Faculty Profiles - TOMIDA Shuta

MISC - TOMIDA Shuta

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Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

S. Tomida, K. Yanagisawa, K. Koshikawa, Y. Yatabe, T. Mitsudomi, H. Osada, T. Takahashi

ONCOGENE 26 ( 31 ) 4600 - 4608 2007.7

Language：English Publisher：NATURE PUBLISHING GROUP

Although widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone, NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. By applying the signature to datasets of human cancer cases, we could demonstrate significant associations with a subset of cases with poor prognosis not only for the two datasets of cancers of the lung but also for cancers of the breast. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant downregulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach in the search for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.

DOI： 10.1038/sj.onc.1210242

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Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1

Hisaaki Tanaka, Kiyoshi Yanagisawa, Keiko Shinjo, Ayurnu Taguchi, Ken Maeno, Shuta Tomida, Yukako Shimada, Hirotaka Osada, Takayuki Kosaka, Hideo Matsubara, Tetsuya Mitsudomi, Yoshitaka Sekido, Mitsune Tanimoto, Yasushi Yatabe, Takashi Takahashi

CANCER RESEARCH 67 ( 13 ) 6007 - 6011 2007.7

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.

DOI： 10.1158/0008-5472.CAN-06-4774

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A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer

Kiyoshi Yanagisawa, Shuta Tomida, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Takashi Takahashi

JOURNAL OF THE NATIONAL CANCER INSTITUTE 99 ( 11 ) 858 - 867 2007.6

Language：English Publisher：OXFORD UNIV PRESS INC

Background Among patients with non-small-cell lung cancer (NSCLC), those with poor prognosis cannot be distinguished from those with good prognosis.
Methods Matrix-assisted laser desorption-ionization mass spectrometry was used to analyze protein profiles of 174 specimens from NSCLC tumors and 27 specimens from normal lung tissue and to derive a prognosis-associated proteomic signature. Frozen resected tissue specimens were randomly divided into a training set (116 NSCLC and 20 normal lung specimens) and an independent, blinded validation set (58 NSCLC and seven normal lung specimens). Mass spectrometry signals from training set specimens that were differentially associated with specimens from patients with a high risk of recurrence (i.e., who died within 5 years of surgical treatment because of relapse) compared with those from patients with a low risk of recurrence (i.e., alive with no symptoms of relapse after a median follow-up of 89 months) were selected by use of the Fisher's exact test, the Kruskal-Wallis test, and the significance analysis of microarray test. These signals were used to build an individualized, weighted voting-based prognostic signature. The signature was then validated in the independent dataset. Survival was assessed by multivariable Cox regression analysis. Proteins corresponding to individual signals were identified by ion-trap mass spectrometry coupled with high-performance liquid chromatography. All statistical tests were two-sided.
Results From 2630 mass spectrometry signals from specimens in the training cohort, we derived a signature of 25 signals that was associated with both relapse-free survival and overall survival. Among stage I NSCLC patients in the validation set, the signature was statistically significantly associated with both overall survival (hazard ratio [HR] of death for patients in the high-risk group compared with those in the low-risk group = 61.1, 95% confidence interval [CI] = 8.9 to 419.2, P<.001) and relapse-free survival (HR of relapse = 11.7, 95% CI = 3.1 to 44.8, P<.001). Proteins corresponding to signals in the signature were identified that had various cellular functions, including ribosomal protein L26-like 1, acylphosphatase, and phosphoprotein enriched in astrocytes 15.
Conclusions We defined a mass spectrometry signature that was associated with survival among NSCLC patients and appeared to distinguish those with poor prognosis from those with good prognosis.

DOI： 10.1093/jnci/djk197

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肺癌細胞において過剰発現を示すmiRNAクラスター、miR-17-92の同定と機能解析

林下陽二, 長田啓隆, 立松義郎, 山田英貴, 柳澤聖, 冨田秀太, 谷田部恭, 川原克信, 関戸好孝, 高橋隆

日本癌学会総会記事 65回 157 - 157 2006.9

遺伝子発現プロファイル解析による転移シグネチャーと転移抑制性ホメオボックス遺伝子DLX4の同定

冨田秀太, 柳澤聖, 越川克己, 谷田部恭, 光冨徹哉, 長田啓隆, 高橋隆

日本癌学会総会記事 65回 264 - 264 2006.9

神経内分泌分化誘導因子ASH1によるWntシグナル抑制因子DKK1の発現抑制

長田啓隆, 立松義朗, 竹内俊幸, 冨田秀太, 堀尾芳嗣, 樋田豊明, 谷田部恭, 光冨徹哉, 関戸好孝, 高橋隆

日本癌学会総会記事 65回 64 - 64 2006.9

Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors

T Takeuchi, S Tomida, Y Yatabe, T Kosaka, H Osada, K Yanagisawa, T Mitsudomi, T Takahashi

JOURNAL OF CLINICAL ONCOLOGY 24 ( 11 ) 1679 - 1688 2006.4

Language：English Publisher：AMER SOC CLINICAL ONCOLOGY

Purpose
This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers.
Methods
Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR, and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms.
Results
This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations.
Conclusion
This study has shed light on heterogeneity in lung cancers, especially in adenocarcinomas, by establishing a molecularly, genetically, and clinically relevant, expression profile-defined classification. Future studies using independent patient cohorts are warranted to confirm the prognostic significance of EGFR mutations in TRU-type adenocarcinoma.

DOI： 10.1200/JCO.2005.03.8224

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A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation

Y Hayashita, H Osada, Y Tatematsu, H Yamada, K Yanagisawa, S Tomida, Y Yatabe, K Kawahara, Y Sekido, T Takahashi

CANCER RESEARCH 65 ( 21 ) 9628 - 9632 2005.11

Language：English Publisher：AMER ASSOC CANCER RESEARCH

MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.

DOI： 10.1158/0008-5472.CAN-05-2352

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網羅的遺伝子発現プロファイリングによる肺癌の個性の描出

冨田秀太, 竹内俊幸, 谷田部恭, 柳澤聖, 光冨徹哉, 高橋隆

日本癌学会総会記事 64回 402 - 402 2005.9

肺癌におけるDicerの発現低下と外科切除後生存期間の短縮

苅部陽子, 田中寿明, 長田啓隆, 冨田秀太, 立松義朗, 柳澤聖, 谷田部恭, 高見澤潤一, 三好新一郎, 光冨徹哉, 高橋隆

日本癌学会総会記事 64回 389 - 389 2005.9

Reduced expression of Dicer associated with poor prognosis in lung cancer patients

Y Karube, H Tanaka, H Osada, S Tomida, Y Tatematsu, K Yanagisawa, Y Yatabe, J Takamizawa, S Miyoshi, T Mitsudomi, T Takahashi

CANCER SCIENCE 96 ( 2 ) 111 - 115 2005.2

Language：English Publisher：WILEY-BLACKWELL

Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P = 0.001) appears to be independent of disease stage (P = 0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P = 0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.

DOI： 10.1111/j.1349-7006.2005.00015.x

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Throwing new light on lung cancer pathogenesis: Updates on three recent topics

S Tomida, Y Yatabe, K Yanagisawa, T Mitsudomi, T Takahashi

CANCER SCIENCE 96 ( 2 ) 63 - 68 2005.2

Language：English Publishing type：Book review, literature introduction, etc. Publisher：WILEY-BLACKWELL

Lung cancers have become the leading cause of cancer deaths in Japan, claiming more than 55 000 lives annually. Unfortunately, substantial improvement in terms of cure rates has not been achieved over the last two decades, although during the same period of time in-depth basic knowledge of the molecular mechanisms, which underlies carcinogenesis and progression of this deadly group of neoplasms, has accumulated at an amazing pace. it has consequently become evident that they have many shared but also distinct features, when comparisons are made not only with other common epithelial cancers of adults, such as colon cancer, but also within the various histologic types of lung cancers themselves. This review article provides an up-date on cutting-edge research into the following three different topics, from which important new insights have been obtained. The first concerns genetic instability, especially chromosome instability, and checkpoint failure in lung cancers. Second, we deal with EGFR mutations, which shows revealing specificities in various aspects. Finally, advances in the expression profiling analysis of both transcriptomes and proteomes of lung cancers are summarized.

DOI： 10.1111/j.1349-7006.2005.00021.x

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Artificial neural network approach for selection of susceptible single nucleotide polymorphisms and construction of prediction model on childhood allergic asthma

Y Tomita, S Tomida, Y Hasegawa, Y Suzuki, T Shirakawa, T Kobayashi, H Honda

BMC BIOINFORMATICS 5 ( 120 ) 2004.9

Language：English Publisher：BIOMED CENTRAL LTD

Background: Screening of various gene markers such as single nucleotide polymorphism ( SNP) and correlation between these markers and development of multifactorial disease have previously been studied. Here, we propose a susceptible marker-selectable artificial neural network ( ANN) for predicting development of allergic disease.
Results: To predict development of childhood allergic asthma (CAA) and select susceptible SNPs, we used an ANN with a parameter decreasing method (PDM) to analyze 25 SNPs of 17 genes in 344 Japanese people, and select 10 susceptible SNPs of CAA. The accuracy of the ANN model with 10 SNPs was 97.7% for learning data and 74.4% for evaluation data. Important combinations were determined by effective combination value (ECV) defined in the present paper. Effective 2-SNP or 3-SNP combinations were found to be concentrated among the 10 selected SNPs.
Conclusion: ANN can reliably select SNP combinations that are associated with CAA. Thus, the ANN can be used to characterize development of complex diseases caused by multiple factors. This is the first report of automatic selection of SNPs related to development of multifactorial disease from SNP data of more than 300 patients.

DOI： 10.1186/1471-2105-5-120

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遺伝子発現プロファイル解析に基づく肺がん患者の予後予測モデルの構築

冨田秀太, 越川克己, 谷田部恭, 原野知子, 小倉信彦, 光冨徹哉, 染真人, 柳澤聖, 高橋利忠, 長田啓隆, 高橋隆

日本癌学会総会記事 63回 452 - 453 2004.9

ヒト肺癌におけるマイクロRNA let-7の発現と各種臨床因子との相関の解析

高見澤潤一, 小西裕之, 柳澤聖, 冨田秀太, 長田啓隆, 遠藤秀紀, 原野知子, 谷田部恭, 梛野正人, 二村雄次, 光冨徹哉, 高橋隆

日本癌学会総会記事 63回 404 - 405 2004.9

高転移性ヒト肺癌細胞亜株(LNM35)における,遺伝子・蛋白の発現プロファイル解析による転移関連因子の探求

柳澤聖, 小西裕之, 冨田秀太, 谷田部恭, 光冨徹哉, 長田啓隆, 高橋隆

日本癌学会総会記事 63回 452 - 452 2004.9

Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival

J Takamizawa, H Konishi, K Yanagisawa, S Tomida, H Osada, H Endoh, T Harano, Y Yatabe, M Nagino, Y Nimura, T Mitsudomi, T Takahashi

CANCER RESEARCH 64 ( 11 ) 3753 - 3756 2004.6

Language：English Publisher：AMER ASSOC CANCER RESEARCH

In this study, we report for the first time reduced expression of the let-7 microRNA in human lung cancers. Interestingly, 143 lung cancer cases that had undergone potentially curative resection could be classified into two major groups according to let-7 expression in unsupervised hierarchical analysis, showing significantly shorter survival after potentially curative resection in cases with reduced let-7 expression (P = 0.0003). Multivariate COX regression analysis showed this prognostic impact to be independent of disease stage (hazard ratio = 2.17; P = 0.009). In addition, overexpression of let-7 in A549 lung adenocarcinoma cell line inhibited lung cancer cell growth in vitro. This study represents the first report of reduced expression of let-7 and the potential clinical and biological effects of such a microRNA alteration.

DOI： 10.1158/0008-5472.CAN-04-0637

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Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction

H Endoh, S Tomida, Y Yatabe, H Konishi, H Osada, K Tajima, T Kuwano, T Takahashi, T Mitsudomi

JOURNAL OF CLINICAL ONCOLOGY 22 ( 5 ) 811 - 819 2004.3

Language：English Publisher：AMER SOC CLINICAL ONCOLOGY

Purpose Recently, several expression-profiling experiments have shown that adenocarcinoma can be classified into subgroups that also reflect patient survival. In this study, we examined the expression patterns of 44 genes selected by these studies to test whether their expression patterns were relevant to prognosis in our cohort as well, and to create a prognostic model applicable to clinical practice,
Patients and Methods Expression levels were determined in 85 adenocarcinoma patients by quantitative reverse transcriptase polymerase chain reaction. Cluster analysis was performed, and a prognostic model was created by the proportional hazards model using a stepwise method.
Results Hierarchical clustering divided the cases into three major groups, and group B, comprising 21 cases, had significantly poor survival (P = .0297). Next, we tried to identify a smaller number of genes of particular predictive value, and eight genes (PTK7, CIT, SCNN1A, PGES, ERO1L, ZWINT, and two ESTs) were selected. We then calculated a risk index that was defined as a linear combination of gene expression values weighted by their estimated regression coefficients. The risk index was a significant independent prognostic factor (P = .0021) by multivariate analysis. Furthermore, the robustness of this model was confirmed using an independent set of 21 patients (P = .0085).
Conclusion By analyzing a reasonably small number of genes, patients with adenocarcinoma could be stratified according to their prognosis. The prognostic model could be applicable to future decisions concerning treatment.
(C) 2004 by American Society of Clinical Oncology.

DOI： 10.1200/JCO.2004.04.109

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cDNAマイクロアレイによって選択された44個の遺伝子の発現解析による肺腺癌患者の予後予測モデル

遠藤秀紀, 冨田秀太, 谷田部恭, 小西裕之, 長田啓隆, 田嶋公平, 桑野博行, 高橋隆, 光冨徹哉

日本癌学会総会記事 62回 502 - 502 2003.8

cDNAマイクロアレイによって選択された44個の遺伝子の発現解析による肺腺癌患者の予後予測モデル

遠藤秀紀, 谷田部恭, 冨田秀太, 桑野博行, 高橋隆, 光冨徹哉

日本外科学会雑誌 104 ( 0 ) 258 - 258 2003.4

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