研究者業績

藤木 亮次

フジキ リョウジ  (Ryoji Fujiki)

基本情報

所属
千葉大学 医学部附属病院がんゲノムセンター 特任助教
学位
博士(2020年3月 東京大学)

研究者番号
40534516
J-GLOBAL ID
202101013027886114
researchmap会員ID
R000016561

論文

 38
  • Takahiro Ochi, Ryoji Fujiki, Masaki Fukuyo, Bahityar Rahmutulla, Takuya Nakagawa, Masayuki Ota, Jun-Ichiro Ikeda, Yukiko Matsui, Ichiro Yoshino, Hidemi Suzuki, Atsushi Kaneda
    Cancer science 2025年4月11日  
    The relationship between cancer prognosis and intratumoral microbiome has recently gained attention. Regarding lung cancer, most studies have focused on bacteria outside tumors, such as sputum or lavage fluid, with few examining intratumoral bacteria and their impact on prognosis. In this study, we extracted DNA from lung tumor samples of 507 patients undergoing surgery at Chiba University Hospital and quantified intratumoral bacterial abundance using bacteria-specific PCR primers. Bacteria were detected in 77.1% of cases, and bacterial abundance was significantly higher in lung adenocarcinoma than in squamous cell carcinoma. Patients were categorized into three groups (High, Low, and Very-Low) based on bacterial abundance, and associations with clinicopathological factors were analyzed. In lung squamous cell carcinoma, higher bacterial abundance was significantly associated with worse recurrent-free survival and overall survival and was found to be a poor prognostic factor independent of pathological tumor stage. In conclusion, intratumoral bacterial abundance was found in the majority of lung cancer tissues, with variations based on pathology. This abundance may serve as a useful marker for stratifying lung squamous cell carcinoma with distinct prognoses.
  • Masahiro Takikawa, Airi Nakano, Jayaraman Krishnaraj, Yuko Tabata, Yuzo Watanabe, Atsushi Okabe, Yukiko Sakaguchi, Ryoji Fujiki, Ami Mochizuki, Tomoko Tajima, Akane Sada, Shu Matsushita, Yuichi Wakabayashi, Kimi Araki, Atsushi Kaneda, Fuyuki Ishikawa, Mahito Sadaie, Rieko Ohki
    Proceedings of the National Academy of Sciences of the United States of America 122(6) e2413126122 2025年2月11日  査読有り
    Tumor progression is suppressed by inherent cellular mechanisms such as apoptosis. The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a pivotal role in tumor suppression. RPRM is a target gene of p53 known to be involved in tumor suppression, but its molecular function has remained elusive. Here, we report that Reprimo (the protein product of RPRM) is secreted and extrinsically induces apoptosis in recipient cells. We identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo acts upstream of the Hippo-YAP/TAZ-p73 axis and induces apoptosis by transactivating various proapoptotic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. These findings identify the p53-Reprimo-Hippo-YAP/TAZ-p73 axis as an extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Our finding of the innate tumor eliminator Reprimo and the downstream pathway offers a promising avenue for the pharmacological treatment of cancer.
  • Koh Iwasaki, Akari Tojo, Haruka Kobayashi, Kai Shimizu, Yoshitaka Kamimura, Yasunori Horikoshi, Atsuhiko Fukuto, Jiying Sun, Manabu Yasui, Masamitsu Honma, Atsushi Okabe, Ryoji Fujiki, Nakako Izumi Nakajima, Atsushi Kaneda, Satoshi Tashiro, Akira Sassa, Kiyoe Ura
    Genes to Cells 29(11) 951-965 2024年9月8日  査読有り
    Abstract Histone modifications are catalyzed and recognized by specific proteins to regulate dynamic DNA metabolism processes. NSD2 is a histone H3 lysine 36 (H3K36)‐specific methyltransferase that is associated with both various transcription regulators and DNA repair factors. Specifically, it has been implicated in the repair of DNA double‐strand breaks (DSBs); however, the role of NSD2 during DSB repair remains enigmatic. Here, we show that NSD2 does not accumulate at DSB sites and that it is not further mobilized by DSB formation. Using three different DSB repair reporter systems, which contained the endonuclease site in the active thymidine kinase gene (TK) locus, we demonstrated separate dose‐dependent effects of NSD2 on homologous recombination (HR), canonical‐non‐homologous end joining (c‐NHEJ), and non‐canonical‐NHEJ (non‐c‐NHEJ). Endogenous NSD2 has a role in repressing non‐c‐NHEJ, without affecting DSB repair efficiency by HR or total NHEJ. Furthermore, overexpression of NSD2 promotes c‐NHEJ repair and suppresses HR repair. Therefore, we propose that NSD2 has functions in chromatin integrity at the active regions during DSB repair.
  • Tianhui Zhu, Atsushi Okabe, Genki Usui, Ryoji Fujiki, Daichi Komiyama, Kie Kyon Huang, Motoaki Seki, Masaki Fukuyo, Hiroyuki Abe, Meng Ning, Tomoka Okada, Mizuki Minami, Makoto Matsumoto, Qin Fan, Bahityar Rahmutulla, Takayuki Hoshii, Patrick Tan, Teppei Morikawa, Tetsuo Ushiku, Atsushi Kaneda
    NAR cancer 6(2) zcae020 2024年6月  
    Enhancer cis-regulatory elements play critical roles in gene regulation at many stages of cell growth. Enhancers in cancer cells also regulate the transcription of oncogenes. In this study, we performed a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin accessibility and expression in two gastric cancer (GC) cell lines compared to normal gastric epithelial cells. We found that GC-specific enhancers marked by histone modifications can activate a population of genes, including some oncogenes, by interacting with their proximal promoters. In addition, motif analysis of enhancer-promoter interacting enhancers showed that GC-specific transcription factors are enriched. Among them, we found that MYB is crucial for GC cell growth and activated by the enhancer with an enhancer-promoter loop and TCF7 upregulation. Clinical GC samples showed epigenetic activation of enhancers at the MYB locus and significant upregulation of TCF7 and MYB, regardless of molecular GC subtype and clinicopathological factors. Single-cell RNA sequencing of gastric mucosa with intestinal metaplasia showed high expression of TCF7 and MYB in intestinal stem cells. When we inactivated the loop-forming enhancer at the MYB locus using CRISPR interference (dCas9-KRAB), GC cell growth was significantly inhibited. In conclusion, we identified MYB as an oncogene activated by a loop-forming enhancer and contributing to GC cell growth.
  • Yukiteru Nakayama, Katsuhito Fujiu, Tsukasa Oshima, Jun Matsuda, Junichi Sugita, Takumi James Matsubara, Yuxiang Liu, Kohsaku Goto, Kunihiro Kani, Ryoko Uchida, Norifumi Takeda, Hiroyuki Morita, Yingda Xiao, Michiko Hayashi, Yujin Maru, Eriko Hasumi, Toshiya Kojima, Soh Ishiguro, Yusuke Kijima, Nozomu Yachie, Satoshi Yamazaki, Ryo Yamamoto, Fujimi Kudo, Mio Nakanishi, Atsushi Iwama, Ryoji Fujiki, Atsushi Kaneda, Osamu Ohara, Ryozo Nagai, Ichiro Manabe, Issei Komuro
    Science immunology 9(95) eade3814 2024年5月24日  
    Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor-β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of "stress memory."

MISC

 18

共同研究・競争的資金等の研究課題

 6