Ppp6c deficiency accelerates K‐rasG12D‐induced tongue carcinogenesis
| Autor: | Keiko Terasaki, Yoji Yamashita, Kazuto Matsuura, Nobuhiro Tanuma, Kosuke Kanazawa, Hiroyuki Tsuji, Koh Miura, Katsuya Fukui, Hiroshi Shima, Miyuki Nomura, Keiichi Tamai, Ikuro Sato, Takuji Tanaka, Issay Kitabayashi, Koreyuki Kurosawa, Taeko Shigemoto-Kuroda, Kazuhiro Kishimoto, Hiroyuki Kato, Masaaki Kawai, Yoshimi Sakamoto, Toshio Watanabe, Jun Yasuda |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Chemokine Genotype Trp53 chemokines Biology medicine.disease_cause head and neck squamous cell carcinoma Transcriptome Mice 03 medical and health sciences 0302 clinical medicine K‐ras Phosphoprotein Phosphatases medicine Animals DNA Breaks Double-Stranded Radiology Nuclear Medicine and imaging Gene protein phosphatase 6 RC254-282 Original Research Cancer Biology Wild type Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Molecular biology Head and neck squamous-cell carcinoma Tongue Neoplasms Genes ras 030104 developmental biology Oncology 030220 oncology & carcinogenesis Mutation Carcinoma Squamous Cell biology.protein Tumor necrosis factor alpha Tumor Suppressor Protein p53 Carcinogenesis Carcinoma in Situ Gene Deletion |
| Zdroj: | Cancer Medicine, Vol 10, Iss 13, Pp 4451-4464 (2021) Cancer Medicine |
| ISSN: | 2045-7634 |
| Popis: | Background Effective treatments for cancer harboring mutant RAS are lacking. In Drosophila, it was reported that PP6 suppresses tumorigenicity of mutant RAS. However, the information how PP6 regulates oncogenic RAS in mammals is limited. Methods We examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K‐rasG12D)‐ and KP (K‐rasG12D + Trp53‐deficient)‐inducible mice. Results Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after the induction of Ppp6c deficiency and was euthanized due to 20% loss of body weight. Transcriptome analysis revealed significantly different gene expressions between tissues of Ppp6c‐deficient tongues and those of Ppp6c wild type, while Trp53 deficiency had a relatively smaller effect. We then analyzed genes commonly altered by Ppp6c deficiency, with or without Trp53 deficiency, and identified a group concentrated in KEGG database pathways defined as ‘Pathways in Cancer’ and ‘Cytokine‐cytokine receptor interaction’. We then evaluated signals downstream of oncogenic RAS and those regulated by PP6 substrates and found that in the presence of K‐rasG12D, Ppp6c deletion enhanced the activation of the ERK‐ELK1‐FOS, AKT‐4EBP1, and AKT‐FOXO‐CyclinD1 axes. Ppp6c deletion combined with K‐rasG12D also enhanced DNA double‐strand break (DSB) accumulation and activated NFκB signaling, upregulating IL‐1β, COX2, and TNF. Here, we examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K‐rasG12D)‐ and KP (K‐rasG12D + Trp53‐deficient)‐inducible mice. Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after the induction of Ppp6c deficiency. Ppp6c deletion in the presence of K‐rasG12D enhanced the activation of the ERK‐Elk1‐FOS, AKT‐4EBP1, and AKT‐FOXO‐CyclinD1 axes. Ppp6c deletion combined with K‐rasG12D also activated NFkB signaling, upregulating TNF which leads to an explosion of cytokines. We found that PP6 functions as a tumor suppressor by suppressing the activity of ERK, AKT, and NFkB. |
| Databáze: | OpenAIRE |
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