Expressional activation and functional roles of human endogenous retroviruses in cancers

Abstract

Summary Human endogenous retroviruses (HERVs) are widely believed to be remnants of ancestral germ line infections by exogenous retroviruses. Although HERVs are deemed as “nonfunctional DNAs” due to loss of most of their viral protein coding capacity during evolution as part of the human genome, cumulative evidences are showing the expressional activation and potential roles of HERVs in diseases especially cancers. Work by other researchers and us has observed the dysregulation of HERVs in cancers, identified new HERV‐related genes, and revealed their potential importance in cancer development. Here, we summarized the current knowledge on the mechanisms of the expressional activation and functional roles of HERVs, with a focus on the H family HERV (HERV‐H), in carcinogenesis. HERV expression is regulated by external chemical or physical substances and exogenous virus infection, as well as host factors such as epigenetic DNA methylation, transcription factors, cytokines, and small RNAs. Diverse roles of HERVs have been proposed by acting in the forms of noncoding RNAs, proteins, and transcriptional regulators during carcinogenesis. However, much remains to be learnt about the contributions of HERVs to human cancers. More investigation is warranted to elucidate the functions of these “fossil remnants” yet important viral DNAs in the human genome.

TIP_finder: An HPC Software to Detect Transposable Element Insertion Polymorphisms in Large Genomic Datasets

“…Despite this not being the objective of the present study, the association between HERV-K and breast cancer in humans was confirmed. HERV-K in human breast cancer are involved in the processes of replication and tumorigenesis [88], derived directly from the protein and gene activities of mobile elements in the host [12]. This association is supported by the literature, indicating that this disease could be caused by the presence of HERVs in chromosomes 6, 7, 8, and 19 [26].…”

“…In humans, these elements (or TE-derived sequences) comprise~50-70% of the sequenced genome [8]. Several studies have indicated that TEs play crucial genomic roles involved in chromosome structuring, structural variation, the alteration of gene expression [5,7], evolution, the variation of genomic size, and environmental adaptation [9][10][11][12][13]. Nevertheless, these elements can also be associated with human diseases, such as different types of cancer [14][15][16].…”

Human Endogenous Retroviruses Long Terminal Repeat Methylation, Transcription, and Protein Expression in Human Colon Cancer

“…Thus, HERV families are originally named by adding the one-letter code of the amino acid specificity of the most likely tRNA as a suffix to the acronym HERV (4). HERV sequences are composed of four protein-encoding genes (gag, pro, pol, and env) flanked at the 5 ′ and 3 ′ ends by two regulatory regions named long terminal repeats (LTRs) (5). In the course of evolution, those sequences accumulated several mutations that eventually led to gene silencing (1).…”

“…In the course of evolution, those sequences accumulated several mutations that eventually led to gene silencing (1). Under normal conditions, HERV gene expression is highly regulated by multiple mechanisms, such as acetylation and methylation (5). However, abnormal HERV gene and protein expression has been documented in cases of malignancy (6), neuroinflammation (7), and autoimmune diseases (8).…”

“…Although controversial, the role of HERVs in cancer development and progression is a major field of research (5). In particular, it is still debated whether HERV dysregulation may be considered a real trigger for carcinogenesis or instead a stochastic effect of the epigenetic alterations commonly observed after cell transformation (9).…”