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

Abstract

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.

Association of CYP24A1 with survival and drug resistance in clinical cancer patients: a meta-analysis

“…Vitamin D signaling has been shown to increase sensitivity of cancers to chemo-drugs [12,13]. Consistently, our previous study demonstrated that vitamin D signaling was associated with chemo-resistance of cancer [14]. Physiologically, vitamin D3 is metabolized to 25(OH)D 3 to produce 1α,25(OH) 2 D 3 , which is also known as calcitriol.…”

Integrative bioinformatics approaches to establish potential prognostic immune-related genes signature and drugs in the non-small cell lung cancer microenvironment

“…Moreover, Chen et al ( Chen et al, 2019 )discovered that acquired resistance to 5-FU in colon cancer can be reversed by inhibiting the miR-215-5p-EREG/TYMS axis. A study ( Zhang et al, 2022 ) in 2022 found that EREG enhanced resistance to chemotherapy in NSCLC by increasing the expression of stemness-associated genes. Notably, the expression of EREG in stromal cells is upregulated and activates several downstream signaling pathways, including the MAPK AKT/mTOR and JAK/STAT pathways, in cancer cells by paracrine signaling, promoting their malignant phenotype and accelerating the progression of cancer ( Wang et al, 2022 ).…”

Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer PDXs

“…EREG (epiregulin) is a member of the EGF family and an EGFR ligand; it is thus involved in inflammation, cell proliferation, and cancer progression. EREG activity has been associated with cetuximab sensitivity in preclinical models and patients 52,53 , and it has been suggested that, in an inflammatory environment, EREG can promote stemness and cancer cell proliferation by stimulating ERK signalling through EGFR activation in a variety of cancer types [54][55][56] .…”