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Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis |
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| Authors: | Kosuke Kanazawa Kazuhiro Kishimoto Miyuki Nomura Koreyuki Kurosawa Hiroyuki Kato Yui Inoue Koh Miura Katsuya Fukui Yoji Yamashita Ikuro Sato Hiroyuki Tsuji Toshio Watanabe Takuji Tanaka Jun Yasuda Nobuhiro Tanuma Hiroshi Shima |
| Affiliation: | 1. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan Division of Surgery, Miyagi Cancer Center, Miyagi, Japan Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan;2. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan Department of Head and Neck Surgery, Kanazawa Medical University, Ishikawa, Japan;3. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan;4. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan Department of Plastic and Reconstructive Surgery, Tohoku University School of Medicine, Miyagi, Japan;5. Division of Surgery, Miyagi Cancer Center, Miyagi, Japan;6. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan;7. Division of Pathology, Miyagi Cancer Center, Miyagi, Japan;8. Department of Head and Neck Surgery, Kanazawa Medical University, Ishikawa, Japan;9. Department of Biological Science, Graduate School of Humanities and Sciences Nara Women’s University, Nara, Japan;10. Research Center of Diagnostic Pathology, Gifu Municipal Hospital, Gifu, Japan;11. Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan Cancer Genome Center, Miyagi Cancer Center Research Institute, Miyagi, Japan Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan |
| Abstract: | According to TCGA database, mutations in PPP6C (encoding phosphatase PP6) are found in c. 10% of tumors from melanoma patients, in which they coexist with BRAF and NRAS mutations. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF(V600E) expression and delete Ppp6c in melanocytes. In these mice, melanoma susceptibility following UVB irradiation exhibited the following pattern: Ppp6c semi-deficient (heterozygous) > Ppp6c wild-type > Ppp6c-deficient (homozygous) tumor types. Next-generation sequencing of Ppp6c heterozygous and wild-type melanoma tumors revealed that all harbored Trp53 mutations. However, Ppp6c heterozygous tumors showed a higher Signature 1 (mitotic/mitotic clock) mutation index compared with Ppp6c wild-type tumors, suggesting increased cell division. Analysis of cell lines derived from either Ppp6c heterozygous or wild-type melanoma tissues showed that both formed tumors in nude mice, but Ppp6c heterozygous tumors grew faster compared with those from the wild-type line. Ppp6c knockdown via siRNA in the Ppp6c heterozygous line promoted the accumulation of genomic damage and enhanced apoptosis relative to siRNA controls. We conclude that in the presence of BRAF(V600E) expression and UV-induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis. |
| Keywords: | BRAF haploinsufficiency melanoma protein phosphatase 6 UV-induced carcinogenesis |