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

Haengdueng Jeong, Kyung Min Lim, Kwang H. Kim, Yejin Cho, Buhyun Lee, Byron C. Knowles, Joseph T. Roland, Jeffrey P. Zwerner, James R. Goldenring, Ki Taek Nam

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Abstract

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.

Original languageEnglish
Pages (from-to)227-240
Number of pages14
JournalJournal of Pathology
Volume249
Issue number2
DOIs
Publication statusPublished - 2019 Oct 1

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Integrins
Squamous Cell Carcinoma
Skin
Neoplasms
Heterologous Transplantation
Recycling
Keratinocytes
Knockout Mice
Carcinogens
Carcinogenesis
Cell Proliferation
Cell Line

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

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. / Loss of Rab25 promotes the development of skin squamous cell carcinoma through the dysregulation of integrin trafficking. In: Journal of Pathology. 2019 ; Vol. 249, No. 2. pp. 227-240.
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abstract = "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.",
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Jeong, H, Lim, KM, Kim, KH, Cho, Y, Lee, B, Knowles, BC, Roland, JT, Zwerner, JP, Goldenring, JR & Nam, KT 2019, 'Loss of Rab25 promotes the development of skin squamous cell carcinoma through the dysregulation of integrin trafficking', Journal of Pathology, vol. 249, no. 2, pp. 227-240. https://doi.org/10.1002/path.5311

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

In: Journal of Pathology, Vol. 249, No. 2, 01.10.2019, p. 227-240.

Research output: Contribution to journalArticle

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AU - Lim, Kyung Min

AU - Kim, Kwang H.

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AU - Lee, Buhyun

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AU - Nam, Ki Taek

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AB - 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.

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