Tissue-specific and exosomal miRNAs in lung cancer radiotherapy: from regulatory mechanisms to clinical implications

Abstract

Lung cancer is the most prevalent and deadly malignancy. Radiotherapy is a major treatment modality for lung cancer. Nevertheless, radioresistance poses a daunting challenge that largely limits the efficacy of radiotherapy. There is a pressing need for deciphering molecular mechanisms underlying radioresistance and elucidating novel therapeutic targets for individualized radiotherapy. MicroRNAs are categorized as small noncoding RNAs that modulate target-gene expression posttranscriptionally and are implicated in carcinogenesis and cancer resistance to treatment. Overwhelming evidence has unraveled that tissue-specific miRNAs are essential for regulation of the radiosensitivity in lung cancer cells through a complex interaction with multiple biological processes and radiation-induced pathways. Moreover, exosome-derived miRNAs are a novel horizon in lung cancer treatment in which exosomal miRNAs act as potential diagnostic and therapeutic biomarkers of radiotherapy. In the present review, we discuss the mediation of key biological processes and signaling pathways by tissue-specific miRNAs in lung cancer radiotherapy. Additionally, we provide new insight into the potential significance of exosomal miRNAs in radiation response. Lastly, we highlight miRNAs as promising predictors and therapeutic targets to tailor personalized lung cancer radiotherapy.

Keywords: exosome; lung cancer; microRNAs; personalized radiotherapy; radioresistance.

Figure 1

An overview of tissue-specific miRNAs in the regulation of lung cancer radiosensitivity.Notes: MiRNAs exert essential function to regulate the radiosensitivity of lung cancer cells, through complex interaction with multiple biological processes including DNA damage response, cell cycle and apoptosis, hypoxic tumor microenvironment, epithelial-mesenchymal transition, cancer stem cells and radiation-induced signaling pathways.

Figure 2

miRNAs in DNA-damage response, cell cycle, and apoptosis.Notes: Radiotherapy utilizes ionizing radiation to generate free radicals and intermediate ions, which damage tumor cells at different levels, especially with DNA double-strand breaks, initiating diverse signaling pathways to repair. Cyclins and CDKs are indispensable regulators of cell-cycle transition, which can be suppressed by checkpoints at G₁/S and G₂/M interphases, ultimately to arrest cell-cycle progression and allow enough time for DNA-damage repair. If DNA damage is too severe to repair, cells will proceed to apoptosis or programmed cell death.Abbreviations: IR, ionizing radiation; PKcs, PK catalytic subunits.

Figure 3

Exosomes and exosomal miRNAs in lung cancer therapy.Notes: Exosomes are small membrane–derived vesicles in circulating body fluids that are released by multiple cell types, including tumor cells and normal cells. Exosomes specialize in intracellular communication, via transporting diverse molecular constitutes. Exosomal cargoes are mainly small regulatory molecules, including miRNAs, mRNAs, DNA, and proteins. Among them, exosomal miRNAs may be promising in regulating cellular radiosensitivity and monitoring radiotherapy effectiveness.