IndraLab

"Moreover, we found that five lncRNAs (RAET1E-AS1, LOC102723591, LOC105373230, LOC112267883, and LINC02595) and five circRNAs (hsa_circ_0017534, hsa_circ_0092630, hsa_circ_0080906, hsa_circ_0075045, and hsa_circ_0080909) were significantly upregulated in O-ASCs, compared with Y-ASCs (Fig. xref c)."

"We randomly selected hsa-miR-145-5p for further analysis; it had ceRNA relationships with four mRNAs (ITGB8, WNT11, BMPER, and RARRES3), two lncRNAs (RAET1E-AS1 and LOC102723591), and one circRNA (hsa_circ_0092630) (Fig. xref e)."

"Correlation analyses revealed that the expression levels of RAET1E-AS1, WNT11, and BMPER had significantly negative correlations with the expression level of hsa-miR-145-5p (Fig. xref g–i), while the other RNAs did not exhibit such relationships (Figure S xref C, D)."

"Interestingly, transcriptome-neuroimaging association analysis demonstrated the correlations between regional rSC-FC coupling variations between MDD patients and HCs and α/β-hydrolase domain-containing 6 (ABHD6), β 1,3-N-acetylglucosaminyltransferase-9(β3GNT9), transmembrane protein 45B (TMEM45B), the correlation between regional dSC-FC coupling variations and retinoic acid early transcript 1E antisense RNA 1(RAET1E-AS1), and the correlations between regional iSC-FC coupling variations and ABHD6, β3GNT9, katanin-like 2 protein (KATNAL2)."

"Furthermore, the expression level of RAET1E-AS1 had a significantly positive correlation with the expression levels of WNT11 and BMPER (Fig. xref j, k)."

"Finally, we found that overexpression of has-miR-145-5p in ASCs could significantly downregulated the expression levels of WNT11, BMPER, RAET1E-AS1, LOC102723591, and hsa_circ_0092630 (Fig. xref l)."

"RAET1E-AS1 and LINC02145 were not expressed in this cell line, as confirmed in RNA-seq data of D425 cells in the CCMA database [ xref ] (expression 0 or < 1 CPM)."

"However, the role of the lncRNA RAET1E-AS1 in cell biology has not been explored."

"RAET1E-AS1 and LINC02145 were not expressed in this cell line, as confirmed in RNA-seq data of D425 cells in the CCMA database [ xref ] (expression 0 or < 1 CPM)."

"According to both the data from GEPIA () and TCGA (), we unveiled that the expression of LINC01559, LINC00483, LINC01296, RAET1E-AS1 and PCED1B-AS1 was significantly high in STAD (stomach adenocarcinoma) tissues in contrast with normal gastric tissues (Fig. xref , Supplementary Fig. xref )."

"ULBP4-NKG2D interaction can not only activate NK cell and NK-mediated cytotoxicity [ xref , xref , xref ], but also serve to stimulate the cytotoxicity of CD8+ T cell [ xref ], which suggests an influence of ULBP4 on both innate and adaptive immune responses."

"In addition, the receptor–ligand analysis using the CellPhoneDB database illustrated that the strength of the interaction between NKG2DLs, including MICB (Micb) and RAET1E (Raet1e), of NP cells and the NKG2D of the identified other cells, was increased at 8 w post‐puncture (Figure 2G)."

"RAET1E binds and activates NKG2D-expressing NK and CD8 T cells, with RAET family members typically absent on normal cells but overexpressed under stress."

"It is intriguing that ULBP-4 and hMSH2 can also bind to NKG2D to induce the cytotoxicity of Vgamma9Vdelta2-T cells against tumor cells through TCR and NKG2D engagement."

"However, it is noteworthy that high expression of ULBP2 and ULBP4 has been paradoxically associated with poor prognosis in ovarian cancer, and it does not appear to be related to an increase of the shedding of these molecules ( xref , xref )."

"RAET1E ∗ 002 was more associated RAET1H ∗ 002 and RAET1E ∗ 005 was associated with RAET1L ∗ 002."

"We also show that ULBP4 binds to a soluble chimeric protein containing TCRgamma9 and delta2 and activates TCR (-) Jurkat T cells transfected with TCRgamma9 and delta2."

"ULBP4 also can bind to Vγ9Vδ2 TCR and thus induce the cytotoxic activity of Vγ9Vδ2T cells toward tumor cells through both TCR and NKG2D engagement ( xref )."

"They can be activated by γδ TCR ligands such as phosphoantigens, or by MHC-associated ligands of the activatory receptor killer cell lectin-like receptor subfamily K, member 1 (KLRK1, best known as NKG2D, such as MHC class I polypeptide-related sequence A (MICA), MICB, and various members of the UL16-binding protein (ULBP) family. γδ T cells also express killer-cell immunoglobulin-like receptors (KIRs), which can be either activatory or inhibitory, including killer cell immunoglobulin-like receptor, 2 domains, long cytoplasmic tail, 1 (KIR2DL1) xref and killer cell immunoglobulin-like receptor, 3 domains, long cytoplasmic tail, 1 (KIR3DL1). xref Tumors possess the ability to manipulate this balance to stimulate tolerance by inhibitory signals, including soluble NKG2D ligands, transforming growth factor β1 (TGFβ1), galectin 3 and prostaglandin E 2 (PGE 2 ) xref , xref , xref , xref Elevated circulating levels of sMICA, sMICB, and sULBP1 might be particularly active against effector γδ T cells, as the latter express high amounts of NKG2D. Of interest, the NKG2D ligand ULBP4 may bind to the TCR of some γδ T-cell subsets, and this may exacerbate their inhibition by neuroblastoma cells. xref "

"Of interest, the NKG2D ligand ULBP4 may bind to the TCR of some gammadelta T-cell subsets, and this may exacerbate their inhibition by neuroblastoma cells."

"However, it is noteworthy that high expression of ULBP2 and ULBP4 has been paradoxically associated with poor prognosis in ovarian cancer, and it does not appear to be related to an increase of the shedding of these molecules ( xref , xref )."

"RAET1E ∗ 002 was more associated RAET1H ∗ 002 and RAET1E ∗ 005 was associated with RAET1L ∗ 002."

"We also show that ULBP4 binds to a soluble chimeric protein containing TCRgamma9 and delta2 and activates TCR (-) Jurkat T cells transfected with TCRgamma9 and delta2."

"ULBP4 also can bind to Vγ9Vδ2 TCR and thus induce the cytotoxic activity of Vγ9Vδ2T cells toward tumor cells through both TCR and NKG2D engagement ( xref )."

"They can be activated by γδ TCR ligands such as phosphoantigens, or by MHC-associated ligands of the activatory receptor killer cell lectin-like receptor subfamily K, member 1 (KLRK1, best known as NKG2D, such as MHC class I polypeptide-related sequence A (MICA), MICB, and various members of the UL16-binding protein (ULBP) family. γδ T cells also express killer-cell immunoglobulin-like receptors (KIRs), which can be either activatory or inhibitory, including killer cell immunoglobulin-like receptor, 2 domains, long cytoplasmic tail, 1 (KIR2DL1) xref and killer cell immunoglobulin-like receptor, 3 domains, long cytoplasmic tail, 1 (KIR3DL1). xref Tumors possess the ability to manipulate this balance to stimulate tolerance by inhibitory signals, including soluble NKG2D ligands, transforming growth factor β1 (TGFβ1), galectin 3 and prostaglandin E 2 (PGE 2 ) xref , xref , xref , xref Elevated circulating levels of sMICA, sMICB, and sULBP1 might be particularly active against effector γδ T cells, as the latter express high amounts of NKG2D. Of interest, the NKG2D ligand ULBP4 may bind to the TCR of some γδ T-cell subsets, and this may exacerbate their inhibition by neuroblastoma cells. xref "

"Of interest, the NKG2D ligand ULBP4 may bind to the TCR of some gammadelta T-cell subsets, and this may exacerbate their inhibition by neuroblastoma cells."

"Reply : For clarification , we amended the text as follows : '' The lack of knowledge on ULBP4 is in part due to the scarcity of reliable detection reagents , since there are only a few `` ULBP4-specific '' antibodies commercially available with some even showing cross-reactivity to undefined antigen ( s ) on cells not containing ULBP4 transcripts ( Zoller et al ., 2018 ) ."

"The lack of knowledge on ULBP4 is in part due to the scarcity of reliable detection reagents , since there are only a few `` ULBP4-specific '' antibodies commercially available with some even showing cross-reactivity to undefined antigen ( s ) on cells not containing ULBP4 transcripts [ 32 ] ."

"Consistent with these findings, we observed that the chemical HDAC inhibitor butyrate activated the WT Raet1e promoter (XREF_FIG)."

"Interestingly, butyrate treatment failed to drive expression from the m18RE * mutant Raet1e promoter (XREF_FIG)."

"Intriguingly, although the results of our multivariate analysis were not significant, in univariate analysis, high RAET1E or RAET1G expression was associated with poor disease-free survival (Table  xref )."

"Given the results of Cao et al.’s study and the fact that many isoforms were also stained during RAET1E and RAET1G IHC staining, it is possible that high RAET1E and RAET1G expression may be associated with poor prognosis."

"Our results indicate that Letal promotes tumor immune surveillance by promoting the survival and intratumoral expansion of antitumor cytotoxic lymphocytes."

"These results suggest that Letal delivers activating signals to NK cells and promotes tumor immune surveillance by inducing the expansion of anti-tumor cytotoxic lymphocytes."

"Simultaneous T-cell receptor activation and engagement of Letal stimulated proliferation of CD8 (+) cells and dramatically increased IL-2 and IFNgamma secretion."

"Here we show that immobilized soluble ULBP4 (rULBP4) induces the proliferation of human ovarian epithelial carcinoma- or colonic carcinoma derived Vdelta2 (+) T cells in vitro."

"Intriguingly, although the results of our multivariate analysis were not significant, in univariate analysis, high RAET1E or RAET1G expression was associated with poor disease-free survival (Table  xref )."

"Given the results of Cao et al.’s study and the fact that many isoforms were also stained during RAET1E and RAET1G IHC staining, it is possible that high RAET1E and RAET1G expression may be associated with poor prognosis."

"Also, TIL but not PBL from paired patients, expressed MICA, ULBP3 and ULBP4 on their cell surface, suggesting that local mechanisms operating in the TME might trigger NKG2DL expression on TIL."

"An analysis of the expression of NKG2DLs on lymphoid cells revealed that TIL, but not PBL from either ccRCC patients or HD, expressed MICA (Figures 4 A and b), ULBP3 (Figures 4 C and d) and ULBP4 (Figures 4 E and f), suggesting that the TME promotes NKG2DL expression on TIL."

"Simultaneous T-cell receptor activation and engagement of Letal stimulated proliferation of CD8 (+) cells and dramatically increased IL-2 and IFNgamma secretion."

"As shown earlier, the intermediate cells had the highest expression of genes involved in co-stimulation and antigen presentation, but also genes involved in NK cell and CD8 T cell activation, such as MICB, RAET1E, RAET1G, RAET1L and ULBP3 were enriched on intermediate monocytes."

"Other human γδT cells recognize stress-induced MIC, ULBP4, or endothelial protein C receptor."

"The transcription of Raet1e was inhibited by the transcription factor JUNB in cell lines and mouse tissues XREF_BIBR."

"Simultaneous T-cell receptor activation and engagement of Letal stimulated proliferation of CD8 (+) cells and dramatically increased IL-2 and IFNgamma secretion."

"In contrast , our self-made mAb DUMO1 specifically binds to ULBP4-transfected cell lines ( but not mock-transfected cells ) and recombinantly produced ULBP4 , but does not bind to cells that do NOT contain ULBP4 / RAET1E transcripts such as HepG2 cells or human monocytes ( see Zoller et al ., 2018 and our present manuscript ) ."

"We also confirmed the specificity of ULBP4 detection as preabsorption of the anti-ULBP4 antibody with the rhULBP4 abolished ULBP4 detection from protein lysates (data not shown)."

"EBV LMP2A reduces MICA and ULBP4 in lymphoblastoid cell lines and inhibits recognition by CD8+ T cells [XREF_BIBR], and this allows it to block its recognition and destruction by NK cells."

"To determine whether the ULBP4 protein is transmembrane or GPI linked, cells expressing the transiently transfected ULBP4 or MICB or ULBP3 were treated with phosphatidylinositol specific phospholipase[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"Unlike ULBP1 and ULBP2, ULBP4 is not bound by the name-giving HCMV glycoprotein UL16 [ xref , xref ], and therefore ULBP4 can be considered as a misnomer."

"Overexpression of the NKG2D ligands ULBP1 and ULBP4 by hematological and epithelial tumors, respectively, drives efficient cytotoxic responses by Vgamma9Vdelta2 T-cells."

"However, UL16 is unable to bind to MICA, ULBP3, and ULBP4."

"The NKG2D ligand ULBP4 binds to TCRgamma9 and delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D."

"The Raet1e promoter is repressed by HDAC3 in an Sp dependent manner."

"In addition, we showed that HCQ did not affect the synthesis or degradation of ULBP4, but induced the translocation of ULBP4 from the cytoplasm to the cell membrane."

"Overexpression of the ULBP1 and ULBP4 on the leukemia, lymphoma and epithelial tumors, respectively, induces cytotoxicity of Vγ9Vδ2 T cells to tumor cells [42]."

"RAET1E belongs to a ligand family for NKG2D in humans and can produce a soluble , 35-kDa protein ( named RAET1E2 ) in tumor cells ."

"RAET1E belongs to a ligand family for NKG2D in humans and can produce a soluble, 35-kDa protein (named RAET1E2) in tumor cells."

"E2F overexpression was sufficient to activate endogenous Raet1 genes in cells as well as a luciferase reporter construct driven by the Raet1e promoter."

"Unlike ULBP1 and ULBP2, ULBP4 is not bound by the name-giving HCMV glycoprotein UL16 [ xref , xref ], and therefore ULBP4 can be considered as a misnomer."

"We then transiently knocked down the expression of Raet1e via siRNA inUbr5 - / -4 T1 tumor ( Figure 5b ) , which , when implanted in mice , caused a partial reversal of the inhibited growth of the parental tumor ( Figure 5c ) , but did not alter thein vitro growth rates ( Figure S1E ) , suggesting that higher Raet1e expression may mediate an adverse response against the tumor and that UBR5 deficiency in tumor cells may generate immunogens that attract anti-tumor responses.Upregulated proteins inUbr5 - / -4 T1 tumor.Potential immunogens and interacting partners controlled by UBR5 ."

"However, UL16 is unable to bind to MICA, ULBP3, and ULBP4."

"The NKG2D ligand ULBP4 binds to TCRgamma9 and delta2 and induces cytotoxicity to tumor cells through both TCRgammadelta and NKG2D."

"It has been shown to function as a ligand for both TCRgamma9delta2and NKG2D through which Raet1e induces T cell-mediated cytotoxicity to tumor cells.18Decreased Raet1e expression is a poor prognostic marker in nasopharyngeal carcinoma ,19 whereas high expression of Raet1e is an indicator of good prognosis in cervical cancer.20We first confirmed the MS finding of Raet1e 's overexpression by Western blot in WT and inUbr5 - / - cells treated with the proteasome inhibitor MG132 ( Figure 5a ) , which also indicated that Raet1e protein level was indeed regulated by a proteasome-mediated mechanism ."

"Although E2F sites in the Raet1e promoter have been shown to drive RAE-1 expression during proliferation, these sites were dispensable for activation of the Raet1e promoter by m18 (XREF_FIG)."

"Ligands for NKG2D include MICA , ULBP4 , and ULBP1 , which are implicated in NKG2D mediated recognition of multiple cancers 8, 9 ."

"In other words , RAET1E might impair NKG2D-mediated NK cell cytotoxicity to tumors [ 43 ] ."

"Altered Expression of Raet1e, a Major Histocompatibility Complex Class 1 Like Molecule, Underlies the Atherosclerosis Modifier Locus Ath11 10b."

"However, UL16 is unable to bind to MICA, ULBP3, and ULBP4."

"The data suggest that a soluble form of ULBP4, which is enriched in the CSF of female patients with MS, can enhance the production of GM-CSF and IFNγ by activated human CD8 T lymphocytes."

"Blocking one of these pathways could only induce minor inhibitory effect on degranulation of Vγ9Vδ2 T cells and cytotoxicity to EL4-ULBP4 + cells, but almost completely inhibited IFNγ production by Vγ9Vδ2 T cells."

"Letal also down-regulated the expression of Fas in CD8+ cells and rendered them resistant to Fas ligand induced apoptosis."

"An investigation of the roles of factors known to regulate the cell cycle showed that E2F1–3, the activating E2F transcription factors, bind to the Raet1e promoter in vivo and transactivate the endogenous Raet1e gene as well as the Raet1e promoter in a reporter plasmid."

"Collectively, the data demonstrate that E2F transcription factors bind and transactivate the Raet1e promoter, play an important role in supporting Raet1 transcription in proliferating cells, and function potentially redundantly in driving Raet1 transcription."

"While ULBP4 specific pAb and mAb 709116 bound ststULBP4_im and ULBP4 transfectants similarly to DUMO1, we did not detect binding of mAb 6E6 neither to ststULBP_im nor to the ULBP4 transfectants by flow cytometry, although mAb 6E6 brightly detected denatured ststULBP4 in immunoblotting (data not shown)."

"It remains unclear, however, whether AP-1 acts directly on the Raet1e gene to repress transcription or by an indirect mechanism that alters Raet1e transcription or mRNA stability."

"Altered Expression of Raet1e, a Major Histocompatibility Complex Class 1 Like Molecule, Underlies the Atherosclerosis Modifier Locus Ath11 10b."

"Reduction of the lncRNA RAET1E-AS indicated that less miRNA sponges were free to interact with miR-145-5p, therefore, overexpression of miRNAs could promote cell proliferation and rejuvenate cellular senescence."

"While ULBP4 specific pAb and mAb 709116 bound ststULBP4_im and ULBP4 transfectants similarly to DUMO1, we did not detect binding of mAb 6E6 neither to ststULBP_im nor to the ULBP4 transfectants by flow cytometry, although mAb 6E6 brightly detected denatured ststULBP4 in immunoblotting (data not shown)."

"Collectively, the presented data exclude that ULBP4 is expressed by human monocytes under normal conditions and upon activation by PAMP."

"Position 82 is polymorphic and occupied either by asparagine (stULBP4) or tyrosine (Uniprot reference sequence at), and therefore ULBP4 glycosylation can be expected to be variable within the human population with potential consequences for expression and detection."

"Stimulation of MKN45 cells with HKHP increased MICA , ULBP4 ( another NKG2DL ) , and TLR4 at the protein and transcriptional levels ."

"Also in accordance with our data, it was shown that the LMP2A latency protein of EBV, which activates signaling pathways to promote the proliferation of latently infected cells, induces MICA and MICB expression at the transcriptional level, while, on the other hand, reducing the cell-surface expression of both MIC proteins and ULBP4 through mechanisms that have not been identified as yet (30, 48)."

"However, UL16 is unable to bind to MICA, ULBP3, and ULBP4."

"To measure the quantity of different soluble NKG2D ligands in cell culture supernatants and serum samples, we used multiplexed ELISAs, namely, the Human Luminex Discovery Assay (R&D Systems), which allows quantitation of MIC-A, MIC-B, ULBP-1, ULBP-2/5/6, ULBP-3, and ULBP-4."

"The Raet1e promoter is repressed by HDAC3 in an Sp dependent manner."

"Treatment of glioma cells with the catalytic LSD1 inhibitors tranylcypromine (TCP) or GSK LSD1 was able to increase MICB and ULBP4 expression, enhancing human NK-cell mediated lysis of the target cells (137)."

"Protein–protein interaction analysis showed that the top 10 proteins associated with the HCST included TYROBP, KLRC4, MICA, MICB, ULBP3, ULBP1, RAET1E, GRB2, KLRK1, and PIK3R1, which are mainly involved in the immune response and tumorigenesis."

"Blocking one of these pathways could only induce minor inhibitory effect on degranulation of Vγ9Vδ2 T cells and cytotoxicity to EL4-ULBP4 + cells, but almost completely inhibited IFNγ production by Vγ9Vδ2 T cells."

"Therefore, the inhibition of EZH2 leads to HCC cell eradication via NKs by upregulating expression of ULBP3 and ULBP4 in tumor cells."

"Consistent with these findings, we observed that the chemical HDAC inhibitor butyrate activated the WT Raet1e promoter (XREF_FIG)."

"Collectively, the data demonstrate that E2F transcription factors bind and transactivate the Raet1e promoter, play an important role in supporting Raet1 transcription in proliferating cells, and function potentially redundantly in driving Raet1 transcription."

"While ULBP4 specific pAb and mAb 709116 bound ststULBP4_im and ULBP4 transfectants similarly to DUMO1, we did not detect binding of mAb 6E6 neither to ststULBP_im nor to the ULBP4 transfectants by flow cytometry, although mAb 6E6 brightly detected denatured ststULBP4 in immunoblotting (data not shown)."

"FGF4, CYP19A1, PTPN2, CYP3A4, SERPINE2, SOX18, MMP20, MASP1, KLF2, ERP44, NUAK1 and RAET1E are directly associated with SCC."

"The results showed that knockdown of CRNDE increased DUSP5, CDKN1A, EMP1, RAET1E, and CDKN2B expression, but decreased RPL23A, EIF4E2, QPRT, ACSS1, and APCDD1 expression (XREF_FIG)."

"In addition, Letal induced the killing of cancer cells by CD8 (+) and NK cells."

"Reduction of the lncRNA RAET1E-AS indicated that less miRNA sponges were free to interact with miR-145-5p, therefore, overexpression of miRNAs could promote cell proliferation and rejuvenate cellular senescence."

"While ULBP4 specific pAb and mAb 709116 bound ststULBP4_im and ULBP4 transfectants similarly to DUMO1, we did not detect binding of mAb 6E6 neither to ststULBP_im nor to the ULBP4 transfectants by flow cytometry, although mAb 6E6 brightly detected denatured ststULBP4 in immunoblotting (data not shown)."