Enhancement of Zyxin Promotes Skin Fibrosis by Regulating FAK/PI3K/AKT and TGF-β Signaling Pathways via Integrins

Huang, Yan; Zhao, Han; Zhang, Yuting; Tang, Yulong; Shi, Xiangguang; Jiang, Shuai; Pu, Weilin; Liu, Jing; Ma, Yanyun; Lin, Juiming; Lin, Jinran; Wu, Wenyu; Gong, Yiyi; Wang, Jiucun; Liu, Qingmei

doi:10.7150/ijbs.77649

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Int J Biol Sci 2023; 19(8):2394-2408. doi:10.7150/ijbs.77649 This issue Cite

Research Paper

Enhancement of Zyxin Promotes Skin Fibrosis by Regulating FAK/PI3K/AKT and TGF-β Signaling Pathways via Integrins

Yan Huang^1#, Han Zhao^1,2#, Yuting Zhang¹, Yulong Tang¹, Xiangguang Shi³, Shuai Jiang¹, Weilin Pu¹, Jing Liu^1,4, Yanyun Ma^4,5, Juiming Lin³, Jinran Lin³, Wenyu Wu^3,6, Yiyi Gong^3✉, Jiucun Wang^1,3,7✉, Qingmei Liu^3,5✉

1. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China.
2. Nanjing Intellectual Property Protection Center, Nanjing, China.
3. Division of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology Shanghai, China.
4. Institute for Six-sector Economy, Fudan University, Shanghai, China.
5. Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
6. Department of Dermatology, Jing' an District Central Hospital, Shanghai, China.
7. Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, China.
#These authors contributed equally.

Citation:

Huang Y, Zhao H, Zhang Y, Tang Y, Shi X, Jiang S, Pu W, Liu J, Ma Y, Lin J, Lin J, Wu W, Gong Y, Wang J, Liu Q. Enhancement of Zyxin Promotes Skin Fibrosis by Regulating FAK/PI3K/AKT and TGF-β Signaling Pathways via Integrins. Int J Biol Sci 2023; 19(8):2394-2408. doi:10.7150/ijbs.77649. https://www.ijbs.com/v19p2394.htm

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Abstract

Skin fibrosis is a common pathological manifestation in systemic sclerosis (SSc), keloid, and localized scleroderma (LS) characterized by fibroblast activation and excessive extracellular matrix (ECM) deposition. However, few effective drugs are available to treat skin fibrosis due to its unclear mechanisms. In our study, we reanalyzed skin RNA-sequencing data of Caucasian, African, and Hispanic SSc patients from the Gene Expression Omnibus (GEO) database. We found that the focal adhesion pathway was up-regulated and Zyxin appeared to be the primary focal adhesion protein involved in skin fibrosis, and we further verified its expression in Chinese skin tissues of several fibrotic diseases, including SSc, keloid, and LS. Moreover, we found Zyxin inhibition could significantly alleviate skin fibrosis using Zyxin knock-down and knock-out mice, nude mouse model and skin explants of human keloid. Double immunofluorescence staining showed that Zyxin was highly expressed in fibroblasts. Further analysis revealed pro-fibrotic gene expression and collagen production increased in Zyxin over-expressed fibroblasts, and decreased in Zyxin interfered SSc fibroblasts. In addition, transcriptome and cell culture analyses revealed Zyxin inhibition could effectively attenuate skin fibrosis by regulating the FAK/PI3K/AKT and TGF-β signaling pathways via integrins. These results suggest Zyxin appears a potential new therapeutic target for skin fibrosis.

Keywords: Systemic sclerosis, Skin fibrosis, ECM, Zyxin, Focal adhesion, Integrins

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APA

Huang, Y., Zhao, H., Zhang, Y., Tang, Y., Shi, X., Jiang, S., Pu, W., Liu, J., Ma, Y., Lin, J., Lin, J., Wu, W., Gong, Y., Wang, J., Liu, Q. (2023). Enhancement of Zyxin Promotes Skin Fibrosis by Regulating FAK/PI3K/AKT and TGF-β Signaling Pathways via Integrins. International Journal of Biological Sciences, 19(8), 2394-2408. https://doi.org/10.7150/ijbs.77649.

ACS

Huang, Y.; Zhao, H.; Zhang, Y.; Tang, Y.; Shi, X.; Jiang, S.; Pu, W.; Liu, J.; Ma, Y.; Lin, J.; Lin, J.; Wu, W.; Gong, Y.; Wang, J.; Liu, Q. Enhancement of Zyxin Promotes Skin Fibrosis by Regulating FAK/PI3K/AKT and TGF-β Signaling Pathways via Integrins. Int. J. Biol. Sci. 2023, 19 (8), 2394-2408. DOI: 10.7150/ijbs.77649.

NLM

CSE

Huang Y, Zhao H, Zhang Y, Tang Y, Shi X, Jiang S, Pu W, Liu J, Ma Y, Lin J, Lin J, Wu W, Gong Y, Wang J, Liu Q. 2023. Enhancement of Zyxin Promotes Skin Fibrosis by Regulating FAK/PI3K/AKT and TGF-β Signaling Pathways via Integrins. Int J Biol Sci. 19(8):2394-2408.

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