RRC ID 64226
著者 Tsuji T, Maeda Y, Kita K, Murakami K, Saya H, Takemura H, Inaki N, Oshima M, Oshima H.
タイトル FOXO3 is a latent tumor suppressor for FOXO3-positive and cytoplasmic-type gastric cancer cells.
ジャーナル Oncogene
Abstract FOXO3 is a member of the FOXO transcription factors thought to play a tumor-suppressor role in gastrointestinal cancer, while tumor-promoting function of FOXO3 has also been reported. These results suggest a context-dependent function of FOXO3 in tumor development. However, the relationship between the FOXO3 expression pattern and its role in tumorigenesis has not been elucidated. We examined the FOXO3 expression in 65 human primary gastric cancer and patient-derived xenograft tissues by immunohistochemistry and identified three subtypes according to subcellular localization: FOXO3-nuclear accumulated (FOXO3-Nuc), FOXO3-nuclear/cytoplasmic or cytoplasmic distributed (FOXO3-Cyt), and FOXO3-negative. In the FOXO3-Cyt gastric cancer cells, the expression of the constitutive active mutant FOXO3 (Act-ER FOXO3) induced the nuclear accumulation of FOXO3 and significantly suppressed colony formation and proliferation. The inhibition of the PI3K-AKT pathway by inhibitor treatment also suppressed the proliferation of FOXO3-Cyt gastric cancer cells, which was associated with the nuclear accumulation of endogenous FOXO3. Furthermore, the expression of Act-ER FOXO3 by an endogenous promoter significantly suppressed gastric tumorigenesis in Gan mice, a model of gastric cancer. Finally, treatment of FOXO3-Cyt human gastric cancer-derived organoids with an AKT inhibitor significantly suppressed the survival and proliferation. These results indicate that FOXO3 is a latent tumor suppressor for FOXO3-Cyt-type gastric cancer cells and that activation of the PI3K-AKT pathway protects this type of gastric cancer cell from FOXO3-mediated growth suppression via constitutive nuclear export. Thus, the inhibition of the PI3K-AKT pathway and nuclear translocation of endogenous FOXO3 may have therapeutic applications in the treatment of FOXO3-positive and cytoplasmic-type gastric cancer.
巻・号 40(17)
ページ 3072-3086
公開日 2021-4-1
DOI 10.1038/s41388-021-01757-x
PII 10.1038/s41388-021-01757-x
PMID 33795838
PMC PMC8084732
MeSH Animals Cell Transformation, Neoplastic Forkhead Box Protein O3 Genes, Tumor Suppressor Mice Phosphatidylinositol 3-Kinases* Proto-Oncogene Proteins c-akt Stomach Neoplasms*
IF 7.971
リソース情報
ヒト・動物細胞 MKN74(RCB1002) Kato III(RCB2088) SH-10-TC(RCB1940)