Circulating Exosomal miR-96 as a Novel Biomarker for Radioresistant Non-Small-Cell Lung Cancer

Abstract

Patients with non-small-cell lung cancer (NSCLC) frequently develop radioresistance, resulting in poor response to radiation and unfavourable prognosis. Early detection of radioresistance hence can guide the adjustment of treatment regimens in time. Exosomes are lipid bilayer-enclosed vesicles with sub-micrometer size that are released by various cells. Exosomes contain a tissue-specific signature wherein a variety of proteins and nucleic acids are selectively packaged. Growing evidence shows exosomes are involved in cancer pathophysiology and exosomes as the latest addition to the liquid biopsy portfolio have been used in cancer diagnosis. Compared to cell free RNA, exosomal lipid envelope can effectively protect RNA cargo against degradation. Therefore, exosomes may hold great promise for the identification of radioresistance. Here, we report six plasma exosomal miRNAs could be used to distinguish radioresistant NSCLC patients from radiosensitive NSCLC patients and to evaluate the prognosis of NSCLC. Samples were obtained from 52 NSCLC patients with or without radioresistance and 45 age-matched healthy volunteers. Exosomes in 1 ml plasma were isolated followed by extraction of small RNA. The expression levels of miRNAs were determined by quantitative real-time PCR. Potential miRNA markers were further evaluated in additional 52 NSCLC patients. We found exosomal miR-1246 and miR-96 are significantly overexpressed in NSCLC patients. Moreover, exosomal miR-96 in patients with radioresistant NSCLC is significantly higher than that of controls. Exosomal miR-96 also demonstrates a significant correlation with vascular invasion and poor overall survival. Altogether, our results indicate that exosomal miR-96 could be a non-invasive diagnostic and prognostic marker of radioresistant NSCLC.

Exosomes: Potential Disease Biomarkers and New Therapeutic Targets

“…Likewise, Xian et al, observed that linc01125 loaded in circulating exosomes could identify subjects with NSCLC and was associated with poor overall survival [198]. cervix miR-125a-5p [191] CircEIF4G2 [192] prostate miR-423-3p [195] miR-532-5p [193] miR-375, miR-451a, miR-486-3p andmiR-486-5p [194] lung miR-1268b and miR-6075 [195] miR-1246 and miR-96 [196] linc01125 [197] complications during pregnancy…”

“…Another study proposed exosomal miR-1246 and miR-96 as biomarkers of non-small cell lung cancer (NSCLC), as they could be shown to be significantly overexpressed in individuals with the disease. Furthermore, exosomal miR-96 was reported to be significantly correlated with radioresistant NSCLC and vascular invasion [197]. Likewise, Xian et al, observed that linc01125 loaded in circulating exosomes could identify subjects with NSCLC and was associated with poor overall survival [198].…”

Small Extracellular Vesicles: Functions and Potential Clinical Applications as Cancer Biomarkers

“…Lung cancer is one of the most dangerous cancers and efficient methods for its diagnosis are lacking. Liquid biopsy of sEVs is a method with high accuracy and specificity for early diagnosis of lung cancer [ 101 ], and sEV-derived miR-96 is a potential serum biomarker for malignant lung cancer [ 102 ]. In addition, the LIM-domain-only protein 7 (LMO7) gene is a target of miR-96.…”

Exosomes in Lung Cancer: Actors and Heralds of Tumor Development

“…Moreover, the overexpression of miR-146a-5p could revert chemoresistance to cisplatin in A549 lung cancer cells by inhibiting autophagy. Regarding radiotherapy, Zheng et al [134] showed that miR-96 can identify lung cancer patients with high efficiency (AUC = 0.97) but it also presents potential utility to identify radioresistant patients (AUC = 0.75). Another treatment option that has become a key strategy against lung cancer is immunotherapy, with PD-1/PD-L1 as one of the targeted checkpoints.…”