Pak1 maintains epidermal stem cells by regulating Langerhans cells and is required for skin carcinogenesis

• Published in: Oncogene 2020-06, Vol.39 (24), p.4756-4769
• Main Authors: Okumura, Kazuhiro, Saito, Megumi, Yoshizawa, Yasuhiro, Ito, Yuki, Isogai, Eriko, Araki, Kimi, Wakabayashi, Yuichi
• Format: Article
• Language: English
• Subjects: 13/31; 13/44; 13/51; 13/89; 42; 42/41; 631/67/1813/1352; 631/67/327; 631/67/395; 64; 64/60; Animals; Apoptosis; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Biology; Cell number; Cell proliferation; Development and progression; Epidermis - metabolism; Epidermis - pathology; Health aspects; Helper cells; Human Genetics; Immunohistochemistry; Immunological diseases; Internal Medicine; Langerhans cells; Langerhans Cells - metabolism; Langerhans Cells - pathology; Lymphocytes T; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Microenvironments; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncology; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Rodents; Serine; Skin; Skin cancer; Skin diseases; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Stem Cells - pathology; Therapeutic applications; Therapeutic targets; Threonine; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1323-3

Pak1 (serine/threonine p21-activated kinases) was previously reported to have oncogenic activity in several cancers. However, its roles in the cancer microenvironment are poorly understood. We demonstrated that Pak1 expression in Langerhans cells (LCs) is essential for the maintenance of epidermal stem cells and skin tumor development. We found that PAK1 is localized in LCs by immunohistochemistry. Furthermore, the number of LCs significantly decreased in MSM/Ms Pak1 homozygous knockout mice (MSM/Ms- Pak1 -/- ). F 1 hybrid (FVB/N×MSM/Ms) Pak1 heterozygous knockout mice (F 1 - Pak1 +/- ) had increased numbers of Th17 cells in the skin. Therefore, Pak1 knockdown cells were prepared using LC-derived XS52 cells (XS52- Pak1 KD) and co-cultured with keratinocyte-derived C5N cells. As a result, XS52- Pak1 KD cell supernatants promoted C5N cell proliferation. We then carried out DMBA/TPA skin carcinogenesis experiments using F 1 - Pak1 +/- mice. Of note, F 1 - Pak1 +/- mice exhibited stronger resistance to skin tumors than control mice. F 1 - Pak1 +/- mice had fewer epidermal stem cells in the skin bulge. Our study suggested that Pak1 regulates the epidermal stem cell number by changing the properties of LCs and functions in skin carcinogenesis. We clarified a novel role of Pak1 in regulating LCs as a potential therapeutic target in skin immune disease and carcinogenesis.