Date Published: February 28, 2019
Publisher: Public Library of Science
Author(s): Susana M. Chan, Tamar Sapir, Sung-Soo Park, Jean-François Rual, Rafael Contreras-Galindo, Orly Reiner, David M. Markovitz, Hodaka Fujii.
Human endogenous retroviruses are remnants of ancient germline infections that make up approximately 8% of the modern human genome. The HERV-K (HML-2) family is one of the most recent entrants into the human germline, these viruses appear to be transcriptionally active, and HERV-K viral like particles (VLPs) are found in cell lines from a number of human malignancies. HERV-K VLPs were first found to be produced in teratocarcinoma cell lines, and since then teratocarcinoma has been thought of as the classical model for HERV-Ks, with the NCCIT teratocarcinoma cell line particularly known to produce VLPs. Treatment for teratocarcinoma has progressed since its discovery, with improved prognosis for patients. Since the introduction of platinum based therapy, first year survival has greatly improved even with disseminated disease; however, it is estimated that 20% to 30% of patients present with metastatic germ cell tumor relapse following initial treatments. Also, the toxicity associated with the use of chemotherapeutic agents used to treat germ cell tumors is still a major concern. In this study, we show that the depletion of the HERV-K accessory protein Np9 increases the sensitivity of NCCIT teratocarcinoma cells to bleomycin and cisplatin. While decreasing the expression of Np9 had only a modest effect on the baseline viability of the cells, the reduced expression of Np9 increased the sensitivity of the teratocarcinoma cells to environmental (serum starvation) and chemical (chemotherapeutic) stresses. Np9 is also essential to the migration of NCCIT teratocarcinoma cells: in a wound closure assay, reduced expression of Np9 resulted in cells migrating into the wound at a slower rate, whereas reintroduction of Np9 resulted in NCCIT cells migrating back into the wound in a manner similar to the control. These findings support the implication that the HERV-K accessory protein Np9 has oncogenic potential.
Human endogenous retroviruses (HERVs) account for 8% of the human genome, yet their potential roles in the biology of the cell and in human health or disease remain poorly understood. These ancient viruses were once exogenous viruses that infected germ cells of mammals and other vertebrates numerous times in the course of millions of years, and subsequently integrated their proviral elements into the host genome. These proviruses have then been transmitted over the generations in a Mendelian fashion [1–3]. HERV elements exist in the human genome as retroviral genes (gag, pol, and env) flanked by two long terminal repeats (LTRs); the LTRs serve as transcriptional promoters . However, most of the HERV proviral sequences have been rendered nonfunctional due to the accumulation of mutations, insertions, and deletions in crucial retroviral genes , with the possible exception of the HERV-K (HML-2) subfamily. The HERV-K (HML-2) subfamily is one of the most recent entrant into the human genome, most having only integrated itself between 200,000 and 5 million years ago, and it is the subfamily of endogenous retroviruses that is most conserved and are transcriptionally active, and some have functional open reading frames (ORFs) to code for all of its viral proteins [4,6–10].
HERVs have long been implicated in autoimmune disorders and oncogenesis [10,20,24,36,52–66]. However, the fact that there are so many copies, over a hundred copies of the standard HERVs and hundreds to thousands of copies of K111 and K222, picking apart the specific contributions of HERV-K to cancer has been quite difficult [15,17]. Adding to the complexity of HERV-K biology in the context of human diseases, there is evidence of HERV-K viral particle production in certain cancers and transformed cell lines, such as teratocarcinoma; however, whether these viral particles are actually replicative remains unknown and the subject of debate [14,16,18–22,67–72].