Abstract
PIWI-like (PIWIL) proteins and small non-coding piRNAs, involved in genome regulation in germline cells, are found aberrantly expressed in human tumors. Gene expression data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the European Genome-Phenome Archive (EGA) indicate that the PIWIL1 gene is ectopically activated in a significant fraction of colorectal cancers (CRCs), where this is accompanied by promoter demethylation, together with germline factors required for piRNA production. Starting from this observation, the PIWIL/piRNA pathway was studied in detail in COLO 205 CRC cells, which express significant levels of this protein, to investigate role and significance of ectopic PIWIL1 expression in human tumors. RNA sequencing and cell and computational biology led to the demonstration that PIWIL1 localizes in a nuage-like structure located in the perinuclear region of the cell and that a significant fraction of the piRNAs expressed in these cells are methylated, and, therefore, present in an active form. This was further supported by RNA immunoprecipitation, which revealed how several piRNAs can be found loaded into PIWIL1 to form complexes also comprising their target mRNAs. The mature transcripts associated with the PIWIL–piRNA complex encode key regulatory proteins involved in the molecular mechanisms sustaining colorectal carcinogenesis, suggesting that the PIWI/piRNA pathway may actively contribute to the establishment and/or maintenance of clinico-pathological features of CRCs.
Highlights
Cancer and germ cells share essential similarities, such a high proliferation rate and self-renewal ability, and cancer cells sometimes re-activate cancer testis antigen (CTA) genes, whose expression is usually restricted to the germline and silenced in adult somatic tissues
The Germline-Specific PIWIL1 Gene is Aberrantly Expressed in Colorectal Adenocarcinomas
We found that the PIWI-interacting RNAs (piRNAs) population identified is expressed at relatively low levels in colorectal cancers (CRCs) cells, where it represents a small percentage of all reads assigned to small RNAs,
Summary
Cancer and germ cells share essential similarities, such a high proliferation rate and self-renewal ability, and cancer cells sometimes re-activate cancer testis antigen (CTA) genes, whose expression is usually restricted to the germline and silenced in adult somatic tissues. A crucial role for the PIWIL–piRNA complex has emerged in somatic cells, where growing evidence indicates that both PIWIL and piRNA expression can be reactivated under pathological stimuli [8,9,10,11]. In this respect, in vitro/in vivo studies demonstrated that PIWIL proteins are a marker of malignancy but are involved in cell cycle regulation, tumorigenesis, drug resistance, and acquisition of self-renewal abilities [12,13]
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