Annual Report 2022
Laboratory of Fundamental Oncology
Rieko Ohki, Yu Chen, Walied Kamel, Kiyono Aoki, Yuko Tabata, Airi Nakano, Tatsuki Yamamoto, Moe Nakamura, Tomoka Moro, Ryunosuke Shirai, Ryoui Zenbayashi, Akane Sada, Yumi Shoji, Yukiko Sakaguchi, Estuko Oguro, Kota Uchiyama, Tomoko Tajima, Makoto Miyazaki
Introduction
In the Laboratory of Fundamental Oncology, we are attempting to elucidate the mechanism of tumorigenesis through the identification of novel cancer-related genes.
The most widespread cause of death among Japanese is "cancer", and research aimed at overcoming cancer leads to great social contributions. Research on cancer-associated genes (tumor suppressor genes, oncogenes) has significantly progressed with advances in molecular biology and cancer genomics, and many important genes have been identified. However, even for cancer types that are comparatively well-studied, such as lung cancer and breast cancer, only a few examples can be explained by specific genetic abnormalities. Therefore, we still need to continue to search for novel cancer-associated genes.
The tumor suppressor gene p53 is the most frequently mutated gene in human cancers and plays a central role in the regulation of tumorigenesis. Elucidation of the tumor suppression ability of p53 and application of p53 research to cancer treatment and diagnosis is one of the most important goals to overcome cancer. p53 is a transcription factor that induces apoptosis, cell cycle arrest, DNA repair, etc., by transcriptionally activating p53 target genes. Mutations are detected within the DNA binding domain of p53 with a high frequency in cancer, and it is obvious that the loss of the transcriptional ability of p53 strongly promotes tumorigenesis. Several p53 target genes are directly related to cancer, such as the oncogene Mdm2 and the tumor suppressor gene PTEN, and we aim to identify novel cancer-related genes by identifying novel p53 target genes.
Research Activities
PHLDA3 is a tumor suppressor gene that encodes a repressor of Akt. PHLDA3 functions as a negative regulator of Akt (Cell, 136, 535-550, 2009) and a tumor suppressor gene that undergoes 2-hit inactivation in various neuroendocrine tumors (NETs) (PNAS, 111, E2404-E2413, 2014, and unpublished data). Furthermore, the loss of PHLDA3 function in NETs is mutually exclusive with the loss of p53 function, suggesting that PHLDA3 is a pivotal downstream mediator of p53 in NET suppression. We have also demonstrated that PHLDA3 represses Akt activity in endocrine cells and that PHLDA3-deficient mice develop endocrine tissue abnormalities. Collectively, these results indicate the existence of a novel p53-PHLDA3-mediated pathway of tumor suppression that is important for the development of NETs.
Education
Young researchers and students were trained in the laboratory of Fundamental Oncology.
Future Prospects
The tumor suppressor gene, p53, is recognized by researchers in the field as one of the most important genes in cancer research. While it may appear that p53 has already been well-studied by many researchers, and that many of its functions have already been elucidated, we are pursuing our research with the conviction that many functions remain to be discovered. We also believe that p53 will be an important target in future applications such as cancer treatment and diagnosis. In contrast to receptors and transporters located on the cell surface, p53 is a transcription factor located in the nucleus and has thus been regarded as a difficult drug target. However, inhibitors of nuclear factors have been more successfully developed in recent years, which imparts increasing importance to the modulation of p53 in both basic and applied research. We would also like to identify novel cancer-related genes, especially genes that are regulated by the tumor suppressor gene p53, and elucidate the tumorigenesis mechanism. Through our research, we hope to contribute to the development of novel diagnosis and treatment methods, and respond to the unmet medical needs of patients with cancer.
List of papers published in 2022
Journal
1. Megumi Saito, Akane Sada, Masaki Fukuyo, Kiyono Aoki, Kazuhiro Okumura, Yuko Tabata, Yu Chen, Atsushi Kaneda, Yuichi Wakabayashi and Rieko Ohki. PHLDA3 is an important downstream mediator of p53 in squamous cell carcinogenesis. Journal of Investigative Dermatology, Volume 142, Issue 4, April 2022, Pages 1040-1049.e8.
2. Makoto Miyazaki, Ayaka Nakabo, Yoshiko Nagano, Yuko Nagamura, Kazuyoshi Yanagihara, Rieko Ohki, Yoshikazu Nakamura, KiyokoFukami, JunKawamoto, Kenji Umayahara, Masaru Sakamoto, Keiichi Iwaya, and Hideki Yamaguchi. Tissue factor-induced fibrinogenesis mediates cancer cell clustering and multiclonal peritoneal metastasis. Cancer Letters, Volume 553, 28 January 2023, 215983. https://doi.org/10.1016/j.canlet.2022.215983