Though cytogenetic aberrations of 19q13.4 as detected in benign thyroid lesions represent one of the most common specific chromosomal alterations in epithelial tumors at all the molecular mechanisms resulting from these frequent genomic alterations still remain obscure. As to tumorigenesis, the stimulation of invasive growth has been attributed to some miRNAs of C19MC [for review see  but the activation of the cluster in thyroid adenomas and nodular goiters with 19q13.4 alterations apparently does not coincide with invasive growth. Thus, it seems unlikely that in general activation of C19MC leads to invasive growth or other features characterizing malignant cells. On the other hand, presumed “physiological functions” of its miRNAs might give us a clue to understand their role in tumorigenesis. Of note, until birth expression of C19MC persists only in the placenta or, more precisely, its trophoblast [10, 11], and is expressed exclusively from the paternal allele whereas the maternal allele is silenced by epigenetic modification .
In general, miRNAs do not necessarily exert their main functions in the cells they are expressed in since considerable amounts of miRNAs can become packed into microvesicles called exosomes. Exosomes are bioactive vesicles derived from endosomal membranes and involved in intercellular communication by their specific cargos of proteins, mRNAs, and miRNAs [for review see . In previous reports placenta-derived exosomes have been demonstrated to interact with immune cells, e.g. resulting in suppression of T-cell signaling components [16, 17].
Donker et al.  were able to demonstrate recently that the cellular miRNA composition of human primary trophoblast cells strongly resembled that of the exosomes secreted from these cells. In both cases those of C19MC represented the majority of mature miRNAs. Of note, six microRNAs of C19MC ranged among the top-ten exosomal miRNAs. Based on their findings the authors have assumed that these miRNAs “may play an important role in placental-maternal communication, possibly directing maternal adaptation to pregnancy.”
Herein, we would like to outline the hypothesis that as one major function miRNAs of C19MC prevent the embryo from being attacked by the maternal immune system. Immunologically, the embryo is considered being a semi-allograft and in case of egg donation even a full allograft . Nevertheless, the embryo efficiently avoids rejection by its mother’s immune system by mechanisms that are not fully understood yet [for review see . Exosomes are known to share membrane characteristics with the cells they are derived from . Thus, it seems tempting to assume that they act like decoy-flairs for a jet. The exosomes can specifically target immune cells in their local environment, i.e. the decidua, as well as systemically thereby transferring their cargo when melting with the membrane of recipient cells. Within these target cells the transferred miRNAs can interact with mRNAs of the recipient cells thereby modulating post-transcriptional regulation. Non-specific systemic side effects of this mechanism may be the mild immunosuppression noted during pregnancy e.g. leading to the improvement of rheumatoid arthritis [for review see .
Tracing back to nodular goiters and thyroid adenomas re-expression of C19MC may protect cells against autoimmune attacks. Of note, a considerable percentage of these lesions develop after a pre-existing autoimmune disease of the thyroid.
Finally, the question arises if malignant tumors can adopt this mechanism to protect themselves. 19q13 is one of the most frequent chromosomal breakpoints identified in human tumors and even if, in particular in case of complex karyotypic aberrations, the small size of chromosome 19 may have resulted in false positive identification of this breakpoint there remain a number of tumor entities where its involvement has been identified unambiguously as e.g. hamartoma of the liver [22, 23]. Also, a number of recent papers point to the role of amplification (e. g. in CNS-PNET  and in embryonal brain tumors with ependymoblastic multilayered rosettes ) or undermethylation of the C19MC locus (e. g. in hepatocellular carcinomas [26, 27]) in several tumor entities.