Therapeutic potential of the human endogenous retroviral envelope protein HEMO: a pan‐cancer analysis

Abstract

Human endogenous retroviruses represent approximately 8% of our genome. Most of these sequences are defective except for a few genes such as the ancestral retroviral HEMO envelope gene (Human Endogenous MER34 ORF), recently characterized by our group. In this study, we characterized transcriptional activation of HEMO in primary tumors from The Cancer Genome Atlas (TCGA) and in metastatic tumors from a Gustave Roussy cohort. Pan-cancer detection of the HEMO protein in a series of patient samples validated these results. Differential gene expression analysis in various TCGA datasets revealed a link between HEMO expression and activation of Wnt/b-catenin signaling, in particular in endometrial cancer. Studies on cell models led us to propose that the Wnt/b-catenin pathway could act as an upstream regulator of this retroviral endogenous sequence in tumor condition. Characterization of transcriptomic profiles of both HEMO Low and HEMO High tumors suggested that activation of HEMO is negatively associated with immune response signatures. Taken together, these results highlight that HEMO, as an endogenous retroviral envelope protein specifically expressed in tumors, represents a promising tumor biomarker and therapeutic target.

Unique Structure and Distinctive Properties of the Ancient and Ubiquitous Gamma-Type Envelope Glycoprotein

“…Aside from work performed in experimental mouse models [ 255 , 256 ], additional research is also needed to confirm and further define the presumed function(s) of many of the placental syncytins of other mammalian lineages. Finally, there are many ERV gamma-type Env “orphans” in the genomes of humans and other vertebrates [ 27 , 45 , 46 ], including the human HEMO and EnvP(b)1 proteins [ 22 , 23 , 48 ] and the Percomorf protein of ray-finned fish [ 24 ], for which host functions remain to be identified.…”

“…Other endogenous retroviral genes have been co-opted during host evolution to confer resistance to infection by exogenous retroviruses [ 44 ]. In addition to the syncytin genes and the receptor interference examples, which are mostly on the order of tens-of-millions of years old, there are numerous examples of ERV loci with intact gamma-type Env ORFs of unknown function [ 23 , 27 , 45 , 46 , 47 ], including some that have remained intact for over 100 million years [ 22 , 24 , 48 ].…”

Transcriptional and reverse transcriptional regulation of host genes by human endogenous retroviruses in cancers

“…HERV-E Clear cell kidney cancer (Cherkasova et al, 2011), breast cancer (Frank et al, 2008) HERV-F Soft tissue sarcoma (Giebler et al, 2018), breast cancer (Frank et al, 2008) HERV-H Gastrointestinal and pancreatic neuroendocrine tumors (Yuan et al, 2021), colon cancer (Liang et al, 2009a(Liang et al, ,b, 2012Li et al, 2012), lung cancer (Zare et al, 2018), breast cancer (Rhyu et al, 2014) HERV-K Breast cancer (Wang-Johanning et al, 2003), soft tissue sarcoma (Giebler et al, 2018), melanoma (Singh et al, 2013(Singh et al, , 2020, germ cell tumor (Chan et al, 2019), leukemia (Chen et al, 2013), colon cancer (Dolci et al, 2020a,b), Hodgkin lymphoma (Barth et al, 2019), lung cancer (Zare et al, 2018) HERV-P Lung cancer (Zare et al, 2018), breast cancer (Tavakolian et al, 2019), primary cutaneous t-cell lymphomas (Bergallo et al, 2018) HERV-R Colon cancer (Dolci et al, 2020a), lung cancer (Zare et al, 2018), breast cancer (Rhyu et al, 2014), ovarian cancer (Jeon et al, 2020), primary cutaneous T-cell lymphomas (Bergallo et al, 2018) HERV-W Endometrial (Strissel et al, 2012), testicular cancer (Gimenez et al, 2010), germ cell tumors (Benesova et al, 2017), non-small cell lung cancer (NSCLC) , endometrial carcinoma (Liu et al, 2019) HERV-FRD Seminomas (Benesova et al, 2017), glioblastoma (Diaz-Carballo et al, 2017) HEMO breast cancer and ovarian cancer (Heidmann et al, 2017), endometrial cancer (Kasperek et ...…”

“…The newly discovered “HEMO” HERV envelope (Env) protein, encoded by the MER34 member 1 of the ERV group, was active in numerous cancerous tissues and most active in breast cancer and ovarian cancer ( Heidmann et al, 2017 ). Recently, Kasperek et al (2021) reported a pan-cancer analysis of HEMO both in primary tumors and metastatic tumors. A link between HEMO expression and Wnt/β-catenin signaling activation was revealed in endometrial cancer ( Kasperek et al, 2021 ).…”

“…Recently, Kasperek et al (2021) reported a pan-cancer analysis of HEMO both in primary tumors and metastatic tumors. A link between HEMO expression and Wnt/β-catenin signaling activation was revealed in endometrial cancer ( Kasperek et al, 2021 ). The aberrant reactivation of HERV-H in cancers, especially colorectal cancer, has been summarized in our previous review ( Zhang et al, 2019 ).…”