Epiregulin increases stemness-associated genes expression and promotes chemoresistance of non-small cell lung cancer via ERK signaling

Background: Chemoresistance often causes the failure of treatment and death of patients with advanced non-small-cell lung Cancer. However, there is still no resistance genes signature and available enriched signaling derived from a comprehensive RNA-Seq data analysis of lung Cancer patients that could act as a therapeutic target to re-sensitize the acquired resistant Cancer cells to chemo-drugs. Hence, in this study, we aimed to identify the resistance signature for clinical lung Cancer patients and explore the regulatory mechanism.

Method: Analysis of RNA-Seq data from clinical lung Cancer patients was conducted in R studio to identify the resistance signature. The resistance signature was validated by survival time of lung Cancer patients and qPCR in chemo-resistant cells. Cytokine application, small-interfering RNA and pharmacological inhibition approaches were applied to characterize the function and molecular mechanism of EREG and downstream signaling in chemoresistance regulation via stemness.

Results: The RTK and vitamin D signaling were enriched among resistance genes, where 6 genes were validated as resistance signature and associated with poor survival in patients. EREG/ERK signaling was activated by chemo-drugs in NSCLC cells. EREG protein promoted the NSCLC resistance to chemo-drugs by increasing stemness genes expression. Additionally, inhibition of EREG/ErbB had downregulated ERK signaling, resulting in decreased expression of stemness-associated genes and subsequently re-sensitized the resistant NSCLC cells and spheres to chemo-drugs.

Conclusions: These findings revealed 6 resistance genes signature and proved that EREG/ErbB regulated the stemness to maintain chemoresistance of NSCLC via ERK signaling. Therefore, targeting EREG/ErbB might significantly and effectively resolve the chemoresistance issue.