LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC

Ruiyan Yuan; Yang Li; Bo Yang; Zhaohui Jin; Jiacheng Xu; Ziyu Shao; Huijie Miao; Tai Ren; Yang Yang; Guoqiang Li; Xiaoling Song; Yunping Hu; Xu'an Wang; Ying Huang; Yingbin Liu

doi:10.1016/j.omtn.2021.01.001

LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC

Mol Ther Nucleic Acids. 2021 Jan 9:23:797-810. doi: 10.1016/j.omtn.2021.01.001. eCollection 2021 Mar 5.

Authors

Ruiyan Yuan¹, Yang Li¹, Bo Yang², Zhaohui Jin¹, Jiacheng Xu³, Ziyu Shao¹, Huijie Miao¹, Tai Ren¹, Yang Yang¹, Guoqiang Li¹, Xiaoling Song¹, Yunping Hu¹, Xu'an Wang⁴, Ying Huang¹, Yingbin Liu⁴

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
² Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Baixiang Road, Wenzhou 325000, China.
³ Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China.
⁴ Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.

Abstract

Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis in vivo and in vitro and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.

Keywords: FBLN5; ICC; Integrin αvβ3; LOXL1; RGD; angiogenesis; intrahepatic cholangiocarcinoma; lysyl oxidase-like 1; tumorigenesis; vascular endothelial cell.