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

Oncogene volume 39, pages 4756–4769 (2020)Cite this article

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Abstract

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-/-). F1 hybrid (FVB/N×MSM/Ms) Pak1 heterozygous knockout mice (F1-Pak1+/-) had increased numbers of Th17 cells in the skin. Therefore, Pak1 knockdown cells were prepared using LC-derived XS52 cells (XS52-Pak1KD) and co-cultured with keratinocyte-derived C5N cells. As a result, XS52-Pak1KD cell supernatants promoted C5N cell proliferation. We then carried out DMBA/TPA skin carcinogenesis experiments using F1-Pak1+/- mice. Of note, F1-Pak1+/- mice exhibited stronger resistance to skin tumors than control mice. F1-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.

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Fig. 1: Pak1-deficient mice exhibited a chronic skin inflammatory phenotype.
Fig. 2: Immunofluorescence microscopic analysis of PAK1 distribution in the skin.
Fig. 3: Activation of the Th17 axis in the skin of F1-Pak1+/- mice.
Fig. 4: Genetic inhibition of Pak1 in LCs resulted in an abnormal mRNA expression pattern.
Fig. 5: Pak1 increases XS52 cell motility and regulates secretomes to keratinocytes in XS52 cells.
Fig. 6: Genetic inhibition of Pak1 prevents chemically induced skin tumors.
Fig. 7: A schematic drawing of resistance to DMBA/TPA skin carcinogenesis via LCs in Pak1-deficient mice.

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Acknowledgements

The authors thank Dr. Naoki Okada of Osaka university and Dr. Akira Takashima for providing XS52 and NS47 cells, and Dr. Allan Balmain of University of California, San Francisco for providing C5N cells. The authors also thank Mrs. Sakura Katori and Mrs. Akemi Hongu for their technical assistance. This study was supported by JSPS KAKENHI grant number JP19K07494. This work was supported by JSPS KAKENHI Grant Number JP15K06817 (AdAMS).

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  1. Department of Carcinogenesis Research, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, 666-2 Nitonacho Chuo-ku, Chiba, 260-8717, Japan

    Kazuhiro Okumura, Megumi Saito, Yasuhiro Yoshizawa, Yuki Ito, Eriko Isogai & Yuichi Wakabayashi

  2. Division of Developmental Genetics, Institute of Resource Development and Analysis, 2-2-1 Honjo Chuo-ku, Kumamoto, 860-0811, Japan

    Kimi Araki

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Okumura, K., Saito, M., Yoshizawa, Y. et al. Pak1 maintains epidermal stem cells by regulating Langerhans cells and is required for skin carcinogenesis. Oncogene 39, 4756–4769 (2020). https://doi.org/10.1038/s41388-020-1323-3

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