The Microprotein Encoded by Exosomal LncAKR1C2 Promotes Gastric Cancer Lymph Node Metastasis by Regulating Fatty Acid Metabolism

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2023 Oct 31

PMID 37903800

Authors

Ke-Gan Zhu

Jiayu Yang

Yuehong Zhu

Qihang Zhu

Wen Pan

Siyu Deng

Yi He

Duo Zuo

Peiyun Wang

Yueting Han

Hai-Yang Zhang

Affiliations

Soon will be listed here.

Abstract

Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.

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