RUNX3, a runt-related transcription factor, plays regulatory roles in cell proliferation, development, cell cycle progression, differentiation, apoptosis, immunity and epithelial-mesenchymal transition [1]. It can integrate signals from pathways like Wnt, TGFβ and Hippo-YAP to influence cell fate decisions [1]. RUNX3 is also significantly associated with tumorigenesis, as its inactivation by epigenetic alterations is frequent in tumors [2].

In mouse models, targeted inactivation of Runx3 in the lung induces adenomas and shortens the latency of adenocarcinoma formation induced by oncogenic K-Ras, indicating its role in protecting cells against oncogenic RAS by participating in the formation of R-point-associated activator complexes [2]. In gastric epithelial stem cell homeostasis, a cancer-derived RUNX3 mutation (R122C) in mice led to an increase in proliferating stem cells, inhibition of differentiation, and a precancerous phenotype [1]. In CD8+ T cells, Runx3-knockout mice experiments showed that Runx3 deficiency reduced CD8+ T infiltration and the differentiation of effector and memory T cells, and Runx3 could be a potential biomarker for immunotherapy [3]. In myeloid malignancies, overexpression of RUNX3 in premalignant stem cells with driver genetic mutations inhibits RUNX1 gene expression and activates key oncogenic pathways like MYC, driving myeloid transformation, while loss of Runx3 in mice did not lead to lethal hematological diseases despite myeloid cell expansion [4].

In summary, RUNX3 is a crucial transcription factor involved in multiple biological processes. Mouse models, especially KO/CKO models, have significantly contributed to understanding its role in cancer-related processes such as tumorigenesis, stem cell homeostasis, and immune-related tumor responses. These models help to clarify the complex functions of RUNX3 in normal and disease conditions, providing a basis for further research and potential therapeutic strategies.

References:

1. Chuang, Linda Shyue Huey, Matsuo, Junichi, Douchi, Daisuke, Bte Mawan, Nur Astiana, Ito, Yoshiaki. 2023. RUNX3 in Stem Cell and Cancer Biology. In Cells, 12, . doi:10.3390/cells12030408. https://pubmed.ncbi.nlm.nih.gov/36766749/

2. Lee, Jung-Won, Lee, You-Soub, Kim, Min-Kyu, Kim, Dohun, Bae, Suk-Chul. 2023. Role of RUNX3 in Restriction Point Regulation. In Cells, 12, . doi:10.3390/cells12050708. https://pubmed.ncbi.nlm.nih.gov/36899846/

3. Liu, Zongzhi, Li, Xiang, Gao, Yibo, Mei, Qian, Sun, Yingli. 2023. Epigenetic reprogramming of Runx3 reinforces CD8 + T-cell function and improves the clinical response to immunotherapy. In Molecular cancer, 22, 84. doi:10.1186/s12943-023-01768-0. https://pubmed.ncbi.nlm.nih.gov/37189103/

4. Yokomizo-Nakano, Takako, Sashida, Goro. 2021. Two faces of RUNX3 in myeloid transformation. In Experimental hematology, 97, 14-20. doi:10.1016/j.exphem.2021.02.005. https://pubmed.ncbi.nlm.nih.gov/33600870/