Transcriptome Analysis of Human Endogenous Retroviruses at Locus-Specific Resolution in Non-Small Cell Lung Cancer

Ferlita, Alessandro La; Distefano, Rosario; Alaimo, Salvatore; Beane, Joal D.; Ferro, Alfredo; Croce, Carlo M.; Tsichlis, Philip N.; Pulvirenti, Alfredo; Nigita, Giovanni

doi:10.3390/cancers14184433

Cited by 4 publications

(7 citation statements)

References 59 publications

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“…Although the importance of miRNAs in cancer is well-defined, and widespread dysregulation of miRNAs have been reported in soft tissue sarcomas 23 , there is much to discover regarding the roles of miRNAs in AS. Previously it has been suggested that miR-210 24 , miR-214 25 , miR-340 26 , and miR-497 27 may elicit tumor-suppressing phenotypes in AS.…”

Section: Introductionmentioning

confidence: 99%

Target gene regulatory network of miR-497 in angiosarcoma

Benton,

Terwilliger,

Moriarty

et al. 2023

Preprint

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Angiosarcoma (AS) is a vascular sarcoma that is highly aggressive and metastatic. Due to its rarity, treatment options for patients are limited, therefore more research is needed to identify possible therapeutic vulnerabilities. We previously found that conditional deletion of Dicer1 drives AS development in mice. Given the role of DICER1 in canonical microRNA (miRNA) biogenesis, this suggests that miRNA loss is important in AS development. After testing miRNAs previously suggested to have a tumor-suppressive role in AS, microRNA-497-5p (miR-497) suppressed cell viability most significantly. We also found that miR-497 overexpression led to significantly reduced cell migration and tumor formation. To understand the mechanism of miR-497 in tumor suppression, we identified clinically relevant target genes using a combination of RNA-sequencing data in an AS cell line, expression data from AS patients, and target prediction algorithms. We validated miR-497 direct regulation of CCND2, CDK6, and VAT1. One of these genes, VAT1, is an understudied protein that has been suggested to promote cell migration and metastasis in other cancers. Indeed, we find that pharmacologic inhibition of VAT1 with the natural product Neocarzilin A reduces AS migration. This work provides insight into the mechanisms of miR-497 and its target genes in AS pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Target gene regulatory network of miR-497 in angiosarcoma

Benton,

Terwilliger,

Moriarty

et al. 2023

Preprint

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“…Recent studies point out the biological relevance of human endogenous retroviruses (HERVs), a class of transposable elements, in cancer biogenesis and also their potential clinical applications as novel diagnostic, prognostic, and treatment response biomarkers for several tumor types ( 6 – 19 ). HERVs are remnants of exogenous retroviruses integrated into the human genome during evolution, accounting for 8% of the human genome ( 20 – 22 ). Indeed, HERVs share genomic similarities with other exogenous retroviruses.…”

mentioning

confidence: 99%

“…Indeed, HERVs share genomic similarities with other exogenous retroviruses. However, due to accumulated mutations, HERVs have preserved the features of their original provirus to a highly variable extent, ranging from the retention of a complete set of long terminal repeats (LTRs) and retroviral genes to the retention of only fragments of the parental viral genomes ( 20 , 21 , 23 ). Based on their sequences, HERVs are usually classified into groups ( 20 , 21 ).…”

mentioning

confidence: 99%

“…However, due to accumulated mutations, HERVs have preserved the features of their original provirus to a highly variable extent, ranging from the retention of a complete set of long terminal repeats (LTRs) and retroviral genes to the retention of only fragments of the parental viral genomes ( 20 , 21 , 23 ). Based on their sequences, HERVs are usually classified into groups ( 20 , 21 ). Precisely, their nomenclature refers to the single-letter amino acid code of the tRNA complementary to the primer binding site formerly used to prime reverse transcription ( 20 , 21 ).…”

mentioning

confidence: 99%

“…Based on their sequences, HERVs are usually classified into groups ( 20 , 21 ). Precisely, their nomenclature refers to the single-letter amino acid code of the tRNA complementary to the primer binding site formerly used to prime reverse transcription ( 20 , 21 ). Among them, the HERV-K family, which harbors the lysine tRNA binding site, includes some of the most recent HERVs acquired by humans around three million years ago, and it is commonly subdivided into 11 subgroups (HML-1 through HML-11) ( 24 – 28 ).…”

mentioning

confidence: 99%

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Expression signature of human endogenous retroviruses in chronic lymphocytic leukemia

Ferlita,

Nigita,

Tsyba

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Chronic lymphocytic leukemia (CLL) is one of the most diagnosed forms of leukemia worldwide and it is usually classified into two forms: indolent and aggressive. These two forms are characterized by distinct molecular features that drive different responses to treatment and clinical outcomes. In this context, a better understanding of the molecular landscape of the CLL forms may potentially lead to the development of new drugs or the identification of novel biomarkers. Human endogenous retroviruses (HERVs) are a class of transposable elements that have been associated with the development of different human cancers, including different forms of leukemias. However, no studies about HERVs in CLL have ever been reported so far. Here, we present the first locus-specific profiling of HERV expression in both the aggressive and indolent forms of CLL. Our analyses revealed several dysregulations in HERV expression occurring in CLL and some of them were specific for either the aggressive or indolent form of CLL. Such results were also validated by analyzing an external cohort of CLL patients and by RT-qPCR. Moreover, in silico analyses have shown relevant signaling pathways associated with them suggesting a potential involvement of the dysregulated HERVs in these pathways and consequently in CLL development.

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Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci

et al. 2023

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Transposable elements (TEs) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, which models the different steps of the tumorigenesis process. RNA-sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses (LTRs). Most differentially methylated regions (DMRs) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in TCGA datasets of breast, colon, and prostate cancer. Overall, these findings indicate that transposable elements, specifically endogenous retroviruses, are demethylated and transcribed during transformation.

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Transcriptome Analysis of Human Endogenous Retroviruses at Locus-Specific Resolution in Non-Small Cell Lung Cancer

Cited by 4 publications

References 59 publications

Target gene regulatory network of miR-497 in angiosarcoma

Target gene regulatory network of miR-497 in angiosarcoma

Expression signature of human endogenous retroviruses in chronic lymphocytic leukemia

Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci

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