HERVs Unveiled: Exploring Their Impact on Cancer Biology and Therapeutics
Human endogenous retrovirus are viruses that have been a part of our genetic makeup before 500,000 years ago. These viruses have been integrated in our DNA and passed down to the offspring by the parents via Mendelian inheritance. The HERV family that has been integrated into the human genome is HERV-K(HML-2). These are non-replicative and defective in retro transposition as mutations have made them stop coding for proteins unlike in other mammals where the HERVs are capable of replication and reinfection. The HERV-K (HML-2) have shown to be advantageous to hosts, since their transcription is strictly regulated by epigenetic mechanisms like DNA methylation, histone modification, and acetylation.
The HERV contains gag, pro, pol, and env genes in their Long Terminal Repeats (LTRs) similar to the replicable retrovirus serving the function of mediators for the integration and regulators with both promoter and enhancer function. The age of the LTRs is calculated to know the epigenetic mechanism which controls them, the young LTAS are controlled through DNA methylation by DNA methyltransferases, the intermediate LTRs are controlled by histone lysis methyltransferases, and old LTRs are also controlled by histone lysis methyltransferases but this inactivation is because of the nonsense mutation.
The HERVs play a crucial role in the formation of syncytia, a fusion of many cells into multinucleated single cells, which fuses the villous trophoblast and the syncytio-trophoblast in the early stage of pregnancy. The syncytin-1 and syncytin-2 fusogenic glycoproteins from HERV-W and HERV-FRD participate in the formation of syncytia, which help in placentation and suppress the invasion from the mother’s body, leading to a healthy pregnancy.
On the negative side, the HERVs especially syncytin-1 can promote mitosis and metastasis of hepatocellular carcinoma (liver cancer), cell to cell adhesion can enhance endometrial carcinoma, and syncytin-2 causes the T- helper-1 immunosuppression by activating mitogen activated protein kinase which in turn inhibit Th1- related cytokines further linking syncytin-2 to immunological tolerance of tumors.
The presence of 292nt long deletion at the pol-env in the HERV-K(HML-2) determines if it is type I or type II virus, which produce env alternative transcripts Np9 and Rec respectively. The Np9 has the ability to trigger multiple molecular pathways in leukemia stem or progenitor cells which enhances the cell growth leading to cell stemness. The Np9 with Rec affects the spermatogonium stem cells leading to tumors by cellular proliferation because of their interaction with Promyelocytic Leukemia Zinc Finger transcription repressor thereby preventing the repression of MYC proto-oncogene. The function of env splicing products, found in malignant and normal tissues are yet to be studied.
The HERV LTRs modify the host genome by using promoters and enhancers that participate in the human carcinogenesis. By the removal of methyl groups in many places in a cancer cell the HERVs can be activated as inappropriate transcriptomes are released, this process is called Global Hypomethylation. The HERV-K(HML-2) 3q12.3 and 11p15.4 proviruses promote malignant tumors in the breast cells. The 11p15.4 provirus is active in more than half the population which contains a polymorphic RORA binding site, which leads to carcinogen.
HERV-H is the most abundant HERV found in the human genome from the embryonic stage. It is found to have the pluripotency feature, by which a mature cell can differentiate itself. The multiple reprogramming transcription factors like octamer- binding transcription factor 4(OCT4), sex determining region Y-box 2(SOX2), and Krüppel-like Factor 4 (KLF4/OSK) activates the LTR7 in HERV-H, which can be inhibited by programmed differentiation. The increase in the mammalian target of rapamycin pathway and the epigenetic modifications by the lysophosphatidylcholine acyltransferase (LPCAT1) induces the stemness, linked to the HERV-K (HML-2) env protein. When the env is inhibited, it results in the differentiation of neural cells by reducing the OCT-4 activity. A new HERV, HEMO [human endogenous MER34 (medium-reiteration-frequency-family-34) Open Reading Frame (ORF)] found in pregnant women and tumors have been identified as the factor influencing stem cells.
The HERV-K (HML-2) plays a significant role in the development of breast cancer as the mRNA and antibodies level increase and when the gene is silenced there was a significant decrease in the levels of cancer promoting proteins. Exposing the T-47D breast cancer cell line with female sex hormones activates the pol and env genes of HERV-K. the presence of the wild-type H-Ras protein is due to the expression of HERV-K. Trojan, a long-noncoding RNA (lncRNA) of endogenous retroviral origin are expressed in Triple Negative Breast Cancer (TNBC), an aggressive type of breast cancer. The presence of HERVs in these types of cancer gives a broader spectrum for therapy. The chimeric antigen receptor T- cells attack the HERV-K env and trigger the inflammatory responses in the breast cancer cells and do not affect the normal cells.
In endometrial carcinoma, the env proteins of HERV influence the cancer. The levels of syncytin-1 and 2 increases as the cancer advances. Different env proteins are expressed for different cancer types. The increase in the levels of env in the ovarian tissues can indicate that the person is suffering from Epithelial Ovarian Cancer. The hypomethylation in this HERV-K was seen to be resisting the platinum treatment. In some cases, the immune system releases T-cells against the HERV-K which may also attack the cancer cells.
The expression of HERV-K (HML-2) increases during the development of melanoma hence increasing the probability of drug therapy as the provirus acts as target. CAR-T cells can also be used for therapy as they target the env proteins. This expression is also crucial as the CD133 antigens are produced, which makes the cell growth faster.
The endogenous retrovirus enhances the gene function related to proliferation of cells in acute myeloid leukemia by the presence of LTR2. Absence of LTR2 has shown a significant decrease in the expressions responsible for cellular proliferation and growth. The patients suffering from Chronic Lymphocytic Leukemia have also shown increased levels of gag and nP9 protein in peripheral blood mononuclear cells. HERV-K was expressed more in pediatric leukemia than in normal children.
The increased levels of syncytin-1 of HERV-W 3’LTR was observed in clear cell Renal cell Carcinoma, which proved to be a more aggressive type of Urinary Tract Cancer. Though, the presence of HERV can be curable through immunotherapy. The aberrant values of syncytin-1 in the hepatic tissues indicates that the patient is suffering from Hepatocellular Carcinoma. The HERV can be transactivated by Hepatitis B or Hepatitis C virus.
Although the correlation between Human Endogenous Retrovirus and cancer remains uncertain, it is assured that the HERV carry out a major role in cancer and other human diseases. The HERVs act as biomarkers for cancers which generally possess challenges to be diagnosed in earlier stages. They have also led to the discovery of new types of treatment of cancer, as they can act as target sites for drugs. It has also brought a new insight to immunotherapy for cancer as the CAR-T cells can act against the proteins of HERV. HERVs can be useful in treating and diagnosing cancer in early stages.
REFERENCE
Kitsou K, Lagiou P, Magiorkinis G. Human endogenous retroviruses in cancer: Oncogenesis mechanisms and clinical implications. Journal of Medical Virology. 2023 Jan;95(1):e28350.
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