Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells

Abstract

Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non-small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth and primary tumor growth and metastatic behavior Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDHCD44CD24 pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC. This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. .

Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer

“…2A). To better assess the tumorigenic potential of these cells, we evaluated the anchorage-independent growth (AIG) in a 3-dimensional assay as previously described 26 . Cells formed fewer and smaller colonies in semisolid medium following both the chronic IL-1β exposure and EMT memory, indicating an impaired potential for solid tumor formation ( Fig.…”

Early Diagnosis and Screening for Lung Cancer

“…One study reported that a combination of p53 KD, KRAS v12 , and ectopic expression of CMYC was able to drive full malignant transformation of HBEC cells (Sato et al 2013). In another study, ectopic expression of the transcriptional repressor Snail in p53 KD, KRAS v12 HBEC cells enabled tumor formation, EMT, and metastatic growth in a murine lung cancer model (Walser et al 2018). Furthermore, this study demonstrated that, in the context of p53 KD, KRAS v12 , HBEC Snail expression promoted the ALDH + CD44 + CD24 − stem cell population that in turn was required for AIG.…”

High expression of ESRP1 regulated by circ-0005585 promotes cell colonization in ovarian cancer

“…In stem cells, the ESRP1-CD44v-xCT axis contributes to the attenuation of oxidative stress [21]. It also plays an important role in the development and progression of cancers [5,[22][23][24]. Previous studies have shown that in patients with ER (Estrogen Receptor) positive breast cancer, OS was significantly shorter in the high ESRP1 group [23].…”