scholarly journals Human Endogenous Retrovirus K Rec Forms a Regulatory Loop with MITF that Opposes the Progression of Melanoma to an Invasive Stage

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1303 ◽  
Author(s):  
Manvendra Singh ◽  
Huiqiang Cai ◽  
Mario Bunse ◽  
Cédric Feschotte ◽  
Zsuzsanna Izsvák
Keyword(s):  
Target Genes ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Mrna Levels ◽  
Long Terminal Repeats ◽  
Normal Tissues ◽  
E Box ◽  
Regulatory Loop ◽  
Species Specific

The HML2 subfamily of HERV-K (henceforth HERV-K) represents the most recently endogenized retrovirus in the human genome. While the products of certain HERV-K genomic copies are expressed in normal tissues, they are upregulated in several pathological conditions, including various tumors. It remains unclear whether HERV-K(HML2)-encoded products overexpressed in cancer contribute to disease progression or are merely by-products of tumorigenesis. Here, we focus on the regulatory activities of the Long Terminal Repeats (LTR5_Hs) of HERV-K and the potential role of the HERV-K-encoded Rec in melanoma. Our regulatory genomics analysis of LTR5_Hs loci indicates that Melanocyte Inducing Transcription Factor (MITF) (also known as binds to a canonical E-box motif (CA(C/T)GTG) within these elements in proliferative type of melanoma, and that depletion of MITF results in reduced HERV-K expression. In turn, experimentally depleting Rec in a proliferative melanoma cell line leads to lower mRNA levels of MITF and its predicted target genes. Furthermore, Rec knockdown leads to an upregulation of epithelial-to-mesenchymal associated genes and an enhanced invasion phenotype of proliferative melanoma cells. Together these results suggest the existence of a regulatory loop between MITF and Rec that may modulate the transition from proliferative to invasive stages of melanoma. Because HERV-K(HML2) elements are restricted to hominoid primates, these findings might explain certain species-specific features of melanoma progression and point to some limitations of animal models in melanoma studies.

scholarly journals Human Endogenous Retrovirus K Rec forms a regulatory loop with MITF that opposes the progression of melanoma to an invasive stage

2020 ◽  
Author(s):  
Manvendra Singh ◽  
Huiqiang Cai ◽  
Mario Bunse ◽  
Cédric Feschotte ◽  
Zsuzsanna Izsvák
Keyword(s):  
Target Genes ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Mrna Levels ◽  
Long Terminal Repeats ◽  
Normal Tissues ◽  
E Box ◽  
Regulatory Loop ◽  
Species Specific

AbstractThe HML2 subfamily of HERV-K (henceforth HERV-K) represents the most recently endogenized retrovirus in the human genome. While the products of certain HERV-K genomic copies are expressed in normal tissues, they are upregulated in a number of pathological conditions, including various tumours. It remains unclear whether HERV-K(HML2)-encoded products overexpressed in cancer contribute to disease progression or are merely by-products of tumorigenesis. Here, we focus on the regulatory activities of the Long Terminal Repeats (LTR5_Hs) of HERV-K and on the potential role of the HERV-K-encoded Rec in melanoma. Our regulatory genomics analysis of LTR5_Hs loci indicates that Melanocyte Inducing Transcription Factor (MITF) binds to a canonical E-box motif (CA(C/T)GTG) within these elements in proliferative type of melanoma, and that depletion of MITF results in reduced HERV-K expression. In turn, experimentally depleting Rec in a proliferative melanoma cell line leads to lower mRNA levels of MITF and its predicted target genes. Furthermore, Rec knockdown leads to an upregulation of epithelial-to-mesenchymal associated genes and to an enhanced invasion phenotype of proliferative melanoma cells. Together these results suggest the existence of a regulatory loop between MITF and Rec that may modulate the transition from proliferative to invasive stages of melanoma. Because HERV-K(HML2) elements are restricted to hominoid primates, these findings might explain certain species-specific features of melanoma progression and point to some limitations of animal models in melanoma studies.

scholarly journals Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue

2010 ◽  
Vol 17 (1) ◽  
pp. 135-146 ◽  
Author(s):  
S Corbetta ◽  
V Vaira ◽  
V Guarnieri ◽  
A Scillitani ◽  
C Eller-Vainicher ◽  
...  
Keyword(s):  
Target Genes ◽  
Parathyroid Tissue ◽  
Growth Factor Receptor ◽  
Mrna Levels ◽  
Aberrant Expression ◽  
Kinase Substrate ◽  
Normal Tissues ◽  
New Class ◽  
Parathyroid Adenomas

Parathyroid carcinoma (PaC) is a rare cause of primary hyperparathyroidism. Though the loss of the oncosuppressor CDC73/HRPT2 gene product, parafibromin, has been involved in the hyperparathyroidism–jaw tumor syndrome and in a consistent set of sporadic PaCs, parathyroid carcinogenesis remains obscure. MicroRNAs are a new class of small, non-coding RNAs implicated in development of cancer, since their deregulation can induce aberrant expression of several target genes. The aim of the present study was to identify differentially expressed microRNAs in parathyroid cancers compared with normal tissues. We performed a TaqMan low-density array profiling of four parathyroid cancers harboring CDC73 inactivating mutations and negative for parafibromin immunostaining. Their microRNA profiling was compared with that of two normal parathyroid biopsies. Out of 362 human microRNAs assayed, 279 (77%) were successfully amplified. Fourteen and three microRNAs were significantly down- and over-expressed in parathyroid cancers respectively. Of these, miR-296 and miR-139 were down-regulated, and miR-503 and miR-222 were over-expressed with a null false discovery rate. Carcinomas could be discriminated from parathyroid adenomas by a computed score based on the expression levels of miR-296, miR-222, and miR-503 as miR-139 was similarly down-regulated in both cancers and adenomas. Finally, miR-296 and miR-222 levels negatively correlated with mRNA levels of the hepatocyte growth factor receptor-regulated tyrosine kinase substrate and p27/kip1 levels respectively. These results suggest the existence of an altered microRNA expression pattern in PaCs together with a potential role of miR-296 as novel oncosuppressor gene in these neoplasia.

scholarly journals Paleogenomic Record of the Extinction of Human Endogenous Retrovirus ERV9

2005 ◽  
Vol 79 (11) ◽  
pp. 6997-7004 ◽  
Author(s):  
Paula López-Sánchez ◽  
Javier C. Costas ◽  
Horacio F. Naveira
Keyword(s):  
Human Genome ◽  
Endogenous Retrovirus ◽  
Ancestral Population ◽  
Human Endogenous Retrovirus ◽  
Long Terminal Repeats ◽  
The Family ◽  
Species Specific ◽  
Outstanding Question ◽  
Analytical Tools ◽  
Single Sequence

ABSTRACT An outstanding question of genome evolution is what stops the invasion of a host genome by transposable elements (TEs). The human genome, harboring the remnants of many extinct TE families, offers an extraordinary opportunity to investigate this problem. ERV9 is an endogenous retrovirus repeatedly mobilized during primate evolution, 15 to 6 million years ago (MYA), which left a trace of over a hundred provirus-like copies and at least 4,000 solitary long terminal repeats (LTRs) in the human genome. Then, its proliferation ceased for unknown reasons, and the family went extinct. We have made a detailed reconstruction of its last active subfamily, ERV9_XII, by examining 115 solitary LTRs from it. These insertions were grouped into 11 sets according to shared nucleotide variants, which could be placed in a sequential order of 10 to 6 MYA. At least 75% of the subfamily was produced 8 to 6 MYA, during a stage of intense proliferation. With new analytical tools, we show that the youngest and most prolific sets may have been produced by effectively instantaneous expansions of corresponding single-sequence variants. The extinction of this family apparently was not a consequence of its slow gradual degeneration, but the outcome of the fixation of specific restrictive alleles in the human-chimpanzee ancestral population. Three species-specific insertions (two in humans and one in chimpanzees) were identified, further supporting that extinction took place when these two species were beginning to diverge. These are the only fixed differences of this kind so far observed between humans and chimpanzees, apart from those belonging to the human endogenous retrovirus K family.

scholarly journals The Role of the FOXO1/β2-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

2021 ◽  
Vol 22 (3) ◽  
pp. 1478
Author(s):  
Jiayin Lu ◽  
Yaoxing Chen ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Restraint Stress ◽  
Target Genes ◽  
Mrna Levels ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Pregnant Mice

Restraint stress causes various maternal diseases during pregnancy. β2-Adrenergic receptor (β2-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β2-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β2-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β2-AR, and even the protein levels of FOXO1 and β2-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β2-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β2-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women.

scholarly journals Potential prognostic value of PD-L1 and NKG2A expression in Indonesian patients with skin nodular melanoma

2021 ◽  
Author(s):  
Ridwan Dwi Saputro ◽  
Hanggoro Tri Rinonce ◽  
Yayuk Iramawasita ◽  
Muhammad Rasyid Ridho ◽  
Maria Fransiska Pudjohartono ◽  
...  
Keyword(s):  
Target Genes ◽  
Therapy Response ◽  
Mrna Levels ◽  
Independent Predictive Factor ◽  
Clinicopathologic Characteristics ◽  
Tissue Samples ◽  
Nodular Melanoma ◽  
Expression Levels ◽  
Melanoma Tissue

Abstract Objective Biomarker mRNA levels have been suggested to be predictors of patient survival and therapy response in melanoma cases. This study aimed to investigate the correlations between the mRNA expression levels of PD-L1 and NKG2A in melanoma tissue and clinicopathologic characteristics and survival in Indonesian patients with primary nodular melanoma. Results Thirty-two tissue samples were analyzed. Upregulated PD-L1 was associated with shorter overall survival (hazard ratio: 2.930; 95% confidence interval: 1.011–8.489, p = 0.048) compared with patients with normoregulated PD-L1. A significant positive correlation was found between the expression levels of PD-L1 and NKG2A (rs: 0.768, p < 0.001). However, no clinicopathologic associations with PD-L1 and NKG2A mRNA levels were statistically proven. Comparison with other studies suggested that the choice of adjuvant therapy and the presence of TILs affect the prognostic role of PD-L1 expression. NKG2A was not proven to be an independent predictive factor but may become an adjunct target for therapy. The strong correlation between PD-L1 and NKG2A suggests that anti-PD-1 and anti-NKG2A agents could be effective in patients with PD-L1 upregulation. The combination of the mRNA levels of these two target genes may provide a novel prognostic and therapeutic direction for immunotherapy.

Abstract C03: Role of human endogenous retrovirus-K in phenotype-switching of metastatic melanoma cells during microenvironment alterations

2016 ◽  
Author(s):  
Ayele Argaw-Denboba ◽  
Emanuela Balestrieri ◽  
Annalucia Serafino ◽  
Ilaria Bucci ◽  
Chiara Cipriani ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Melanoma Cells ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Phenotype Switching

scholarly journals Human endogenous retrovirus-W envelope (syncytin) is expressed in both villous and extravillous trophoblast populations

2006 ◽  
Vol 87 (7) ◽  
pp. 2067-2071 ◽  
Author(s):  
A. Muir ◽  
A. M. L. Lever ◽  
A. Moffett
Keyword(s):  
Cell Lines ◽  
First Trimester ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Extravillous Trophoblast ◽  
Human Endogenous Retrovirus ◽  
Human Trophoblast ◽  
Human Endogenous Retroviruses ◽  
Normal Tissues ◽  
Villous Trophoblast

The placenta is unique amongst normal tissues in transcribing numerous different human endogenous retroviruses at high levels. In this study, RT-PCR and immunohistochemistry were used to investigate the expression of syncytin in human trophoblast. Syncytin transcripts were found in first-trimester trophoblast cells with both villous and extravillous phenotypes and also in the JAR and JEG-3 choriocarcinoma cell lines. Syncytin protein was detected in villous trophoblast and in all extravillous trophoblast subpopulations of first- and second-trimester placental tissues. It was also present in ectopic trophoblast from tubal implantations. This study confirms that syncytin is expressed widely by a variety of normal human trophoblast populations, as well as choriocarcinoma cell lines.

scholarly journals Human Endogenous Retrovirus HERV-K14 Families: Status, Variants, Evolution, and Mobilization of Other Cellular Sequences

2005 ◽  
Vol 79 (5) ◽  
pp. 2941-2949 ◽  
Author(s):  
Aline Flockerzi ◽  
Stefan Burkhardt ◽  
Werner Schempp ◽  
Eckart Meese ◽  
Jens Mayer
Keyword(s):  
Human Genome ◽  
Germ Line ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Long Terminal Repeats ◽  
Essential Information ◽  
Human Endogenous Retroviruses ◽  
Consensus Sequences

ABSTRACT The human genome harbors many distinct families of human endogenous retroviruses (HERVs) that stem from exogenous retroviruses that infected the germ line millions of years ago. Many HERV families remain to be investigated. We report in the present study the detailed characterization of the HERV-K14I and HERV-K14CI families as they are represented in the human genome. Most of the 68 HERV-K14I and 23 HERV-K14CI proviruses are severely mutated, frequently displaying uniform deletions of retroviral genes and long terminal repeats (LTRs). Both HERV families entered the germ line ∼39 million years ago, as evidenced by homologous sequences in hominoids and Old World primates and calculation of evolutionary ages based on a molecular clock. Proviruses of both families were formed during a brief period. A majority of HERV-K14CI proviruses on the Y chromosome mimic a higher evolutionary age, showing that LTR-LTR divergence data can indicate false ages. Fully translatable consensus sequences encoding major retroviral proteins were generated. Most HERV-K14I loci lack an env gene and are structurally reminiscent of LTR retrotransposons. A minority of HERV-K14I variants display an env gene. HERV-K14I proviruses are associated with three distinct LTR families, while HERV-K14CI is associated with a single LTR family. Hybrid proviruses consisting of HERV-K14I and HERV-W sequences that appear to have produced provirus progeny in the genome were detected. Several HERV-K14I proviruses harbor TRPC6 mRNA portions, exemplifying mobilization of cellular transcripts by HERVs. Our analysis contributes essential information on two more HERV families and on the biology of HERV sequences in general.

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