HUMAN TROPHOBLAST AND CHORIOCARCINOMA EXPRESSION OF THE GROWTH-FACTORPLEIOTROPHIN ATTRIBUTABLE TO GERM-LINE INSERTION OF AN ENDOGENOUS RETROVIRUS

Retroviral elements are found in abundance throughout the human genome but only rarely have alterations of endogenous genes by retroviral in sertions been described. Herein we report that a human endogenous retr ovirus (HERV) type C is inserted in the human growth factor gene pleio trophin (PTN) between the 5' untranslated and the coding region. This insert in the human genome expands the region relative to the murine g ene. Studies with promoter-reporter constructs show that the HERV inse rt in the human PTN gene generates an additional promoter with trophob last-specific activity. Due to this promoter function, fusion transcri pts between HERV and the open reading frame of PTN (HERV-PTN) were det ected in all normal human trophoblast cell cultures as early as 9 week s after gestation (n = 7) and in all term placenta tissues (n = 5) but not in other normal adult tissues. Furthermore, only trophoblast-deri ved choriocarcinoma cell lines expressed HERV-PTN mRNA whereas tumor c ell lines derived from the embryoblast (teratocarcinoma) or from other lineages failed to do so, We investigated the significance of HERV-PT N mRNA in a choriocarcinoma model by targeting this transcript with ri bozymes and found that the depletion of HERV-PTN mRNA prevents human c horiocarcinoma growth, invasion, and angiogenesis in mice, This sugges ts that the tissue-specific expression of PTN due to the HERV insertio n in the human genome supports the highly aggressive growth of human c horiocarcinoma and possibly of the human trophoblast.