A nanobody targeting the LIN28:let-7 interaction fragment of TUT4 blocks uridylation of let-7

Yu, Chenggang; Wang, Long; Rowe, R. Grant; Han, A-Reum; Ji, Wang; McMahon, Conor; Baier, Alexander; Huang, Yu-Chung; Marion, William; Pearson, Daniel S.; Kruse, Andrew C.; Daley, George Q.; Wu, Hao; Sliz, Piotr

doi:10.1073/pnas.1919409117

Cited by 16 publications

(14 citation statements)

References 43 publications

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“…This miRNA is a direct regulator of numerous genes involved in cell proliferation and differentiation, and it shows a tumor suppressor function for several oncogenes (e.g., RAS , MYC ), which may explain why a reduction in its expression in a variety of cancers has been associated with poor prognosis and increased epithelial-mesenchymal transition [ 43 , 44 , 45 , 46 ]. Due to its important role in both physiology and disease, miR-Let-7e is now considered a target for therapeutic drug development [ 47 ]. Two studies have reported a reduction of miR-Let-7e expression in the tissue of GC patients [ 48 , 49 ], and lower levels in GC patients with H. pylori infection than controls [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in Pepsinogen C and miRNA Genes Associate with High Serum Pepsinogen II in Gastric Cancer Patients

Zorzi

Caggiari

et al. 2021

Microorganisms

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Background: Pepsinogen (PG) II (PGII) is a serological marker used to estimate the risk of gastric cancer but how PGII expression is regulated is largely unknown. It has been suggested that PGII expression, from the PGC (Progastricsin) gene, is regulated by microRNAs (miRNA), but how PGII levels vary with Helicobacter pylori (H. pylori) infection and miRNAs genotype remains unclear. Methods: Serum levels of PGI and PGII were determined in 80 patients with gastric cancer and persons at risk for gastric cancer (74 first-degree relatives of patients, 62 patients with autoimmune chronic atrophic gastritis, and 2 patients with dysplasia), with and without H. pylori infection. As control from the general population, 52 blood donors were added to the analyses. Associations between PGII levels and genetic variants in PGC and miRNA genes in these groups were explored based on H. pylori seropositivity and the risk for gastric cancer. The two-dimensional difference in gel electrophoresis (2D-DIGE) and the NanoString analysis of messenger RNA (mRNAs) from gastric cancer tissue were used to determine the pathways associated with increased PGII levels. Results: PGII levels were significantly higher in patients with gastric cancer, and in those with H. pylori infection, than in other patients or controls. A PGI/PGII ratio ≤ 3 was found better than PGI < 25 ng/mL to identify patients with gastric cancer (15.0% vs. 8.8%). For two genetic variants, namely rs8111742 in miR-Let-7e and rs121224 in miR-365b, there were significant differences in PGII levels between genotype groups among patients with gastric cancer (p = 0.02 and p = 0.01, respectively), but not among other study subjects. Moreover, a strict relation between rs9471643 C-allele with H. pylori infection and gastric cancer was underlined. Fold change in gene expression of mRNA isolated from gastric cancer tissue correlated well with polymorphism, H. pylori infection, increased PGII level, and pathway for bacteria cell entry into the host. Conclusions: Serum PGII levels depend in part on an interaction between H. pylori and host miRNA genotypes, which may interfere with the cut-off of PGI/PGII ratio used to identify persons at risk of gastric cancer. Results reported new findings regarding the relation among H. pylori, PGII-related host polymorphism, and genes involved in this interaction in the gastric cancer setting.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in Pepsinogen C and miRNA Genes Associate with High Serum Pepsinogen II in Gastric Cancer Patients

Zorzi

Caggiari

et al. 2021

Microorganisms

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“…For example, nanobodies inhibiting PD1-PDL1 interaction, LIN28:let-7 interaction, and T cell marker CD3 are all promising candidates for targeting and activating cytotoxic T lymphocytes (CTLs) to induce anti-tumor responses. GRP78, CD38, and GPC3 expression on cancer cells have also been targeted for nanobody expression and purification, which provide useful cancer cell markers and potential therapeutic markers ( Aghamollaei et al, 2020 , p. 78; Hambach et al, 2020 ; Li et al, 2020 ; Moradi-Kalbolandi et al, 2020 ; L. L. Xia et al, 2020 ; S. Xia et al, 2020 ; C. J. Yu et al, 2020 ; C. Yu et al, 2020 ).…”

Section: Use Of Nanobodies Against Coronavirusesmentioning

confidence: 99%

“…Recently, Yu and colleagues reported that DNA vaccine encoding the SARS-CoV-2 S protein can protect rhesus macaques after challenge with SARS-CoV-2 (J. J. Yu et al, 2020 ; C. Yu et al, 2020 ). Currently, two SARS-CoV-2 DNA vaccines are under development.…”

Section: Dna Vaccinesmentioning

confidence: 99%

Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development

et al. 2020

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Highlights SARS-CoV-2 binds more strongly to ACE2 as compare to SARS-CoV. The viral Spike protein is most important target for vaccine design. Antibody dependent enhancement enhances the viral entry and replication in the host cell. Nanobody is alternative to avoid Antibody dependent enhancement. Different strategies for vaccine development. Spike protein-based vaccines.

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“…It was even proposed that miR-324 arm ratios may serve as a reporter for TUT4/7 activity in vivo and could be used for cancer diagnosis (28). In addition, the components of the LIN28:pre-let-7:TUTase complex are currently considered as targets for therapy (55) . Thus for miRNA therapeutics it is important to know whether the canonical sequence or one of its isomiRs is the functional molecule (56) .…”

Section: Discussionmentioning

confidence: 99%

Unbiased and UMI-informed sequencing of cell-free miRNAs at single-nucleotide resolution

Aparicio‐Puerta

Gómez-Martín

et al. 2021

Preprint

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Terminal nucleotidyl transferases are enzymes that add non-templated nucleotides to RNA molecules. In the case of microRNAs, this process was shown to be functionally relevant for their maturation process and generation of isomiRs with non-canonical mRNA targets. Deconvolution of these posttranscriptional modifications is challenging in particular for extracellular miRNAs that are considered as a target for minimally-invasive diagnostics. Massively parallel RNA sequencing is the only method that can truthfully reveal isomiR diversity in biological samples and determine relative quantities. Improvements aside, current small RNA sequencing strategies remain imprecise. We developed IsoSeek that diverges from these methods by making use of randomized 5’- and 3’-adapters combined with a 10N unique molecular identifier (UMI). Using synthetic miRNA and isomiR spike-in sets and testing depletion and RNA competition strategies in 7 sequencing rounds of >100 samples, we rigorously optimized and validated the technical accuracy of the IsoSeek method. In genetically-altered HEK293, we characterized the terminal uridylase (TUT4/TUT7) dependent miRNA uridylome and discovered extensive uridylation of disease-associated miRNAs. Notably, 3’-uridylated isomiR profiles of plasma extracellular vesicles (EVs) rely on UMI-correction. Thus, IsoSeek advances our knowledge of cell-free miRNAs and supports development into non-invasive biomarkers.

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A nanobody targeting the LIN28:let-7 interaction fragment of TUT4 blocks uridylation of let-7

Cited by 16 publications

References 43 publications

Polymorphisms in Pepsinogen C and miRNA Genes Associate with High Serum Pepsinogen II in Gastric Cancer Patients

Polymorphisms in Pepsinogen C and miRNA Genes Associate with High Serum Pepsinogen II in Gastric Cancer Patients

Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development

Unbiased and UMI-informed sequencing of cell-free miRNAs at single-nucleotide resolution

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