**6. Conclusions**

*Methods in Molecular Medicine*

non-cancer cells [172].

in renal carcinoma [130, 176].

use with other cancer therapies.

activity is a great therapeutic target for cancer. Sciamanna et al., 2005, uncovered that pharmacologic L1 inhibition by two reverse transcriptase inhibitors slows down the growth of malignant melanoma and prostatic cancer [166]. Carlini et al. similarly demonstrated the efficacy of reverse transcription inhibition of prostate cancer growth [167]. Furthermore, a clinical trial showed that Efavirenz, a nonnucleoside reverse transcriptase inhibitor (NNRTI), provides a therapeutic benefit by increasing the progression free survival in a high-stage castration-resistant prostate cancer cohort [168]. Recently, Efavirenz has been shown to suppress L1 activity and promote morphological differentiation in melanoma cells [169]. On the other hand, another class of RT inhibitor, the nucleoside reverse transcriptase inhibitor (NRTI), has also been shown to suppress L1 activity and induce anticancer activity in prostate cancer cell lines. Importantly, no significant effects were observed in normal cells [167]. Despite these successful findings, it is still unclear regarding the

molecular function of RT inhibition in the gene expression regulation.

RNA interference (RNAi)-mediated downregulation of L1 generated identical effects to those observed with RT inhibitory drugs in human melanoma, which indicates that RT activity has a crucial role in L1 activity in human cancer [170]. Recently, a phase II human trial using Efavirenz on a cohort of metastatic patients with prostate cancer showed nonprogression when Efavirenz reached an optimal concentration in the blood [171]. Altogether, preclinical and clinical data provide evidence that RT inhibition is a potentially effective tool in a novel anticancer therapy against diverse human cancers with noncytotoxic effects on

Another approach regarding REs is an immunotherapy approach to target the pro-oncogenic effects of HERV ENV, which is possibly involved in tumor progression and in downstream metastatic spread, in a number of tissues. HERV ENVs exclusively upregulated in tumor tissues will be suitable targets to direct both passive and active immunotherapy against in cancer cells [130]. The antibodies recognizing the HERV ENVs has been developed, and currently, a monoclonal antibody against HERV-K (HML2) ENV successfully inhibits human breast cancer proliferation, with the activation of apoptosis [173]. On the other hand, various HERV-derived ENVs have been investigated as candidates of anticancer immunotherapy, either as tumor-associated or tumor-specific antigens in cancer cells [130]. ERVs were first used for antitumor immunization in the murine cancer models expressing ERV [9]. Similarly, in humans, protective immunity against the HERV-K MEL antigen in melanoma development has been investigated. This active immunotherapy is considered more advantageous with respect to passive immunization [130]. However, despite the antigenic similarity between HERV-K-MEL and yellow fever virus (YFV), no significant protective effects were shown in the 10 years post-anti-YFV vaccinations in the melanoma cohorts [174, 175]. HERV-H ENV (Xp22.3) is an another antigen significantly upregulated in a subset of gastrointestinal cancers. T cells that was sensitized to HERV-H ENV (Xp22.3) had lytic effects against colorectal cancer expressing the ENV. HERV-E ENV showed similar effects

In addition, demethylating drugs are commonly used as anticancer agents and are known to trigger RE reexpression [177]. Interestingly, DNA methyl transferase inhibitors are caused by immune attacks that increase the expression of HERV and thereby increase the viral dsRNA [178]. Accordingly, individual knocking down of MDA5, MAVS, or IRF7 inhibits the ability of DNA methyl transferase inhibitor to target colorectal cancers resulting in significantly reduced the anticancer activity [179]. Altogether, immunotherapy approaches targeting HERV ENV in a broad spectrum of cancers might be valuable for the expansion of target cancers and for

**90**

In this chapter, we reviewed and summarized the functions and regulatory mechanisms of retroelements in the development and progression of cancers, and further presented applications in the development of diagnosis and treatment targets using these characteristics (**Table 1**). We looked at the retrovirus as a functional genomic element that forms the genome, not as an ancient infected virus and its useless remnants. Reactivation of retroelements means that it affects various regulation processes of cells beyond not only controlling the functions of surrounding genes but also increasing the protein formed therefrom or its function, or prompting its reinsertion into a new position. Because of this, it is very important to analyze and understand retroelements' functions with regard to various target substances, for example, miRNA, transcription factors, epigenetic modifiers, and so on (**Figure 1**).



**93**

**Acknowledgements**

**Figure 1.**

**Conflict of interest**

*Endogenous Retroelements in Cancer: Molecular Roles and Clinical Approach*

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science and ICT (#2016M3A9B6026771) and by (NRF-2019R1I1A1A01060265) at least partially. J.Y.C. conceived and developed the entire study and revised the chapter, and K.H.L. mainly wrote the first draft. We thank Hyeon-Ji Hwang for data

*Overall involvement of REs in cancer studies. RE expression was regulated by epigenomic controls such as histone modification and methylation. Reactivated RE by hypomethylation causes genome instability and the enrichment of cytoplasmic RE transcripts which may increase inflammatory signal. These may be involved in diverse biological process as a source of ncRNA including miRNAs. RE proteins are also involved in tumorigenesis process, and PIWI and APOBEC3 systems regulate RE activity in various ways.*

acquisition, and Johannes Schabort for English editing.

The authors declare no conflict of interest.

*DOI: http://dx.doi.org/10.5772/intechopen.93370*

**Table 1.** *RE expression in human cancers.* *Endogenous Retroelements in Cancer: Molecular Roles and Clinical Approach DOI: http://dx.doi.org/10.5772/intechopen.93370*

#### **Figure 1.**

*Methods in Molecular Medicine*

L1 Breast, ovarian,

cancer

L1 Melanoma, prostate cancer

*RE expression in human cancers.*

pancreatic, lung, prostate

**RE type Cancer type Experimental technique References** L1 Liver cancer RC-seq, whole genome sequencing [99] L1 Encephalopathy DNA-seq, RT-PCR [116] Alu Multiple cancer cell lines RNA immunoprecipitation, RT-PCR [118]

L1 Multiple cancer cell lines IF, LINE-1 activation assay, RT-PCR [124] L1 Leukemia ChIP-seq, RNA-seq [125] L1 Oral cancer Bisulfite-pyrosequencing [126]

sequencing PCR

HERV-W Endometrial cancer RT-PCR, DNA-seq, immunoblot [134]

L1 Colon, prostate cancer Immunoblot, IF, IHC [138] HERV Breast cancer RT-PCR [141] HERV-K Teratocarcinoma CRISPR/Cas9, immunoblot [144] HERV-K Breast cancer GST pull-down assay, Co-IP [145]

RNA-seq for TCGA

HERV Multiple cancer types SNV, DNA functional elements analysis [150] L1 Liver cancer Bisulfite pyrosequencing [154] L1 NSCLC Methylation-specific real-time PCR assay [155] L1 Colon cancer Bisulfite pyrosequencing [162] L1 Breast cancer Bisulfite sequencing, MSRED, and RT-PCR [163] HERV Lung cancer RT-PCR [166] HERV-K Liver cancer RT-PCR [167] HERV-H Multiple cancer types Immunohistochemistry [168] HERV-K Breast cancer ELISA, RT-PCR [169] L1 Multiple cancer types Immunohistochemistry [172] L1 Breast cancer Western blot, IHC [173]

L1 Prostate cancer RT activity assay, RT-PCR [176] L1 Melanoma IF, RT-PCR, western blot, xenograft model [178]

L1 Gastrointestinal cancer Tea (TE analyzer) from paired-end whole-

immunoprecipitation, xenograft models

Immunohistochemistry [136]

genome sequencing, somatic SNV, indel call,

IF, Western blot, xenograft model [175]

[122]

[133]

[149]

ERV-9 Multiple cancer cell lines RT-PCR, western blot, RNA

HERV-W Testicular cancer HERV GeneChip microarray, bisulfite

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**Table 1.**

*Overall involvement of REs in cancer studies. RE expression was regulated by epigenomic controls such as histone modification and methylation. Reactivated RE by hypomethylation causes genome instability and the enrichment of cytoplasmic RE transcripts which may increase inflammatory signal. These may be involved in diverse biological process as a source of ncRNA including miRNAs. RE proteins are also involved in tumorigenesis process, and PIWI and APOBEC3 systems regulate RE activity in various ways.*

### **Acknowledgements**

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science and ICT (#2016M3A9B6026771) and by (NRF-2019R1I1A1A01060265) at least partially. J.Y.C. conceived and developed the entire study and revised the chapter, and K.H.L. mainly wrote the first draft. We thank Hyeon-Ji Hwang for data acquisition, and Johannes Schabort for English editing.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Methods in Molecular Medicine*
