Abstract
Non-small-cell lung cancer is the leading cause of cancer death worldwide and is comprised of several histological subtypes, the two most common being adenocarcinoma (AC) and squamous cell carcinoma (SCC). Targeted therapies have successfully improved response rates in patients with AC tumors. However, the majority of SCC tumors lack specific targetable mutations, making development of new treatment paradigms for this disease challenging. In the present study, we used iterative non-negative matrix factorization, an unbiased clustering method, on mRNA expression data from the cancer genome atlas (TCGA) and a panel of 24 SCC cell lines to classify three disease segments within SCC. Analysis of gene set enrichment and drug sensitivity identified an immune-evasion subtype that showed increased sensitivity to nuclear factor-κB and mitogen-activated protein kinase (MAPK) inhibition, a replication-stress associated subtype that showed increased sensitivity to ataxia telangiectasia inhibition, and a neuroendocrine-associated subtype that showed increased sensitivity to phosphoinositide 3-kinase and fibroblast growth factor receptor inhibition. Additionally, each of these subtypes exhibited a unique microRNA expression profile. Focusing on the immune-evasion subtype, bioinformatic analysis of microRNA promoters revealed enrichment for binding sites for the MAPK-driven ETS1 transcription factor. Indeed, we found that knockdown of ETS1 led to upregulation of eight microRNAs and downregulation of miR-29b in the immune-evasion subtype. Mechanistically, we found that miR-29b targets the DNA-demethylating enzyme, TET1, for downregulation resulting in decreased 5-hmC epigenetic modifications. Moreover, inhibition of MAPK signaling by gefitinib led to decreased ETS1 and miR-29b expression with a corresponding increase in TET1 expression and increase in 5-hmC. Collectively, our work identifies three subtypes of lung SCC that differ in drug sensitivity and shows a novel mechanism of miR-29b regulation by MAPK-driven ETS1 expression which leads to downstream changes in TET1-mediated epigenetic modifications.
Highlights
Non-small-cell lung cancer is the most prevalent type of lung cancer in the world and the leading cause of cancer death, accounting for 1.4 million deaths annually.[1]
We demonstrate that the ETS1 transcription factor, driven by pathways enriched in the immune-evasion subtype, drives the differential expression of a subset of microRNAs expressed in this subtype
We demonstrate that lung squamous cell carcinoma (SCC) is composed of three subtypes that are driven by diverse cell signaling pathways, exhibit differential microRNA expression and differential drug sensitivity profiles
Summary
Non-small-cell lung cancer is the most prevalent type of lung cancer in the world and the leading cause of cancer death, accounting for 1.4 million deaths annually.[1]. MicroRNAs are small (20–30 nucleotide) non-coding RNAs that can function as either tumor promoters or suppressors during tumorigenesis by exerting post-transcriptional effects on gene expression.[6] microRNAs are often expressed in a tissue- and disease-specific manner,[7] making them ideal candidates as biomarkers.[7,8] In this study, we used global gene expression profiling to define subtypes present within lung SCC. We demonstrate that the ETS1 transcription factor, driven by pathways enriched in the immune-evasion subtype, drives the differential expression of a subset of microRNAs expressed in this subtype. Through this analysis, we identified miR-29b as a microRNA whose expression is driven by ETS1, through activated mitogen-activated protein kinase (MAPK) signaling. We found that miR-29b targets the 5-hydroxymethylcytosine dioxygenase, TET1 for downregulation and has downstream effects on TET1-mediated epigenetic modifications
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