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RETRACTED ARTICLE: Extracellular vesicle-associated microRNA-221-3p secreted by drug-resistant lung cancer cells targets HMBOX1 to promote the progression of lung cancer

Cancer Gene Therapy volume 28, pages 679–692 (2021)Cite this article

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A Retraction to this article was published on 20 July 2021

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Abstract

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.

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Fig. 1: EVs released by drug-resistant lung cancer cells contain miR-221-3p, which promotes the progression of lung cancer.
Fig. 2: EVs transfer miR-221-3p from GR donor cells to gemcitabine-sensitive receptor cells and play an important role in cell migration and invasion sensitivity.
Fig. 3: Overexpression of HMBOX1 reverses the effects of miR-221-3p on the malignant progression of lung cancer.
Fig. 4: HMBOX1 regulates the Akt/mTOR pathway to inhibit the malignant progression of lung cancer.
Fig. 5: miR-221-3p targets HMBOX1 to regulate the Akt/mTOR signaling pathway promoting the malignant progression of lung cancer.
Fig. 6: The distribution of the EVs across multiple organs after injection into a mouse model.
Fig. 7: The mechanism diagram of EVs-secreted miR-221-3p in lung cancer.

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Acknowledgements

We would like to express our sincere appreciation to the reviewers for critical comments on this article.

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Authors and Affiliations

  1. Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, 130031, Changchun, P.R. China

    Jun Li

  2. Department of Respiratory Medicine, China-Japan UnionHospital of Jilin University, 130031, Changchun, P.R. China

    Yongjuan Zhao & Jing Wang

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Contributions

JL and YZ designed the study. JL and YZ collated the data, carried out data analyses, and produced the initial draft of the manuscript. YZ and JW contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Jing Wang.

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This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1038/s41417-021-00364-y

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Li, J., Zhao, Y. & Wang, J. RETRACTED ARTICLE: Extracellular vesicle-associated microRNA-221-3p secreted by drug-resistant lung cancer cells targets HMBOX1 to promote the progression of lung cancer. Cancer Gene Ther 28, 679–692 (2021). https://doi.org/10.1038/s41417-020-00249-6

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