Abstract
Human endogenous retroviruses (HERVs), which are critical to normal embryologic development and downregulated during normal maturation, have been implicated in a variety of cancers. Abnormal persistent production of HERVs has been suggested to play a role in oncogenesis and to confer stem cell properties to cells. We recently demonstrated that the most recently incorporated HERV element (HERV-K HML-2) has been associated with the pathogenesis of the embryonal atypical teratoid rhabdoid tumor (AT/RT), shifting our understanding of embryonal tumor development. HML-2 expression is vital for proper human development and its expression is suppressed via methylation or chromatin remodeling as cells differentiate. We previously found that dysfunctional chromatin remodeling due to loss of SMARCB1 expression induces HML-2 envelope (env) expression, impairing cellular differentiation and migration, and facilitating tumor growth in AT/RT. Epigenetic dysregulation in other embryonal tumors with concomitant expression of stem-cell markers may facilitate HML-2 expression. Future studies could utilize HML-2 as potential diagnostic criteria, use its expression as a treatment biomarker, and investigate the efficacy of therapies targeting cells with high HML-2 expression.
Highlights
Discovery of Endogenous RetrovirusesEndogenous retroviruses have been incorporated into the genomes of many organisms throughout evolution by inserting into the genomes of germ cells and thereafter being inherited in the same way as Mendelian genes [1]
National Cancer Institute, Center for Cancer Research, Neuro-Oncology Branch, Building 37, Room 1000, National Institutes of Neurological Disorders and Stroke (NINDS), Surgical Neurology Branch, Abstract: Human endogenous retroviruses (HERVs), which are critical to normal embryologic development and downregulated during normal maturation, have been implicated in a variety of cancers
We found that targeting HML-2 env expression in atypical teratoid rhabdoid tumor (AT/RT) resulted in significantly lower cell proliferation and disrupted the cell–cell communication required for cells to maintain pluripotency [30]
Summary
Endogenous retroviruses have been incorporated into the genomes of many organisms throughout evolution by inserting into the genomes of germ cells and thereafter being inherited in the same way as Mendelian genes [1]. A ‘virus-transformed phenotype’ appeared to be heritable in the absence of viral replication [5] This observation later led Temin to hypothesize that the RNA Rous sarcoma virus (RSV) made a DNA copy that could integrate into the host genome [6]. Human endogenous retrovirus K (HERV-K), subtype HML-2, incorporated into the germline of ancestors of Homo sapiens millions of years ago and have been maintained in our genome [15]. These elements have been noted to be highly expressed in pluripotent stem cells and in germ-cell tumors likely due to their undifferentiated nature and embryonal origin [16,17,18]. This suggests that HML-2 transcription coincides with other pluripotent genes during development and in undifferentiated cells
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