Endogenous retroviral elements (EREs) are genomic DNA fragments that may retain the capability of replication and reinsertion into the host genome, affecting its structure and integrity. Such are usually deregulated in many human cancers and may trigger the cellular immunogenicity through the activation of innate and adoptive immunity, thus representing promising candidates as immunotherapeutic targets and markers. The regulation of EREs expression occurs at transcriptional and post-transcriptional levels through the piwi-family of RNAs and their associated Argonaut proteins from the PIWIL family (PIWIL1, 2, 3 and 4); among these, PIWIL4 protein is expressed in somatic tissues, whereas other family members are restricted to germline tissues. Therefore, this project seeks to evaluate the role of PIWIL4 as a regulator of EREs in gastric cancer (GC), and the influence of its deregulation on the immune activation in this cancer. For this end, GC cell lines will be comprehensively characterized (methylome, transcriptome, characterization of an antiviral immune response mediated by type I IFNs and identification of neoepitopes) upon PIWIL4 deletion or hyper-expression, analyses in GC patient biopsies will also be performed (gene expression analyses and characterization of the intratumor immune cell composition). In silico analyses performed by our group have indicated that PIWIL4 is aberrantly expressed in GC patients and correlates with overall survival. Besides, PIWIL4 also correlates with the expression of EREs, which in turn correlates with antiviral response genes. Therefore, PIWIL4 may act as a central element on the regulation of EREs in GC and may have implications on anti-tumor immune responses.
News published in Agência FAPESP Newsletter about the scholarship: