been considered to harbour driver genes that promote tumorigenesis or tumor progression by the gain of function. The aim of this study is to identify novel candidate driver genes on chromosome 7 and to clarify the clinical significance of their expression in CRC. Material and Methods 1. We have selected the candidate genes which satisfied the following criteria using CRC data from The Cancer Genome Atlas (TCGA), 1) their DNA copy number and the mRNA expression is positively correlated with each other, 2) overexpressed in tumor tissues compared to normal tissues. 2. We measured the mRNA expression of the candidate genes in 125 surgically-resected primary CRC tissues and the paired normal colon tissues in our hospital by quantitative RT-PCR. Difference of mRNA expression between CRC tissues and normal colon tissues was analyzed by Mann Whitney U-test. 3. Survival analysis between high and low expression group of the candidate genes was performed by Kaplan-Meier method. Correlation between the mRNA expression of the candidate genes and clinicopathological factors were analyzed by Fisher's exact test. 4. We performed Gene Set Enrichment Analysis (GSEA) in CRC data from TCGA to elucidate the correlation between the candidate genes and gene sets that are associated with tumorigenesis or tumor progression. Results We focused on phosphoserine phosphatase(PSPH), the rate-limiting enzyme in serine biosynthesis pathway(SSP), as a novel candidate driver gene on chromosome 7 in CRC. PSPH expression was significantly higher in CRC tissues than in normal colon tissues (p & lt;0.005). PSPH expression positively correlated with depth of invasion (p & lt;0.05), venous invasion (p & lt;0.05), and distant metastasis (p & lt;0.05). The high PSPH expression group had a significantly poorer prognosis than the low expression group (p & lt;0.001). On multivariate analysis, high PSPH expression was an independent prognostic factor affecting 5-years OS (p & lt;0.005) with hazard ratios (95% CI) of 4.85(1.77-16.2) among conventional clinicopathological factors. The high PSPH expression group in TCGA data set also had poorer prognosis than the low expression group (p & lt;0.05). GSEA showed that PSPH expression was positively correlated with expression of gene set of c-Myc-downstream. Conclusions We identified PSPH as a promising candidate driver gene on chromosome 7. Moreover, PSPH expression was a prognostic factor in CRC. It has been reported that c-Myc upregulates expression of SSP enzymes including PSPH. Therefore, PSPH is suggested to be involved in tumorigenesis or tumor progression as a downstream molecule of c-Myc in CRC. PSPH should be an important gene on chromosome 7 to promote the progression of CRC. Citation Format: Kuniaki Sato, Qingjiang Hu, Shinya Kidogami, Yushi Ogawa, Tomoko Saito, Sho Nambara, Hisateru Komatsu, Hidenari Hirata, Shotaro Sakimura, Ryutaro Uchi, Naoki Hayashi, Tomohiro Iguchi, Hidetoshi Eguchi, Shuhei Ito, Takaaki Masuda, Takashi Nakagawa, Koshi Mimori. Identification of novel candidate of driver genes on chromosome 7 in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4927.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5439-5439
    Abstract: Background: Colorectal cancer (CRC) is a major cause of cancer-associated death in the world. Despite surgical resection and pre- and postoperative chemotherapy, recurrence is common in patients with CRC. Many studies have examined potential biomarker of recurrence in CRC in attempt to improve patients’ prognosis. MicroRNAs (miRNAs), the small noncoding RNAs that are associated with the development of cancer, in serum have been shown to be potential biomarkers in various type of cancers and several miRNAs have been reported in colorectal cancer. However, no miRNAs has been applied in a clinical setting because of small amount of each samples. In the present study, we evaluated the clinical effectiveness of previously-reported serum miRNAs expression in CRC using periodically gathered serum. Materials and Methods: We obtained 328 serum samples, which gathered periodically (preoperative, postoperative one month, three months, six months, one year, and two years), from 71 patients with stageII/III CRC (stageII: 31 patients, stageIII: 40 patients). Thirteen patients had a recurrence. The miRNAs were extracted from serums, and miRNA microarray analysis was performed. Previously-reported sixteen miRNAs (let-7a, miR-15b, miR-18a, miR-19a, miR-21, miR-23a, miR-29a, miR-31, miR-92a, miR-150, miR-181b, miR-203, miR-223, miR-335, miR-1229 and miR-1246) were quantified by microRNA microarray analysis. Results: In no recurrence cases, preoperative miR-1246 expression is higher than postoperative miR-1246 expression; preoperative; 5.6 ± 1.8, postoperative one month: 4.1 ± 1.6 (p & lt; 0.05), postoperative three months: 3.4 ± 1.9 (p & lt; 0.05) , postoperative six months: 4.8 ± 1.5 (p & lt; 0.05) , postoperative one year: 4.0 ± 1.6 (p & lt; 0.05) , postoperative two years: 4.8 ± 1.5 (p & lt; 0.05). We observed trend of miR-1246 re-elevation before recurrence. The sensitivity and specificity of miR-1246 for detection of CRC are 52.8% and 84.9% (AUC=0.746). This result is almost as same as that of serum CEA which is major tumor marker of CRC (sensitivity: 22-48%, specificity: 63-100%). In our data, the sensitivity of CEA is 38% and the specificity is 94% (cutoff: & gt; 5 ng/ml). The sensitivity and specificity of miR-1246 is higher than of CEA. Conclusion: Serum miR-1246 are best promising biomarker for CRC because of high sensitivity and specificity. On the other hand, previous reported miRNAs excluding miR-1246 are inadequate as biomarker of CRC in our data. Next we are going to identify novel microRNAs which has higher sensitivity and specificity using our microarray analysis. Note: This abstract was not presented at the meeting. Citation Format: Yukihiro Yoshikawa, Mitsuko Fukunaga, Takaaki Masuda, Miwa Noda, Hiroaki Wakiyama, Yuta Koyama, Shinya Kidogami, Kuniaki Sato, Qingjiang Hu, Sho Nambara, Tomoko Saito, Shotaro Sakimura, Naoki Hayashi, Yohsuke Kuroda, Shuhei Ito, Yuichiro Doki, Masaki Mori, Koshi Mimori. The chronological analysis of previously-reported serum microRNA expression in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5439. doi:10.1158/1538-7445.AM2017-5439
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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