PARP1 Is Up-Regulated in Non-small Cell Lung Cancer Tissues in the Presence of the Cyanobacterial Toxin Microcystin

Abstract

Non-small cell lung cancer (NSCLC) is the major form of lung cancer, with adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being its major subtypes. Smoking alone cannot completely explain the lung cancer etiology. We hypothesize that altered lung microbiome and chronic inflammatory insults in lung tissues contribute to carcinogenesis. Here we explore the microbiome composition of LUAD samples, compared to LUSC and normal samples. Extraction of microbiome DNA in formalin-fixed, paraffin-embedded (FFPE) lung tumor and normal adjacent tissues was meticulously performed. The 16S rRNA product from extracted microbiota was subjected to microbiome amplicon sequencing. To assess the contribution of the host genome, <i>CD36</i> expression levels were analyzed then integrated with altered NSCLC subtype-specific microbe sequence data. Surprisingly phylum <i>Cyanobacteria</i> was consistently observed in LUAD samples. Across the NSCLC subtypes, differential abundance across four phyla (<i>Proteobacteria, Bacteroidetes, Actinobacteria</i>, and <i>Firmicutes</i>) was identified based on the univariate analysis (<i>p</i>-value < 6.4e-4 to 3.2e-2). <i>In silico</i> metagenomic and pathway analyses show that presence of microcystin correlates with reduced CD36 and increased PARP1 levels. This was confirmed in microcystin challenged NSCLC (A427) cell lines and <i>Cyanobacteria</i> positive LUAD tissues. Controlling the influx of <i>Cyanobacteria-like</i> particles or microcystin and the inhibition of PARP1 can provide a potential targeted therapy and prevention of inflammation-associated lung carcinogenesis.