CD82 attenuates TGF-β1-mediated epithelial-mesenchymal transition by blocking smad-dependent signaling in ARPE-19 cells

Hyesook Lee; Jung-Hwa Han; Yun Jeong Kang; Hyun Hwangbo; Aeseon Yoon; Hyung-Sik Kim; Dongjun Lee; Soo Yong Lee; Byung Hyun Choi; Jae-Joon Kim; Seo Rin Kim; Yung Hyun Choi; Jin Hur

doi:10.3389/fphar.2022.991056

CD82 attenuates TGF-β1-mediated epithelial-mesenchymal transition by blocking smad-dependent signaling in ARPE-19 cells

Front Pharmacol. 2022 Oct 25:13:991056. doi: 10.3389/fphar.2022.991056. eCollection 2022.

Authors

Hyesook Lee¹, Jung-Hwa Han^{1

2}, Yun Jeong Kang¹, Hyun Hwangbo³, Aeseon Yoon¹, Hyung-Sik Kim⁴, Dongjun Lee¹, Soo Yong Lee⁵, Byung Hyun Choi⁶, Jae-Joon Kim⁷, Seo Rin Kim⁸, Yung Hyun Choi^{3

9}, Jin Hur^{1

2}

Affiliations

¹ Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, South Korea.
² PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan, South Korea.
³ Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan, South Korea.
⁴ Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, South Korea.
⁵ Division of Cardiology, Department of Internal Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea.
⁶ Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea.
⁷ Medical Oncology and Hematology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, South Korea.
⁸ Department of Nephrology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea.
⁹ Anti-Aging Research Center and Core-Facility Center for Tissue Regeneration, Dong-eui University, Busan, South Korea.

Abstract

In retinal pigment epithelial (RPE) cells, transforming growth factor-beta (TGF-β) plays a critical role in epithelial-mesenchymal transition (EMT), which contributes to various fibrotic retinal disorders. In the present study, we investigated the effect of recombinant human cluster of differentiation 82 (rhCD82), a tumor metastasis suppressor, on TGF-β-induced EMT in the human RPE cell line APRE-19. The results show that TGF-β1 significantly enhanced cell migration, invasion and the expression of EMT-mediate factors in ARPE-19 cells. However, rhCD82 markedly inhibited cell mobility and the expression of epithelial marker, zonula occludens-1, as well as increased the expression of mesenchymal markers, such as vimentin and α-smooth muscle actin in TGF-β1-treated APRE-19 cells. In addition, TGF-β1 upregulated the phosphorylation of Smad, extracellular signal regulated kinase (ERK) and glycogen synthase kinase-3β (GSK-3β), but only phosphorylation of Smad was suppressed by rhCD82. Noteworthy, rhCD82 greatly suppressed the expression of TGF-β receptor I (TGFRI), TGFRII and integrins in TGF-β1-treated APRE-19 cells. In particular, the result of molecular docking analysis and structural modeling show that rhCD82 partially interacts with the TGF-β1 binding sites of TGFRI, TGFRII, integrin β1 and integrin αv. Taken together, this finding suggested that rhCD82 suppressed TGF-β1-induced EMT of RPE by blocking of Smad-dependent pathway, which is caused by rhCD82 interaction with TGFRs and integrins, suggesting new insight into CD82 as a potential therapeutic strategy in fibrotic retinal disorders.

Keywords: epithelial-mesenchymal transition (EMT); fibrotic retinal disorders; recombinant human cluster of differentiation 82 (rhCD82); retinal pigment epithelial (RPE); transforming growth factor-beta (TGF-β).