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.
Bibliographical noteFunding Information:
This research was supported by the Korea Mouse Phenotyping Project (NRF-2016M3A9D5A01952416) of a National Research Foundation grant funded by the Korean government (MSIP), the Brain Korea 21 PLUS Project for Medical Science at Yonsei University (to KTN). KML was supported by grants from NRF (2018R1A5A2025286 and 2018R1D1A1B07042919). JRG was supported by grants from the NIH (RO1 DK48370 and R21 CA187307). Production of the skin cancer tissue microarray was supported in part by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH and was constructed in the Translational Pathology Shared Resource using a Grandmaster robotic arrayer acquired through NIH S10 OD016355. This work was supported by core resources of the Vanderbilt Digestive Disease Center (P30 DK058404), the Vanderbilt-Ingram Cancer Center (P30 CA68485), and imaging in the Vanderbilt Digital Histology Shared Resource supported by a VA Shared Instrumentation grant (1IS1BX003097). We would like to thank Dong-su Jang, MFA (medical illustrator), for his help with the illustrations.
© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine