Inhibition of FNDC1 suppresses gastric cancer progression by interfering with Gβγ-VEGFR2 complex formation

Yao Lu; Panpan Huang; Xueliang Zeng; Wenyu Liu; Rui Zhao; Jing Li; Gaolu Cao; Yaqiong Hu; Qiuxiang Xiao; Meng Wu; Weicai Huang; Xuerui Tang; Xiaojian Liu; Hulai Wei

doi:10.1016/j.isci.2023.107534

Inhibition of FNDC1 suppresses gastric cancer progression by interfering with Gβγ-VEGFR2 complex formation

iScience. 2023 Aug 12;26(9):107534. doi: 10.1016/j.isci.2023.107534. eCollection 2023 Sep 15.

Authors

Yao Lu^{1

2}, Panpan Huang², Xueliang Zeng^{1

3}, Wenyu Liu², Rui Zhao², Jing Li², Gaolu Cao², Yaqiong Hu², Qiuxiang Xiao⁴, Meng Wu⁴, Weicai Huang², Xuerui Tang², Xiaojian Liu⁵, Hulai Wei¹

Affiliations

¹ Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China.
² School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
³ Department of Pharmacy, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
⁴ Department of Pathology, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
⁵ Department of Surgery, Tongxiang First People's Hospital, Jiaxing, Zhejiang 314500, China.

Abstract

Gastric cancer (GC) is a prevalent digestive tract malignant tumor characterized by an insidious onset, ease of metastasis, rapid growth, and poor prognosis. Here, we report that fibronectin type III domain containing 1 (FNDC1) has high expression in GC and indicates poor outcomes in patients with GC. FNDC1 over-expression or knockdown promotes or inhibits tumorigenesis and metastasis, respectively. The expression of FNDC1 is upregulated by TWIST1, strengthening its interaction with Gβγ and VEGFR2. The formation of the trimers, TWIST1 plus Gβγ and VEGFR2, increases VEGFR2 phosphorylation and Gβγ trafficking, which activates RAS-MAPK and PI3K-AKT signaling, benefiting GC progression. In this study, we demonstrated that arsenite can efficiently suppress FNDC1 expression, attenuating the formation of the trimers and downstream pathways. Altogether, our results indicate that FNDC1 might be a promising target for clinical treatment and prognostic judgment, while FNDC1 inhibition by arsenite provides a new opportunity for overcoming this fatal disease.

Keywords: Cancer; Drugs; Molecular biology.