Open AccessHypoxic bone marrow mesenchymal cell‐extracellular vesicles containing miR‐328‐3p promote lung cancer progression via the NF2‐mediated Hippo axis
Author(s) -
Liu Xi,
Jiang Feng,
Wang Zhilinag,
Tang Lang,
Zou Bin,
Xu Pengfei,
Yu Tenghua
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15865
Subject(s) - cancer research , lung cancer , mesenchymal stem cell , bone marrow , microrna , cancer , extracellular vesicle , ectopic expression , epithelial–mesenchymal transition , hippo signaling pathway , cancer cell , biology , pathology , medicine , immunology , microvesicles , microbiology and biotechnology , cell culture , signal transduction , metastasis , biochemistry , gene , genetics
Lung cancer is the most aggressive tumour afflicting patients on a global scale. Extracellular vesicle (EV)‐delivered microRNAs (miRs) have been reported to play critical roles in cancer development. The current study aimed to investigate the role of hypoxic bone marrow mesenchymal cell (BMSC)‐derived EVs containing miR‐328‐3p in lung cancer. miR‐328‐3p expression was determined in a set of lung cancer tissues by RT‐qPCR. BMSCs were infected with lentivirus‐mediated miR‐328‐3p knock‐down and then cultured in normoxic or hypoxic conditions, followed by isolation of EVs. Following ectopic expression and depletion experiments in lung cancer cells, the biological functions of miR‐328‐3p were analysed using CCK‐8 assay, flow cytometry and Transwell assay. Xenograft in nude mice was performed to test the in vivo effects of miR‐328‐3p delivered by hypoxic BMSC‐derived EVs on tumour growth of lung cancer. Finally, the expression of circulating miR‐328‐3p was detected in the serum of lung cancer patients. miR‐328‐3p was highly expressed in EVs derived from hypoxic BMSCs. miR‐328‐3p was delivered to lung cancer cells by hypoxic BMSC‐derived EVs, thereby promoting lung cancer cell proliferation, invasion, migration and epithelial‐mesenchymal transition. miR‐328‐3p targeted NF2 to inactivate the Hippo pathway. Moreover, EV‐delivered miR‐328‐3p increased tumour growth in vivo. Additionally, circulating miR‐328‐3p was bioactive in the serum of lung cancer patients. Taken together, our results demonstrated that hypoxic BMSC‐derived EVs could deliver miR‐328‐3p to lung cancer cells and that miR‐328‐3p targets the NF2 gene, thereby inhibiting the Hippo pathway to ultimately promote the occurrence and progression of lung cancer.