Abstract
Introduction: Recently we have identified a novel RASSF1C-PIWIL1-piRNA pathway that promotes lung cancer cell progression and migration. PIWI-like proteins interact with piRNAs to form complexes that regulate gene expression at the transcriptional and translational levels. We have illustrated in previous work that RASSF1C modulates the expression of the PIWIL1-piRNA gene axis, suggesting the hypothesis that the RASSF1C-PIWI-piRNA pathway could potentially contribute to lung cancer stem cell development and progression, in part, through modulation of gene methylation of both oncogenic and tumor suppressor genes. Therefore, we tested this hypothesis using a non-small cell lung cancer (NSCLC) cell model to identify Candidate Differentially Methylated Regions (DMRs) modulated by the RASSF1C-PIWIL1-piRNA pathway.Materials and Methods: We studied the impact of over-expressing RASSF1C and knocking down RASSF1C and PIWIL1 expression on global gene DNA methylation in the NSCLC cell line H1299 using the Reduced Representation Bisulfite Sequencing (RRBS) method.Results: DMRs were identified by comparing DNA methylation profiles of experimental and control cells. Over-expression of RASSF1C and knocking down RASSF1C and PIWIL1 modulated DNA methylation of genomic regions; and statistically significant candidate genes residing DMR regions in lung cancer cells were identified, including oncogenes and tumor suppressors. One of the hypermethylated genes, Gem Interacting Protein (GMIP), displays tumor suppressor properties. GMIP expression attenuates lung cancer cell migration, and its over-expression is associated with longer survival of lung cancer patients.Conclusions: The RASSF1C-PIWI-piRNA pathway modulates key oncogenes and tumor suppressor genes. GMIP is hypermethylated by this pathway and has tumor suppressor properties.
Highlights
We have identified a novel RASSF1C-PIWIL1-PIWI-interacting RNAs (piRNAs) pathway that promotes lung cancer cell progression and migration
Materials and Methods: We studied the impact of over-expressing RASSF1C and knocking down RASSF1C and PIWIL1 expression on global gene DNA methylation in the non-small cell lung cancer (NSCLC) cell line H1299 using the Reduced Representation Bisulfite Sequencing (RRBS) method
We have demonstrated that RASSF1C stimulates in vitro cell cycle, proliferation, and migration of human lung cancer cells, size/number of tumor spheres produced by lung cancer stem cells (CSC), and in vivo tumor growth [4,5,6,7,8,9]
Summary
We have identified a novel RASSF1C-PIWIL1-piRNA pathway that promotes lung cancer cell progression and migration. We have illustrated in previous work that RASSF1C modulates the expression of the PIWIL1-piRNA gene axis, suggesting the hypothesis that the RASSF1C-PIWI-piRNA pathway could potentially contribute to lung cancer stem cell development and progression, in part, through modulation of gene methylation of both oncogenic and tumor suppressor genes. RASSF1C regulates expression of several genes/ proteins important in maintaining a CSC-like phenotype and oncogenesis [5] In this regard, we have illustrated that RASSF1C modulates the expression of the PIWIL1piRNA gene axis [5, 9] suggesting the hypothesis that a RASSF1C-PIWI-piRNA pathway could potentially be a driver pathway that promotes lung cancer cell growth and progression. Gaining insights about the role PIWIL1-piRNA gene axis in human cancer growth and progression is very desirable
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