Extracellular vesicle-associated microRNA-221-3p secreted by drug-resistant lung cancer cells targets HMBOX1 to promote the progression of lung cancer.

Extracellular vesicles (EVs) have received increasing attention for their role as possible regulators of cancer. miR-221-3p is a microRNA (miR) up-regulated in EVs secreted by drug-resistant A549-GR lung cancer cells. However, the underlying mechanism through which miR-221-3p-containing EVs regulate the progression of lung cancer remains elusive. Here, we attempted to reveal the mechanism by which miR-221-3p-containing EVs secreted by drug-resistant lung cancer cells regulate the functions of surrounding cells during the progression of lung cancer. A gemcitabine-sensitive lung cancer cell line was treated with isolated drug-resistant lung cancer EVs followed by an evaluation of the proliferation and migration of sensitive lung cancer cell lines and their resistance to gemcitabine treatment. Moreover, the miR-221-3p target gene HMBOX1 was identified by the Targetscan database while the progression of lung cancer was detected by knocking down miR-221-3p or overexpressing HMBOX1, or by treating sensitive cell lines with Akt/mTOR activator and inhibitor, respectively. Furthermore, an in vivo study was performed to validate the relationship between miR-221-3p and HMBOX1 and their roles in the progression of lung cancer. The proliferation and migration of sensitive lung cancer cell lines and their resistance to drugs were significantly enhanced after the treatment with drug-resistant EVs. Knockdown of miR-221-3p (in the EV of drug-resistant lung cancer or overexpression of HMBOX1 in sensitive lung cancer cell lines) reduced the transformation of sensitive lung cell lines, whereas, the treatment of sensitive lung cell lines with Akt/mTOR activator or inhibitor significantly affected the progression of lung cancer. In vivo experiments further confirmed that miR-221-3p released by drug-resistant lung cancer cells targeted the HMBOX1 to regulate the Akt/mTOR signaling pathway and affected the progression of lung cancer. We conclude that miR-221-3p-containing EVs secreted by drug-resistant lung cancer cells can potentially activate the Akt/mTOR signaling pathway by inhibiting HMBOX1, promoting the progression of lung cancer. The regulation of miR-221-3p represents a novel therapeutic target for the treatment of lung cancer.