Unveiling the origin and functions of diagnostic circulating microRNAs in lung cancer

Circulating microRNAs (c-miRs) were shown to be effective biomarkers for lung cancer early detection. However, the understanding of c-miRs origin and their biological functions still remains elusive.

We analysed miRNA expression in a large panel of lung cancer (LC) and hematopoietic cell lines (N = 252; CCLE database) coupled with c-miR profile of a large cohort of serum samples (N = 975), from high-risk subjects underwent annual LD-CT for 5 years. Furthermore, we examined intracellular and extracellular miR-29a-3p/223-3p expression profile in lung adenocarcinoma (LUAD) tissues, in matched serum samples and in LC and stromal cell lines. Lastly, through the modulation of expression of selected c-miRs by using mimic (OE) or antisense microRNA (KD), we explored their impact on lung cancer transcriptome and cancer and immune phenotypes.

Here, we investigated the origin of an extensively validated 13 c-miRs signature diagnostics for asymptomatic lung cancer (LC) in high-risk subjects (smokers, >20 packs/y; >50 y old). Overall, we found a mixed origin of these c-miRs, originating both from tumour cells and the tumour microenvironment (TME). Intriguingly, we revealed that circulating miR-29a-3p and miR-223-3p are abundantly released from LC epithelial cells and immune cells, respectively. In particular, we found that miR-223-3p triggered several lung cancer related phenotypes such as invasion, migration and tumour-promoting inflammation.

Our study highlights a mixed tumour epithelial and stroma-associated origin of LC c-miRs with new evidences on the multifaceted role of miR-223-3p in LC pathogenesis and immune modulation.