Annual Report 2024
Laboratory of Fundamental Oncology
Rieko Ohki, Yu Chen, Yuko Tabata, Walied abdelghany Kamel, Krishnaraj Jayaraman, Airi Nakano, Tatsuki Yamamoto, Tong Lu, Yao Huang, Naoya Kobayashi, Chihiro Hoshino, Zisheng Zhang, Yuri Mitsui, Rina Takahashi, Musashi Kagaya, Ami Mochizuki, Chizuru Ueda, Eren Tsuda, Masateru Okudaira, Yumi Shoji, Yukiko Sakaguchi, Estuko Oguro, Tomoko Tajima
Introduction
The Laboratory of Fundamental Oncology is dedicated to elucidating the essence of cancer through the identification and functional analysis of novel cancer-related genes.
Cancer remains the leading cause of death among the Japanese population, and research aimed at overcoming it represents a crucial mission of high social importance. Advances in molecular biology and genome analysis have greatly accelerated studies on tumor suppressor genes and oncogenes, leading to the identification of numerous key genes. However, even in well-studied cancer types such as lung and breast cancers, the currently known genetic alterations can only partially explain tumor initiation and progression, leaving many unresolved questions. This underscores the continued necessity of steady and fundamental biological investigation in cancer research.
Among cancer-related genes, the tumor suppressor gene p53 is the most frequently mutated gene in human cancers and plays a central role in tumor suppression. Deepening our understanding of p53 function and translating this knowledge into clinical applications for cancer diagnosis and therapy remain among the most critical goals in cancer research. p53 functions as a transcription factor that induces the expression of its target genes, thereby preventing tumorigenesis through the regulation of apoptosis, cell-cycle arrest, and DNA repair. In many cancers, mutations occur within the DNA-binding domain of p53, resulting in the loss of its transcriptional activity—a major event in oncogenic transformation.
Many p53 target genes, such as the oncogene Mdm2 and the tumor suppressor PTEN, are directly involved in tumorigenesis. Our laboratory seeks to identify novel p53 target genes and elucidate their biological functions, thereby uncovering new mechanisms of cancer regulation and potential therapeutic targets.
Research Activities
The main focus of our research is to elucidate the function of p53, one of the most crucial cancer-related genes in human malignancies. In particular, we have uncovered the previously unknown function of the p53 target gene Reprimo and reported our findings (Proc. Natl. Acad. Sci. U.S.A., 2025).
Discovery of a Novel Cell-Death Pathway Mediated by the Reprimo Protein
Through functional analysis of the RPRM gene product Reprimo, which is transcriptionally regulated by p53, we discovered a novel mechanism by which Reprimo is secreted into the extracellular space, binds to protocadherin receptors on the surface of cancer cells, and induces apoptosis via activation of the Hippo signaling pathway (Figure 1).
Figure 1. A novel extrinsic apoptosis pathway Regulated via the p53-Reprimo-Hippo-YAP/TAZ axis
This finding revealed that Reprimo acts as a unique molecule that switches YAP activity from a tumor-promoting to a cell-death–inducing function. Since YAP plays a pivotal role in tumorigenesis and therapeutic resistance in many solid tumors, our study highlights the potential of Reprimo-based strategies as a novel anticancer therapy. The results of this study were widely publicized through an institutional press release.
Education
We provided comprehensive supervision and research guidance to two research fellows, one international research fellow supported by the Asia Regional Joint Research Program, and one foreign research fellow supported by the Takeda Science Foundation. In addition, we supervised two graduate students from Tokyo University of Science, one from Chiba University, two from Kanazawa University, one from Nagasaki University, one from Gunma University, two undergraduate students from Kitasato University, three from Hoshi University, two students from the Tokyo College of Biotechnology, and four research assistants, supporting their independent research activities and overall scientific development.
Future Prospects
The tumor suppressor gene p53 is widely recognized as one of the most critical genes in cancer research. Although numerous researchers worldwide have conducted extensive studies, many of its functions remain unresolved. We aim to further elucidate the multifaceted roles of p53 to gain a comprehensive understanding of the molecular mechanisms underlying tumor suppression.
Because p53 functions as a transcription factor localized in the nucleus, it has long been considered a challenging target for drug development. However, recent progress in the development of inhibitors and molecular modulators that act on nuclear factors has greatly enhanced the translational potential of p53 research. Moving forward, we intend to bridge these fundamental discoveries to clinical applications to establish novel strategies for cancer therapy and diagnosis. In parallel, we will continue to foster the next generation of scientists and contribute to the sustainable advancement of cancer research.
List of papers published in 2024
Journal
1. Mitsui E, Kikuchi S, Okura T, Tazawa H, Une Y, Nishiwaki N, Kuroda S, Noma K, Kagawa S, Ohara T, Ohtsuka J, Ohki R, Fujiwara T. Novel treatment strategy targeting interleukin-6 induced by cancer associated fibroblasts for peritoneal metastasis of gastric cancer. Scientific reports, 15:3267, 2025
2. Takikawa M, Nakano A, Krishnaraj J, Tabata Y, Watanabe Y, Okabe A, Sakaguchi Y, Fujiki R, Mochizuki A, Tajima T, Sada A, Matsushita S, Wakabayashi Y, Araki K, Kaneda A, Ishikawa F, Sadaie M, Ohki R. Extrinsic induction of apoptosis and tumor suppression via the p53-Reprimo-Hippo-YAP/TAZ-p73 pathway. Proceedings of the National Academy of Sciences of the United States of America, 122:e2413126122, 2025
3. Krishnaraj J, Ueno S, Nakamura M, Tabata Y, Yamamoto T, Asano Y, Tanaka T, Kuzuyama T, Saya H, Ohki R. IER5 Promotes Ovarian Cancer Cell Proliferation and Peritoneal Dissemination. Cancers, 17:610, 2025
4. Kamel WA, Krishnaraj J, Ohki R. The Role of PHLDA3 in Cancer Progression and Its Potential as a Therapeutic Target. Cancers, 17:1069, 2025
5. Ohki R, Itahana K, Iwakuma T. "The 10th International MDM2 Workshop": Opening up new avenues for MDM2 and p53 research, the First International MDM2 Workshop in Asia. Genes to cells : devoted to molecular & cellular mechanisms, 29:451-455, 2024
6. Tabuchi M, Kikuchi S, Tazawa H, Okura T, Ogawa T, Mitsui E, Une Y, Kuroda S, Sato H, Noma K, Kagawa S, Ohara T, Ohtsuka J, Ohki R, Urata Y, Fujiwara T. Functional remodeling of intraperitoneal macrophages by oncolytic adenovirus restores anti-tumor immunity for peritoneal metastasis of gastric cancer. Molecular therapy. Oncology, 32:200806, 2024
7. Hu D, Kobayashi N, Ohki R. FUCA1: An Underexplored p53 Target Gene Linking Glycosylation and Cancer Progression. Cancers, 16:2753, 2024