Autocrine Pro-legumain Promotes Breast Cancer Metastasis Via Binding to Integrin αvβ3

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2022 Jul 19

PMID 35854065

Authors

Cui Liu

Junlei Wang

Yajuan Zheng

Yue Zhu

ZhengHang Zhou

Zhaoyuan Liu

Changdong Lin

YaoYing Wan

Yating Wen

Chunye Liu

Mengya Yuan

Yi Arial Zeng

Zhanjun Yan

Gaoxiang Ge

Jianfeng Chen

Affiliations

Soon will be listed here.

Abstract

Tumor metastasis is the leading cause of cancer-associated mortality. Unfortunately, the underlying mechanism of metastasis is poorly understood. Expression of legumain (LGMN), an endo-lysosomal cysteine protease, positively correlates with breast cancer metastatic progression and poor prognosis. Here, we report that LGMN is secreted in the zymogen form by motile breast cancer cells. Through binding to cell surface integrin αvβ3 via an RGD motif, the autocrine pro-LGMN activates FAK-Src-RhoA signaling in cancer cells and promotes cancer cell migration and invasion independent of LGMN protease activity. Either silencing LGMN expression or mutationally abolishing pro-LGMN‒αvβ3 interaction significantly inhibits cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Finally, we developed a monoclonal antibody against LGMN RGD motif, which blocks pro-LGMN‒αvβ3 binding, and effectively suppresses cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Thus, disruption of pro-LGMN‒integrin αvβ3 interaction may be a potentially promising strategy for treating breast cancer metastasis.

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