Erratum: CircZCCHC2 decreases pirarubicin sensitivity and promotes triple-negative breast cancer development via the miR-1200/TPR axis.

[This corrects the article DOI: 10.1016/j.isci.2024.109057.].

CircZCCHC2 decreases pirarubicin sensitivity and promotes triple-negative breast cancer development via the miR-1200/TPR axis.

Triple-negative breast cancer (TNBC) has attracted attention due to its poor prognosis and limited treatment options. The mechanisms underlying the association between circular RNAs (circRNAs) and the occurrence and development of TNBC remain unclear. CircZCCHC2 is observed to be upregulated in TNBC cells, tissues, and plasma exosomes. Knockdown of circZCCHC2 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of TNBC cells in vitro and in vivo. Pirarubicin (THP) treatment downregulated circZCCHC2, and circZCCHC2 affected the sensitivity to THP. CircZCCHC2/miR-1200/translocated promoter region, the nuclear basket protein (TPR) pathway was cascaded and verified. It is demonstrated that circZCCHC2 plays a crucial role in the malignant progression of TNBC via the miR-1200/TPR axis, thereby activating the RAS-RAF-MEK-ERK pathway. The present results indicate that circZCCHC2 has the potential to serve as a novel prognostic biomarker for TNBC.

Umifenovir Epigenetically Targets the IL-10 Pathway in Therapy against Coxsackievirus B4 Infection.

Umifenovir, a broad-spectrum nonnucleoside antiviral drug, has a promising efficacy against coxsackievirus B4 (CVB4) infection, but its mechanism remains unclear. CVB4 is a common human single-stranded RNA virus that belongs to the Picornaviridae family and the Enterovirus genus. Enterovirus can cause severe diseases, such as meningitis, myocarditis, pancreatitis, insulin-dependent diabetes, and several other diseases, in both adults and children. We have previously demonstrated the critical role of interleukin 10 (IL-10) in promoting CVB4 infection and the downregulation of IL-10 by umifenovir. To further explore the underlying mechanisms of umifenovir, we characterized the epigenetic regulation of IL-10 in IL-10 knockout RAW264.7 cells and a BALB/c mouse splenocyte model. Mechanistically, we found that umifenovir inhibited CVB4-activated IL-10 by enhancing the methylation level of the repressive histones H3K9me3 and H3K27me3 while reducing the acetylation level of the activating histone H3K9ac in the promoter region of the IL-10 gene. Furthermore, using a chromosome conformation capture approach, we discovered that CVB4 infection activated the IL-10 gene by forming an intrachromosomal interaction between the IL-10 gene promoter and an intronic enhancer of the downstream MK2 (mitogen-activated protein kinase [MAPK]-activated protein kinase 2 [MAPKAPK2]) gene, a critical component of the p38-MAPK signaling pathway, which is required for IL-10 gene expression. However, umifenovir treatment abolished this spatial conformation and chromatin interaction, thus reducing the continuous expression of IL-10 and subsequent CVB4 replication. In conclusion, this study reveals a novel epigenetic mechanism by which umifenovir controls CVB4 infections, thus laying a theoretical foundation for therapeutic use of umifenovir. IMPORTANCE Viral infections are major threats to human health because of their strong association with a variety of inflammation-related diseases, especially cancer. Many antiviral drugs are performing poorly in treating viral infections. This is probably due to the immunosuppressive effect of highly expressed IL-10, which is caused by viral infection. Umifenovir is a broad-spectrum antiviral drug. Our recent studies showed that umifenovir has a significant inhibitory effect on CVB4 infection and can reduce IL-10 expression caused by CVB4. However, another antiviral drug, rupintrivir, showed good antiviral activity but had no effect on the expression of IL-10. This suggests that the regulation of IL-10 expression is a key part of the antiviral mechanism of umifenovir. Therefore, due to the dual function of the inhibition of CVB4 replication and the regulation of immune antiviral pathway, the mechanism of umifenovir is of great value to study.

Direct MYD88L265P gene detection for diffuse large B-cell lymphoma (DLBCL) via a miniaturised CRISPR/dCas9-based sensing chip.

Traditional methods for single-nucleotide variants based on amplification and fluorescence signals require expensive reagents and cumbersome instruments, and they are time-consuming for each trial. Here, a porous anodised aluminium (PAA)-based sensing chip modified with deactivated Cas9 (dCas9) proteins and synthetic guide RNA (sgRNA) as the biorecognition receptor is developed, which can be used for the label-free sensing of the diffuse large B-cell lymphoma (DLBCL) MYD88L265P gene by integrating with electrochemical ionic current rectification (ICR) measurement. The sgRNA that can specifically identify and capture the MYD88L265P gene was screened, which has been proved to be workable to activate dCas9 for the target MYD88L265P. In the sensing process, the dCas9 proteins can capture the genome sequence, thus bringing negative charges over the PAA chip and correspondingly resulting in a variation in the ICR value due to the uneven transport of potassium anions through the ion channels of the PAA chip. The whole sensing can be finished within 40 min, and there is no need for gene amplification. The CRISPR/dCas9-based sensor demonstrates ultrasensitive detection performance in the concentration range of 50 to 200 ng µL-1 and it has been proved to be feasible for the genome sequence of patient tissues. This sensor shows the potential of targeting other mutations by designing the corresponding sgRNAs and expands the applications of CRISPR/dCas9 technology to the on-chip electrical detection of nucleic acids, which will be very valuable for rapid diagnosis of clinically mutated genes. This makes the hybrid CRISPR-PAA chip an ideal candidate for next-generation nucleic acid biosensors.

A Novel Type of PD-L1 Inhibitor rU1 snRNPA From Human-Derived Protein Scaffolds Library.

Three marketed anti-PD-L1 antibodies almost have severe immune-mediated side effects. The therapeutic effects of anti-PD-L1 chemical inhibitors are not satisfied in the clinical trials. Here we constructed human-derived protein scaffolds library and screened scaffolds with a shape complementary to the PD-1 binding domain of PD-L1. The RNA binding domain of U1 snRNPA was selected as one of potential binders because it had the most favorable binding energies with PD-L1 and conformed to pre-established biological criteria for the screening of candidates. The recombinant U1 snRNPA (rU1 snRNPA) in Escherichia coli exhibits anti-cancer activity in melanoma and breast cancer by reactivating tumor-suppressed T cells in vitro and anti-melanoma activity in vivo. Considering hydrophobic and electrostatic interactions, three residues were mutated on the interface of U1 snRNPA and PD-L1 complex, and the ranked variants by PatchDock and A32D showed an increased active phenotype. The screening of human-derived protein scaffolds may become the potential development of therapeutic agents.

Molecular Basis of Artemisinin Derivatives Inhibition of Myeloid Differentiation Protein 2 by Combined in Silico and Experimental Study.

Artemisinin (also known as Qinghaosu), an active component of the Qinghao extract, is widely used as antimalarial drug. Previous studies reveal that artemisinin and its derivatives also have effective anti-inflammatory and immunomodulatory properties, but the direct molecular target remains unknown. Recently, several reports mentioned that myeloid differentiation factor 2 (MD-2, also known as lymphocyte antigen 96) may be the endogenous target of artemisinin in the inhibition of lipopolysaccharide signaling. However, the exact interaction between artemisinin and MD-2 is still not fully understood. Here, experimental and computational methods were employed to elucidate the relationship between the artemisinin and its inhibition mechanism. Experimental results showed that artemether exhibit higher anti-inflammatory activity performance than artemisinin and artesunate. Molecular docking results showed that artemisinin, artesunate, and artemether had similar binding poses, and all complexes remained stable throughout the whole molecular dynamics simulations, whereas the binding of artemisinin and its derivatives to MD-2 decreased the TLR4(Toll-Like Receptor 4)/MD-2 stability. Moreover, artemether exhibited lower binding energy as compared to artemisinin and artesunate, which is in good agreement with the experimental results. Leu61, Leu78, and Ile117 are indeed key residues that contribute to the binding free energy. Binding free energy analysis further confirmed that hydrophobic interactions were critical to maintain the binding mode of artemisinin and its derivatives with MD-2.

Activation of FcRn Mediates a Primary Resistance Response to Sorafenib in Hepatocellular Carcinoma by Single-Cell RNA Sequencing.

Sorafenib is the first-line therapeutic option for advanced hepatocellular carcinoma (HCC). Many patients exhibit a primary resistance (PR) response after initial treatment. In previous studies, compared to acquired resistance, the mechanism of PR is unclear. The present study aimed to evaluate the response of patient samples to sorafenib by patient-derived xenograft (PDX) models, and the differences at the transcriptome level between the sorafenib PR group and the sorafenib sensitive group were analyzed by single-cell sequencing technology. A specific cell cluster may be differentiated by the liver bud hepatic cells, and the JUN transcription factors in this cell cluster were highly activated. The albumin is secreted by other cell clusters, and the cluster stimulates the FcRn complex receptor to activate the HIF pathway and cell proliferation, resulting in a poor response to sorafenib. These findings are validated by both cell communication analysis and experiments. Thus, the current studies provided a novel approach for the treatment of sorafenib-resistant HCC.