研究者詳細 - 田中　一大

論文 - 田中　一大

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Resistance to mutant KRASV12-induced senescence in an hTERT/Cdk4-immortalized normal human bronchial epithelial cell line 査読有り

Muraki N., Yamada M., Doki H., Nakai R., Komeda K., Goto D., Kawabe N., Matsuoka K., Matsushima M., Kawabe T., Tanaka I., Morise M., Shay J.W., Minna J.D., Sato M.

Experimental Cell Research 414 巻 ( 1 ) 2022年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Experimental Cell Research

Mutant KRAS, the most frequently occurring (∼30%) driver oncogene in lung adenocarcinoma, induces normal epithelial cells to undergo senescence. This phenomenon, called “oncogene-induced senescence (OIS)”, prevents mutant KRAS-induced malignant transformation. We have previously reported that mutant KRASV12 induces OIS in a subset of normal human bronchial epithelial cell line immortalized with hTERT and Cdk4. Understanding the mechanism and efficacy of this important cancer prevention mechanism is a key knowledge gap. Therefore, this study investigates mutant KRASV12-induced OIS in upregulated telomerase combined with the p16/RB pathway inactivation in normal bronchial epithelial cells. The normal (non-transformed and non-tumorigenic) human bronchial epithelial cell line HBEC3 (also called “HBEC3KT”), immortalized with hTERT (“T”) and Cdk4 (“K”), was used in this study. HBEC3 that expressed mutant KRASV12 in a doxycycline-regulated manner was established (designated as HBEC3-RIN2). Controlled induction of mutant KRASV12 expression induced partial epithelial-to-mesenchymal transition in HBEC3-RIN2 cells, which was associated with upregulated expression of ZEB1 and SNAIL. Mutant KRASV12 caused the majority of HBEC3-RIN2 to undergo morphological changes; suggestive of senescence, which was associated with enhanced autophagic flux. Upon mutant KRASV12 expression, only a small HBEC3-RIN2 cell subset underwent senescence, as assessed by a senescence-associated β-galactosidase staining (SA-βG) method. Furthermore, mutant KRASV12 enhanced cell growth, evaluated by colorimetric proliferation assay, and liquid and soft agar colony formation assays, partially through increased phosphorylated AKT and ERK expression but did not affect cell division, or cell cycle status. Intriguingly, mutant KRASV12 reduced p53 protein expression but increased p21 protein expression by prolonging its half-life. These results indicate that an hTERT/Cdk4 -immortalized normal bronchial epithelial cell line is partially resistant to mutant KRASV12-induced senescence. This suggests that OIS does not efficiently suppress KRASV12-induced transformation in the context of the simultaneous occurrence of telomerase upregulation and inactivation of the p16/Rb pathway.

DOI： 10.1016/j.yexcr.2022.113053

Scopus

Mutational Activation of the NRF2 Pathway Upregulates Kynureninase Resulting in Tumor Immunosuppression and Poor Outcome in Lung Adenocarcinoma 査読有り

Fahrmann Johannes F., Tanaka Ichidai, Irajizad Ehsan, Mao Xiangying, Dennison Jennifer B., Murage Eunice, Casabar Julian, Mayo Jeffrey, Peng Qian, Celiktas Muge, Vykoukal Jody V., Park Soyoung, Taguchi Ayumu, Delgado Oliver, Tripathi Satyendra C., Katayama Hiroyuki, Soto Luisa Maren Solis, Rodriguez-Canales Jaime, Behrens Carmen, Wistuba Ignacio, Hanash Samir, Ostrin Edwin J.

CANCERS 14 巻 ( 10 ) 2022年5月

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancers

Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 pathway through siRNA-mediated knockdown of KEAP1 or via chemical induction with the NRF2-activator CDDO-Me confirmed that NRF2 is a regulator of KYNU expression in LUAD. Metabolomic analyses confirmed KYNU to be enzymatically functional. Analysis of multiple independent gene expression datasets of LUAD, as well as a LUAD tumor microarray demonstrated that elevated KYNU was associated with immunosuppression, including potent induction of T-regulatory cells, increased levels of PD1 and PD-L1, and resulted in poorer survival. Our findings indicate a novel mechanism of NRF2 tumoral immunosuppression through upregulation of KYNU.

DOI： 10.3390/cancers14102543

Web of Science

Scopus

Amelanotic Malignant Melanoma with a BRAF V600E Mutation Mimicking Primary Lung Cancer. 査読有り

Matsuzawa R, Morise M, Tanaka I, Hayai S, Tamiya Y, Koyama J, Hase T, Wakahara K, Deoksu K, Shimoyama Y, Hashimoto N

Internal medicine (Tokyo, Japan) 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

Amelanotic melanoma is a rare type of melanoma that shows little or no melanin pigmentation. When tumor lesions are not detected in cutaneous sites, the presence of melanin is the hallmark sign of malignant melanoma. We herein report a case of amelanotic melanoma with a BRAF V600E mutation mimicking primary lung cancer that was finally diagnosed on an autopsy. The current case suggests important caveats for the differential diagnosis of patients with BRAF V600E mutation-positive poorly differentiated lung tumors. In terms of the pathological diagnosis, routine immunohistochemical staining may be useful, especially in patients with a poorly differentiated lung tumor without TTF-1 expression.

DOI： 10.2169/internalmedicine.6657-20

PubMed

Is area under the curve the best parameter for carboplatin induced emetic risk stratification? 査読有り

Ozone S., Ichikawa K., Morise M., Matsui A., Kinoshita F., Matsuzawa R., Koyama J., Tanaka I., Hashimoto N.

Nagoya Journal of Medical Science 83 巻 ( 4 ) 頁： 773 - 785 2021年

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Nagoya Journal of Medical Science

Carboplatin (CBDCA)-induced emetic risk is currently classified on the basis of CBDCA-area under the curve (CBDCA-AUC). We investigated the utility of three CBDCA dosage parameters for predicting emesis by CBDCA. Patients with thoracic cancer treated with CBDCA were included. The endpoints were complete response (CR) and total control (TC). CR was defined as no vomiting and no use of rescue medication during the overall assessment period, whereas TC was defined as no vomiting, nausea, nor use of rescue medication during the overall assessment period. The parameters of CBDCA were defined as follows: (1) CBDCA-AUC; (2) CBDCA/body surface area (BSA): the administered dose of CBDCA per body surface area (mg/m2); and (3) total CBDCA/body: the total administered dose of CBDCA (mg). Eighty-five patients were evaluated. The median CBDCA/BSA but not CBDCA-AUC was higher in patients with non-CR compared to those with CR. Receiver operating characteristic curve analysis revealed that the AUC of CBDCA/BSA for predicting non-CR was higher than that of CBDCA-AUC. CBDCA/BSA shows greater potential for predicting CBDCA-induced emetic risk compared with CBDCA-AUC, which is the parameter in current antiemetic guidelines.

DOI： 10.18999/nagjms.83.4.773

Scopus

Primary Prophylaxis Indication for Docetaxel Induced Febrile Neutropenia in Elderly Patients with Non-Small Cell Lung Cancer 査読有り国際誌

Matsui Akira, Morise Masahiro, Tanaka Ichidai, Ozone Sachiko, Matsuzawa Reiko, Koyama Junji, Hase Tetsunari, Hashimoto Naozumi, Sato Mitsuo, Hasegawa Yoshinori

CANCER INVESTIGATION 38 巻 ( 7 ) 頁： 424 - 430 2020年8月

Plasma-Derived Extracellular Vesicles Convey Protein Signatures That Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas 査読有り国際共著国際誌

Fahrmann Johannes F., Mao Xiangying, Irajizad Ehsan, Katayama Hiroyuki, Capello Michela, Tanaka Ichidai, Kato Taketo, Wistuba Ignacio I., Maitra Anirban, Ostrin Edwin J., Hanash Samir M., Vykoukal Jody

CANCERS 12 巻 ( 5 ) 2020年5月

UHRF1, a Regulator of Methylation, as a Diagnostic and Prognostic Marker for Lung Cancer 査読有り

Goto D., Komeda K., Uwatoko N., Nakashima M., Koike M., Kawai K., Kodama Y., Miyazawa A., Tanaka I., Hase T., Morise M., Hasegawa Y., Kawabe T., Sato M.

Cancer Investigation 38 巻 ( 4 ) 頁： 240 - 249 2020年4月

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Investigation

We evaluated the value of UHRF1, a regulator of methylation, as a biomarker for lung cancer. UHRF1 is expressed at higher levels in both lung adenocarcinoma (AD) and squamous cell carcinoma (SQ); however, a meta-analysis showed that UHRF1 expression is correlated with worse survival in patients with AD but not in those with SQ. UHRF1 knockdown suppressed the growth of lung cancer cell lines through G1 cell cycle arrest in some cell lines. These results suggest that UHRF1 may server as a diagnostic marker for AD and SQ and as a prognostic marker for AD in lung cancer.

DOI： 10.1080/07357907.2020.1747483

Scopus

Impact of Combined Evaluation Using Tumor Volume and Metastatic Nodal Extent in Stage III NSCLC Treated with CRT 査読有り国際誌

Tamiya Y., Morise M., Matsuzawa R., Tanaka I., Okada T., Iwano S., Hase T., Hashimoto N., Sato M., Itoh Y., Hasegawa Y.

JOURNAL OF THORACIC ONCOLOGY 14 巻 ( 10 ) 頁： S909 - S910 2019年10月

UHRF1 as a Potential Therapeutic Target for KRAS Mutated Non-Small Cell Lung Cancer 査読有り国際誌

Goto D., Kizuki M., Uwatoko N., Kawai K., Koike M., Nakashima M., Miyazawa A., Tanaka I., Hase T., Morise M., Hasegawa Y., Minna J., Sato M.

JOURNAL OF THORACIC ONCOLOGY 14 巻 ( 10 ) 頁： S692 - S692 2019年10月

Impact of Combined Evaluation Using Tumor Volume and Metastatic Nodal Extent in Stage III NSCLC Treated with CRT 査読有り国際誌

Tamiya Y, Morise M, Matsuzawa R, Tanaka I, Okada T, Iwano S, Hase T, Hashimoto N, Sato M, Itoh Y, Hasegawa Y

JOURNAL OF THORACIC ONCOLOGY 14 巻 ( 10 ) 頁： S909 - S910 2019年10月

CADM1 associates with Hippo pathway core kinases; membranous co-expression of CADM1 and LATS2 in lung tumors predicts good prognosis 査読有り国際誌

Ito Takeshi, Nakamura Atsuko, Tanaka Ichidai, Tsuboi Yumi, Morikawa Teppei, Nakajima Jun, Takai Daiya, Fukayama Masashi, Sekido Yoshitaka, Niki Toshiro, Matsubara Daisuke, Murakami Yoshinori

CANCER SCIENCE 110 巻 ( 7 ) 頁： 2284 - 2295 2019年7月

Mechanobiology of Lung Cancer Cells: Regulation of PD-L1 Expression by Matrix Stiffness

Miyazawa A., Ito S., Asano S., Tanaka I., Sato M., Kondo M., Hasegawa Y.

JOURNAL OF THORACIC ONCOLOGY 13 巻 ( 10 ) 頁： S518-S518 2018年10月

eIF2 beta, A Subunit of Translation-Initiation Factor EIF2, as a Potential Therapeutic Target for Non-Small Cell Lung Cancer

Goto D., Tanaka I., Sato M., Kato T., Miyazawa A., Hase T., Morise M., Sekido Y., Girard L., Minna J., Byers L., Heymach J., Coombes K., Kondo M., Hasegawa Y.

JOURNAL OF THORACIC ONCOLOGY 13 巻 ( 10 ) 頁： S516 - S517 2018年10月

eIF2 beta, a subunit of translation-initiation factor EIF2, is a potential therapeutic target for non-small cell lung cancer 査読有り国際誌

Tanaka Ichidai, Sato Mitsuo, Kato Toshio, Goto Daiki, Kakumu Tomohiko, Miyazawa Ayako, Yogo Naoyuki, Hase Tetsunari, Morise Masahiro, Sekido Yoshitaka, Girard Luc, Minna John D., Byers Lauren A., Heymach John V., Coombes Kevin R., Kondo Masashi, Hasegawa Yoshinori

CANCER SCIENCE 109 巻 ( 6 ) 頁： 1843 - 1852 2018年6月

Regulation of PD-L1 expression by matrix stiffness in lung cancer cells 査読有り国際誌

Miyazawa Ayako, Ito Satoru, Asano Shuichi, Tanaka Ichidai, Sato Mitsuo, Kondo Masashi, Hasegawa Yoshinori

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 495 巻 ( 3 ) 頁： 2344 - 2349 2018年1月

An EGFR-mutated Lung Adenocarcinoma Undergoing Squamous Cell Carcinoma Transformation Exhibited a Durable Response to Afatinib 査読有り国際誌

Sato Mitsuo, Matsui Akira, Shimoyama Yoshie, Omote Norihito, Morise Masahiro, Hase Tetsunari, Tanaka Ichidai, Suzuki Kojiro, Hasegawa Yoshinori

INTERNAL MEDICINE 57 巻 ( 23 ) 頁： 3429 - 3432 2018年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

Squamous cell carcinoma (SCC) transformation has been identified as a mechanism of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib, in EGFR-mutated lung cancer. However, whether second- or third-generation TKIs can overcome resistance due to SCC transformation remains unclear. We herein report an EGFR-mutated lung adenocarcinoma undergoing transformation into SCC that exhibited a durable response to afatinib, which is a second-generation irreversible EGFR-TKI. We suggest that afatinib can be considered as a treatment option for EGFR-mutated tumor undergoing SCC transformation, particularly in the absence of a T790M mutation.

DOI： 10.2169/internalmedicine.0999-18

Web of Science

Scopus

PubMed

A phase II trial of Ifosfamide combination with recommended supportive therapy for recurrent SCLC in second-line and heavily treated setting 査読有り

Ichidai Tanaka Kenji Kawada Masahiro Morise Tetsunari Hase Hiroaki Hayashi Akihiko Sokai Asuki Fukatsu Masashi Kondo Fumio Nomura Yoshinori Hasegawa

Cancer Chemotherapy and Pharmacology 2017年12月

Plasma-derived extracellular vesicle proteins as a source of biomarkers for lung adenocarcinoma 査読有り国際共著国際誌

Vykoukal Jody, Sun Nan, Aguilar-Bonavides Clemente, Katayama Hiroyuki, Tanaka Ichidai, Fahrmann Johannes F., Capello Michela, Fujimoto Junya, Aguilar Mitzi, Wistuba Ignacio I., Taguchi Ayumu, Ostrin Edwin J., Hanash Samir M.

ONCOTARGET 8 巻 ( 56 ) 頁： 95466 - 95480 2017年11月

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer 査読有り国際誌

Dayde Delphine, Tanaka Ichidai, Jain Rekha, Tai Mei Chee, Taguchi Ayumu

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 18 巻 ( 3 ) 2017年3月

【特集】呼吸器科医に役立つ最先端のメカノバイオロジー研究　2）各論：3．肺癌・悪性中皮腫のメカノバイオロジーとYAP/TAZの役割査読有り

田中一大

呼吸臨床 1 巻 ( 2 ) 2017年

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：論文集(書籍)内論文出版者・発行元：COSMIC

生体を構成する細胞は，さまざまな物理的刺激（メカニカルストレス）に応答して，増殖・分化・形態形成を制御する。近年，物理的刺激が感知された後の応答分子として，Hippoシグナル経路およびその標的因子である転写共役因子YAP/TAZが同定された。Hippoシグナル経路・YAP/TAZは，発生過程で臓器サイズを決定する重要な役割を担う一方で，腫瘍の悪性化にも深く関連している。肺癌においては，YAP/TAZが細胞外基質の硬度に応答して細胞増殖に寄与している可能性が高い。それに対し，悪性中皮腫においてはHippoシグナル経路の破綻が基軸となり，YAPの恒常的活性化を引き起こしている。YAP/TAZの活性化は，細胞外基質の再構築にも関与し腫瘍進展を促進している。

DOI： 10.24557/kokyurinsho.1.e00020

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