Annual Report 2018
Laboratory of Fundamental Oncology
Rieko Ohki, Masahiro Takikawa, Kiyono Aoki, Yu Chen, Kohei Tominaga, Akane Sada, Ayumi Suzuki, Yumi Shoji, Yukiko Sakaguchi, Usa Sano, Naoko Tsurusawa, Sho Furukawa, Kenta Amano, Mitsuhiro Tomosugi
Introduction
In the Laboratory of Fundamental Oncology, we are trying 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 largely progressed with the advance of 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, there are only a few examples that 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 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, which 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 clear that the loss of the transcriptional ability of p53 strongly promotes tumorigenesis. Several p53 target genes are directly related to cancer, such as oncogene Mdm2 and tumor suppressor gene PTEN, and we aim to identify novel cancerrelated genes by identifying novel p53 target genes.
The most important function of p53 is the transcriptional regulation of p53 target genes. We have performed an exhaustive screening of p53-inducible genes and reported the molecular function of several novel p53 target genes, including Noxa, Reprimo, AEN, FUCA1, IER5 and PHLDA3. These genes are involved in fundamental tumor suppression pathways, including apoptosis, growth suppression and stress response.
Research activities
PHLDA3 is a tumor suppressor gene encoding 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, loss of PHLDA3 function in NETs is mutually exclusive with loss of p53 function, suggesting that PHLDA3 is a pivotal downstream mediator of p53 in NET suppression. We also demonstrate that PHLDA3 represses Akt activity in endocrine cells and that PHLDA3-deficient mice develop abnormalities in endocrine tissues. 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
We would like to elucidate the mechanism of tumorigenesis through the identification of novel cancer-related genes, especially genes that are regulated by tumor suppressor gene p53. Through our research, we hope that we can contribute to the development of novel diagnosis and treatment methods, and respond to the unmet medical needs of cancer patients.
List of papers published in 2018
Journal
1. Ohtsuka J, Oshima H, Ezawa I, Abe R, Oshima M, Ohki R. Functional loss of p53 cooperates with the in vivo microenvironment to promote malignant progression of gastric cancers. Sci Rep, 8:2291, 2018
2. Chen Y, Takikawa M, Tsutsumi S, Yamaguchi Y, Okabe A, Shimada M, Kawase T, Sada A, Ezawa I, Takano Y, Nagata K, Suzuki Y, Semba K, Aburatani H, Ohki R. PHLDA1, another PHLDA family protein that inhibits Akt. Cancer Sci, 109:3532-3542, 2018
3. Kojima M, Chen Y, Ikeda K, Tsukada Y, Takahashi D, Kawano S, Amemiya K, Ito M, Ohki R, Ochiai A. Recommendation of longterm and systemic management according to the risk factors in rectal NETs patients. Sci Rep, 9:2404, 2019
4. Magi S, Iwamoto K, Yumoto N, Hiroshima M, Nagashima T, Ohki R, Garcia-Munoz A, Volinsky N, Von Kriegsheim A, Sako Y, Takahashi K, Kimura S, Kholodenko BN, Okada-Hatakeyama M. Transcriptionally inducible Pleckstrin homology-like domain, family A, member 1, attenuates ErbB receptor activity by inhibiting receptor oligomerization. J Biol Chem, 293:2206-2218, 2018
5. Wang X, Li G, Koul S, Ohki R, Maurer M, Borczuk A, Halmos B. PHLDA2 is a key oncogene-induced negative feedback inhibitor of EGFR/ErbB2 signaling via interference with AKT signaling. Oncotarget, 9:24914-24926, 2018