miR-498 inhibits autophagy and M2-like polarization of tumor-associated macrophages in esophageal cancer via MDM2/ATF3

Structured abstract

Aim: To elucidate the effect of miRNA (miR)-498 on autophagy and M2-like macrophage polarization in esophageal cancer. Methods: Autophagy was evaluated in esophageal cancer. Macrophage markers specific for M1- or M2-like phenotype were determined. The binding relationships between miR-498 and MDM2, MDM2 and ATF3 were analyzed. Results: miR-498 was downregulated in esophageal cancer and was associated with disease-free and overall patient survival. Enhanced miR-498 reduced LC3I conversion to LC3II and increased p62 accumulation in KYSE-150 cells, and increased macrophage polarization to M2-like phenotype in KYSE-150 and TAM co-culture. miR-498 inhibited MDM2-mediated ATF3 degradation, thus suppressing autophagy and M2-like polarization of macrophages in esophageal cancer. Conclusion: miR-498 may inhibit autophagy and M2-like polarization of macrophages to suppress esophageal cancer via MDM2/ATF3.

Lay abstract

In this study, we aimed to elucidate the therapeutic mechanism of miRNA (miR)-498 in autophagy and macrophage polarization to M2-like phenotype in esophageal cancer. This study reports lower miR-498 expression in esophageal cancer tissues compared with adjacent normal tissues. According to the experimental results, miR-498 negatively targets MDM2 by binding to its 3′UTR, which leads to attenuated ubiquitination and degradation of ATF3 induced by MDM2. Specifically, overexpressed miR-498 reduces ratio of LC3II (a marker that is commonly utilized to detect cell autophagy) to LC3I and increases p62 (a common cargo receptor for autophagy) accumulation in KYSE-150 cells, and elevates macrophage polarization to M2-like phenotype by depressing MDM2-mediated ATF3 degradation. The present study deepened our understanding of the causes of esophageal cancer and provided at least three novel therapeutic targets for the development of effective targeted therapy for esophageal cancer.

Keywords: :

• ATF3
• autophagy
• degradation
• esophageal cancer
• inflammation
• M1-like polarization
• M2-like polarization
• MDM2
• microRNA-498
• tumor-associated macrophages

Acknowledgments

The authors acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

Financial & competing interests disclosure

This study was supported by National Natural Science Foundation of China (General Program) (no. 81172496), Key project of Nanchong Science and Technology Bureau (no. 18SXHZ0410) and Innovation Team Project of Sichuan Provincial Department of Education (Scientific Research and Innovation Team of Provincial Universities) (no. 17TD0016). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data sharing statement

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.