Ppp6c deficiency accelerates K-rasG12D-induced tongue carcinogenesis

Kazuhiro Kishimoto, Kosuke Kanazawa, Miyuki Nomura, Takuji Tanaka, Taeko Shigemoto-Kuroda, Katsuya Fukui, Koh Miura, Koreyuki Kurosawa, Masaaki Kawai, Hiroyuki Kato, Keiko Terasaki, Yoshimi Sakamoto, Yoji Yamashita, Ikuro Sato, Nobuhiro Tanuma, Keiichi Tamai, Issay Kitabayashi, Kazuto Matsuura, Toshio Watanabe, Jun YasudaHiroyuki Tsuji, Hiroshi Shima

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)4451-4464
Number of pages14
JournalCancer medicine
Volume10
Issue number13
DOIs
Publication statusPublished - 2021 Jul

Keywords

  • K-ras
  • Trp53
  • chemokines
  • head and neck squamous cell carcinoma
  • protein phosphatase 6

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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