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Anti-angiogenesis is an important and promising strategy in cancer therapy. However, the current methods using anti-vascular endothelial growth factor A (VEGFA) antibodies or inhibitors targeting VEGFA receptors are not as efficient as expected partly due to their low efficiencies in blocking VEGFA signaling . Until now, there is still no method to effectively block VEGFA production in cancer cells from the very beginning, i.e., from the transcriptional level. Here, we aimed to find bioactive small molecules to block VEGFA transcription. We screened our natural compound pool containing 330 small molecules derived from Chinese traditional herbs for small molecules activating the expression of seryl-tRNA synthetase (SerRS), which is a newly identified potent transcriptional repressor of VEGFA, by a cell-based screening system in MDA-MB-231 cell line. The activities of the candidate molecules on regulating SerRS and VEGFA expression were first tested in breast cancer cells. We next investigated the antiangiogenic activity by testing the effects of candidate drugs on the vascular development in zebrafish and by matrigel plug angiogenesis assay in mice. We further examined the antitumor activities of candidate drugs in two triple-negative breast cancer (TNBC)-bearing mouse models. Furthermore, streptavidin-biotin affinity pull-down assay, coimmunoprecipitation assays, docking analysis and chromatin immunoprecipitation were performed to identify the direct targets of candidate drugs. We identified emodin that could greatly increase SerRS expression in TNBC cells, consequently reducing VEGFA transcription. Emodin potently inhibited vascular development of zebrafish and blocked tumor angiogenesis in TNBC-bearing mice, greatly improving the survival. We also identified nuclear receptor corepressor 2 (NCOR2) to be the direct target of emodin. Once bound by emodin, NCOR2 got released from SerRS promoter, resulting in the activation of SerRS expression and eventually the suppression of VEGFA transcription. We discovered a herb-sourced small molecule emodin with the potential for the therapy of TNBC by targeting transcriptional regulators NCOR2 and SerRS to suppress VEGFA transcription and tumor angiogenesis.

Despite the rapidly identified numbers of lncRNA in humans, exploration of the molecular mechanisms of lncRNA is lagging, because the molecular mechanisms of lncRNA can be various and complex in different conditions. In this study, we found a new molecular mechanism for a versatile molecule, MIR22HG. MIR22HG is an lncRNA that contributes to the initiation and progression of many human cancers, including hepatocellular carcinoma (HCC). We report that MIR22HG was downregulated in 120 HCC samples compared with adjacent nontumor liver tissues. More interestingly, decreased expression of MIR22HG in HCC could predict poor prognosis of HCC patients. Knockdown of MIR22HG promoted the growth, migration and invasion of HCC cells. In exploring the molecular mechanism of MIR22HG, we found that MIR22HG functioned as a tumor suppressor in hepatocellular carcinomas, in part through serving as a competing endogenous RNA to modulate the miRNA‐10a‐5p level. Moreover, NCOR2 was verified to act as the downstream target gene of MIR22HG/miR‐10a‐5p. In addition, the MIR22HG/miRNA‐10a‐5p/NCOR2 axis inhibited the activation of the Wnt/β‐catenin pathway. Together, our results demonstrated that MIR22HG inhibited HCC progression in part through the miR‐10a‐5p/NCOR2 signaling axis and might act as a new prognostic biomarker for HCC patients. A schematic model depicting the molecular mechanism of MIR22HG in hepatocellular carcinoma.

BackgroundRett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).MethodsWe performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.ResultsPathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2).ConclusionsOur study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

Xanthogranulomatous epithelial tumor (XGET) and HMGA2::NCOR2 fusion keratin-positive giant cell–rich tumor (KPGCT) are recently described morphologically overlapping rare neoplastic entities characterized by HMGA2::NCOR2 fusions, low-grade biological behavior, and a strong predilection for young females. To date, 47 cases have been reported with only four occurring in head and neck anatomic locations. In this study, we describe the clinicopathologic, immunohistochemical, and molecular findings of seven XGET/KPGCTs occurring in the head and neck region. The patients were six females and one male, aged 3.5–59 years old (median, 25 years). The tumors involved the ear, vocal cord, skull, neck soft tissue, and sinonasal cavity. Tumor sizes ranged from 1.5 to 6.7 cm. Histologically, the tumors were characterized by xanthogranulomatous histiocytes, osteoclast-like giant cells, and keratin-positive epithelioid cells. The XGET/KPGCTs involving the ear was remarkable for more cytologic atypia than previously described. Four cases had the HMGA2::NCOR2 fusion identified by NGS and three had HMGA2 gene locus alterations by FISH. Follow-up information was available for 3 of 7 patients (range 6–46 months). The patient with a vocal cord XGET/KPGCTs developed a local recurrence treated with excision. This study illustrates that XGET/KPGCTs involves the head and neck region as well, where it may be unexpected and hence under-recognized, and expands the anatomic locations of involvement to include unreported sites (ear, vocal cord, and sinonasal tract).

Objective This study aimed to test the hypothesis that the NCOR2/DLL-4/Jagged-1 axis is dysregulated in cord blood of offspring from mothers with preeclampsia (PE) and gestational hypertension (GH), favoring an anti-angiogenic profile. We compared expression levels of these Notch pathway components among PE, GH, and healthy control groups to explore their potential role in fetal vascular programming. Methods This is a prospective cohort study, including 17 mother-offspring pairs with gestational hypertension, 17 mother-offspring pairs with preeclampsia, and 34 healthy mother-offspring pairs as controls. Standardized questionnaires were used to collect family and birth information, medical records were used to collect clinical data, and Western blot was employed to measure the expression levels of NCOR2, DLL-4, and Jagged-1 in cord blood. We analyzed the differences in offspring cord blood proteins among the three groups. Results Cord blood protein expression revealed significant dysregulation of the NCOR2/DLL-4/Jagged-1 axis. Compared to the control group (1.36 ± 0.44), the GH (1.00 ± 0.12) and PE (0.94 ± 0.15) groups were characterized by a significant downregulation of NCOR2 ( p  = 0.001). Furthermore, a progressive and significant increase in DLL-4 ( p  = 0.001) was observed across the control (0.82 ± 0.28), GH (0.98 ± 0.17), and PE (1.27 ± 0.40) groups, which was accompanied by a significant stepwise decrease in Jagged-1 expression (control: 1.36 ± 0.28, GH: 1.02 ± 0.12, PE: 0.87 ± 0.18, p  < 0.001). Conclusion The cord blood levels of NCOR2 and Jagged-1 proteins were significantly decreased in offspring of PE and GH, while DLL-4 protein expression was significantly increased in offspring of PE. These findings suggest that dysregulated Notch signaling, characterized by an anti-angiogenic profile in the fetal circulation, may contribute to the vascular programming observed in offspring of preeclamptic pregnancies.

Purpose Vitamin D (VD) deficiency significantly contributes to intervertebral disc degeneration (IDD), a common cause of low back pain, yet the underlying mechanisms remain unclear. This study investigates how VD deficiency exacerbates IDD and identifies potential therapeutic targets. Methods We used real-time quantitative PCR, immunoblots, immunoprecipitation, liquid chromatography with tandem mass spectrometry analysis, co-immunoprecipitation, and chromatin immunoprecipitation to study gene and protein expressions, protein complex assembly, and transcriptional complex binding. Degeneration of IVDs was assessed via hematoxylin and eosin staining. Results Eight members of ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are enriched in lumbar discs of both VD-deficient and VD receptor (VDR)-knockout (VDR −/− ) mice. Sufficient VD suppresses ADAMTS genes through a complex formed by nuclear receptor corepressor 2 (NCoR2) and signal transducer and activator of transcription 6 (STAT6). VD deficiency activates p38 kinase, leading to NCoR2 phosphorylation and subsequent degradation by a Cullin 4-RING (CRL4) E3 ligase, impairing NCoR2’s transrepression function and upregulating ADAMTS genes, accelerating extracellular matrix (ECM) degradation in discs. This mechanism is replicated in VDR-deficient cells. In vitro treatments with p38 inhibitor (BIRB-796) and CRL4 inhibitor (KH-4-43) reduce ADAMTS expression, and in vivo application of these inhibitors improves disc integrity in VD-deficient mice. Conclusion Our findings highlight NCoR2 degradation, mediated by p38 kinase and CRL4 E3 ligase, as crucial in VD deficiency-induced IDD. Targeting this pathway offers promising therapeutic potential to mitigate IDD progression in individuals with VD deficiency or VDR abnormalities.

Keratin-positive giant cell-rich tumor (KPGCT) is an extremely rare and recently described mesenchymal neoplasm that occurs in both soft tissue and bone, frequently found in young women. It has locally recurrent potential if incompletely excised but low risk for metastasis. KPGCT is histologically similar to conventional giant cell tumors of soft tissue but shows the presence of keratin-positive mononuclear cells. Interestingly, KPGCT also shares some morphological features with xanthogranulomatous epithelial tumors. These two tumors have recently been shown to harbor an HMGA2–NCOR2 fusion, arguing in favor of a single entity. Surgery is the treatment of choice for localized KPGCT. Therapeutic options for advanced or metastatic disease are unknown. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology, and treatment of KPGCT. In addition, we will discuss the differential diagnosis of this emerging entity.

Background Precision medicine incorporating genetic profiling is becoming a standard of care in medical oncology. However, in the field of radiation oncology there is limited use of genetic profiling and the impact of germline genetic biomarkers on radiosensitivity, radioresistance, or patient outcomes after radiation therapy is poorly understood. In HNSCC, the toxicity associated with treatment can cause delays or early cessation which has been associated with worse outcomes. Identifying potential biomarkers which can help predict toxicity, as well as response to treatment, is of significant interest. Methods Patients with HNSCC who received RT and underwent next generation sequencing of somatic tumor samples, transcriptome RNA-seq with matched normal tissue samples were included. Patients were then grouped by propensity towards increased late vs. early toxicity (Group A) and those without (Group B), assessed by CTCAE v5.0. The groups were then analyzed for association of specific germline variants with toxicity and clinical outcomes. Results In this study we analyzed 37 patients for correlation between germline variants and toxicity. We observed that TSC2, HLA-A, TET2, GEN1, NCOR2 and other germline variants were significantly associated with long term toxicities. 34 HNSCC patients treated with curative intent were evaluated for clinical outcomes. Group A had significantly improved overall survival as well as improved rates of locoregional recurrence and metastatic disease. Specific variants associated with improved clinical outcomes included TSC2, FANCD2, and PPP1R15A, while the HLA-A and GEN1 variants were not correlated with survival or recurrence. A group of five HLA-DMA/HLA-DMB variants was only found in Group B and was associated with a higher risk of locoregional recurrence. Conclusions This study indicates that germline genetic biomarkers may have utility in predicting toxicity and outcomes after radiation therapy and deserve further investigation in precision radiation medicine approaches.

Abstract This report presents a case of a Glioma-associated homologue-1 (GLI1)-altered mesenchymal tumour with novel gene fusion arising from the pleura in a 25-year-old female undergoing treatment for primary colorectal adenocarcinoma. A pleural nodule was incidentally detected during staging, and biopsy revealed a mesenchymal tumour with a novel NCOR2(exon 7)::GLI1(exon 6) gene fusion. The tumour showed an indolent course over 10 months of surveillance during chemotherapy, with no significant growth. Despite the absence of malignant features, such as high mitotic rate, necrosis, or large size, and a low proliferation index, surgical excision was chosen due to the rarity and uncertain prognosis of this fusion. Histology confirmed a low-grade tumour with unusual SOX10 expression. This case expands the understanding of GLI1-altered mesenchymal tumours, especially in uncommon sites like the pleura, and highlights the importance of multidisciplinary decision-making. Ongoing molecular and pathological analysis is critical to establish robust diagnostic and prognostic frameworks for such rare tumour entities.

MicroRNAs function as negative regulators of posttranscriptional gene expression, having major roles in cellular differentiation. Several neuroblastoma cell lines can be induced to undergo differentiation by all-trans-retinoic acid (ATRA) and are used for modeling signaling pathways involved in this process. To identify miRNAs contributing to differentiation, we profiled 364 loci following ATRA treatment of neuroblastoma cell lines and found miR-10a and miR-10b to be highly overexpressed in SK-N-BE, LAN5 and SHSY-5Y. Ectopic overexpression of these miRNAs led to a major reprogramming of the transcriptome and a differentiated phenotype that was similar to that induced by ATRA in each of these cell lines. One of the predicted downregulated miR-10a/b targets was nuclear receptor corepressor 2 ( NCOR2 ), a corepressor of gene transcription, which is known to suppress neurite outgrowth. NCOR2 was experimentally validated as a direct target of miR-10a/b, and siRNA-mediated inhibition of this mRNA alone resulted in neural cell differentiation. Moreover, induction of differentiation could be blocked by ectopic upregulation of NCOR2 using an expression construct lacking the miR-10a/b 3′ untranslated region target site. We conclude that miR-10a/b has major roles in the process of neural cell differentiation through direct targeting of NCOR2 , which in turn induces a cascade of primary and secondary transcriptional alterations, including the downregulation of MYCN.