Loss of Rab25 promotes the development of skin squamous cell carcinoma through the dysregulation of integrin trafficking

• Published in: The Journal of pathology Vol. 249; no. 2; pp. 227 - 240
• Main Authors: Jeong, Haengdueng, Lim, Kyung‐Min, Kim, Kwang H, Cho, Yejin, Lee, Buhyun, Knowles, Byron C, Roland, Joseph T, Zwerner, Jeffrey P, Goldenring, James R, Nam, Ki Taek
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.10.2019; Wiley Subscription Services, Inc
• Subjects: Animals; Carcinogenesis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell differentiation; Cell Line, Tumor; Cell Proliferation; Down-Regulation; epidermis; Gene Expression Regulation, Neoplastic; Humans; integrin; Integrins; Integrins - genetics; Integrins - metabolism; Keratinocytes - metabolism; Keratinocytes - pathology; Mice; Mice, 129 Strain; Mice, Knockout; Protein Transport; Proteins - genetics; Proteins - metabolism; rab GTP-Binding Proteins - deficiency; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Rab25; Signal Transduction; skin; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Squamous cell carcinoma; squamous cell carcinoma (SCC); Tumor Burden; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Xenografts; skin; integrin; squamous cell carcinoma (SCC); Rab25; epidermis
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5311

Rab25 can function as both a tumor suppressor and a tumor promoter across different tissues. This study sought to clarify the role of Rab25 as a tumor suppressor in skin squamous cell carcinoma (SCC). Rab25 loss was closely associated with neoplastic transition in both humans and mice. Rab25 loss was well correlated with increased cell proliferation and poor differentiation in human SCC. While Rab25 knockout (KO) in mice did not induce spontaneous tumor formation, it did significantly accelerate tumor generation and promote malignant transformation in a mouse two‐stage skin carcinogenesis model. Xenografting of a Rab25‐deficient human keratinocyte cell line, HaCaT, also elicited neoplastic transformation. Notably, Rab25 deficiency led to dysregulation of integrins β1, β4, and α6, which matched well with increased epidermal proliferation and impaired desmosome–tight junction formation. Rab25 deficiency induced impairment of integrin recycling, leading to the improper expression of integrins. In line with this, significant attenuation of integrin β1, β4, and α6 expression was identified in human SCCs where Rab25 was deficient. Collectively, these results suggest that loss of Rab25 promotes the development and neoplastic transition of SCC through dysregulation of integrin trafficking. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.