The Wnt/β-catenin pathway is constitutively active and promotes multiple tumor processes, including breast cancer metastasis. However, the underlying mechanism by which the Wnt/β-catenin pathway is constitutively activated in breast cancer metastasis remains unclear. Inhibition of Wnt antagonists is important for Wnt/β-catenin signaling activation, and post-transcriptional regulation of these antagonists by microRNAs (miRNAs) might be a possible mechanism underlying signaling activation. Regulation of nuclear pre-mRNA domain-containing 1A (RPRD1A) is a known inhibitor of cell growth and Wnt/β-catenin signaling activity, but the function and regulatory mechanism of RPRD1A in breast cancer have not been clarified. The aim of this study was to understand how regulators of the Wnt/β-catenin pathway may play a role in the metastasis of this cancer. Methods: RPRD1A expression and its association with multiple clinicopathological characteristics was analyzed immunohistochemically in human breast cancer specimens. miR-454-3p expression was analyzed using real-time PCR. RPRD1A or miR-454-3p knockdown and overexpression were used to determine the underlying mechanism of their functions in breast cancer cells. Xenografted tumor model, 3D invasive culture, cell migration and invasion assays and sphere formation assay were used to determine the biofunction of RPRD1A and miR-454-3p in breast cancer. Electrophoretic mobility shift assay (EMSA), luciferase reporter assay, and RNA immunoprecipitation (RIP) were performed to study the regulation and underlying mechanisms of RPRD1A and miR-454-3p expression and their correlation with the Wnt/β-catenin pathway in breast cancer. Results: The Wnt/β-catenin signaling antagonist RPRD1A was downregulated and its upstream regulator miR-454-3p was amplified and overexpressed in metastatic breast cancer, and both were correlated with overall and relapse-free survival in breast cancer patients. The suppression by miR-454-3p on RPRD1A was found to activate Wnt/β-catenin signaling, thereby promoting metastasis. Simultaneously, three other negative regulators of the Wnt/β-catenin pathway, namely, AXIN2, dickkopf WNT signaling pathway inhibitor (DKK) 3 and secreted frizzled related protein (SFRP) 1, were also found to be targets of miR-454-3p and were involved in the signaling activation. miR-454-3p was found to be involved in early metastatic processes and to promote the stemness of breast cancer cells and early relapse under both in vitro and in vivo conditions. Conclusions: The findings indicate that miR-454-3p-mediated suppression of Wnt/β-catenin antagonist RPRD1A, as well as AXIN2, DKK3 and SFRP1, sustains the constitutive activation of Wnt/β-catenin signaling; thus, miR-454-3p and RPRD1A might be potential diagnostic and therapeutic targets for breast cancer metastasis.

MiR-454-3p-Mediated Wnt/β-catenin Signaling Antagonists Suppression Promotes Breast Cancer Metastasis.

Multifaceted transforming growth factor-beta (TGFβ) signalling in glioblastoma

Hepatocellular carcinoma is one of the most common cancer types worldwide. In cases of advanced-stage disease, sorafenib is considered the treatment of choice. However, resistance to sorafenib remains a major obstacle for effective clinical application. Based on integrated phosphoproteomic and The Cancer Genome Atlas (TCGA) data, we identified a transcription factor, Y-box binding protein-1 (YB-1), with elevated phosphorylation of Ser102 in sorafenib-resistant HuH-7R cells. Phosphoinositide-3-kinase (PI3K) and protein kinase B (AKT) were activated by sorafenib, which, in turn, increased the phosphorylation level of YB-1. In functional analyses, knockdown of YB-1 led to decreased cell migration and invasion in vitro. At the molecular level, inhibition of YB-1 induced suppression of zinc-finger protein SNAI1 (Snail), twist-related protein 1 (Twist1), zinc-finger E-box-binding homeobox 1 (Zeb1), matrix metalloproteinase-2 (MMP-2) and vimentin levels, implying a role of YB-1 in the epithelial-mesenchymal transition (EMT) process in HuH-7R cells. Additionally, YB-1 contributes to morphological alterations resulting from F-actin rearrangement through Cdc42 activation. Mutation analyses revealed that phosphorylation at S102 affects the migratory and invasive potential of HuH-7R cells. Our collective findings suggest that sorafenib promotes YB-1 phosphorylation through effect from the EGFR/PI3K/AKT pathway, leading to significant enhancement of hepatocellular carcinoma (HCC) cell metastasis. Elucidation of the specific mechanisms of action of YB-1 may aid in the development of effective strategies to suppress metastasis and overcome resistance.

https://www.mdpi.com/1422-0067/22/1/224/pdf

Y-Box Binding Protein-1 Promotes Epithelial-Mesenchymal Transition in Sorafenib-Resistant Hepatocellular Carcinoma Cells.

The present study was designed to investigate the significance of non-structural maintenance of chromosomes (non-SMC) chromosome-associated polypeptide G (NCAPG), a subunit of condensin complex I, in the development of hepatocellular carcinoma (HCC). NCAPG protein expression in human HCC and paracancerous hepatic tissues were examined using immunohistochemistry, and NCAPG mRNA expression in HCC cell lines were quantified using quantitative RT-PCR. Lentivirus-mediated RNA interference was used to silence NCAPG in HCC cells. Cell proliferation was monitored by MTT assay. Cell colony-forming capacity was measured by colony formation assay. Apoptosis was determined by flow cytometry. The results showed that increased protein expression of NCAPG was found in HCC tissues compared with the matched paracancerous hepatic tissues. At the mRNA level, increased expression of NCAPG was found in HCC cells as opposed to the normal hepatocytes. Silencing of NCAPG in BEL-7404 and SMMC-7721 cells led to decreased cell proliferation and increased apoptosis. These changes were associated with increased mRNA expressions of P53, P27, and Bad, but decreased mRNA expression of EGFR, Akt, survivin, and JNK. NCAPG might play an oncogenic role in the development of liver cancer. Further studies to clarify its role and underlying mechanisms in the development of liver cancer are warranted.

Silencing non-SMC chromosome-associated polypeptide G inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells

Glioblastomas (GBMs), are the most common intrinsic brain tumors in adults and are almost universally fatal. Despite the progresses made in surgery, chemotherapy, and radiation over the past decades, the prognosis of patients with GBM remained poor and the average survival time of patients suffering from GBM was still short. Discovering robust gene signatures toward better understanding of the complex molecular mechanisms leading to GBM is an important prerequisite to the identification of novel and more effective therapeutic strategies. Herein, a comprehensive study of genome-scale mRNA expression data by combining GBM and normal tissue samples from 48 studies was performed. The 147 robust gene signatures were identified to be significantly differential expression between GBM and normal samples, among which 100 (68%) genes were reported to be closely associated with GBM in previous publications. Moreover, function annotation analysis based on these 147 robust DEGs showed certain deregulated gene expression programs (e.g., cell cycle, immune response and p53 signaling pathway) were associated with GBM development, and PPI network analysis revealed three novel hub genes (RFC4, ZWINT and TYMS) play important role in GBM development. Furthermore, survival analysis based on the TCGA GBM data demonstrated 38 robust DEGs significantly affect the prognosis of GBM in OS (p < 0.05). These findings provided new insights into molecular mechanisms underlying GBM and suggested the 38 robust DEGs could be potential targets for the diagnosis and treatment.

/pdf/genome-wide-expression-profiling-of-glioblastoma-using-a-2369zigvrd.pdf

Genome-wide expression profiling of glioblastoma using a large combined cohort

Overexpression of structural maintenance of chromosomes 4 (SMC4) has been reported to be involved in tumor cell growth, migration and invasion, and to be correlated with poor prognosis of cancer patient. However, its clinical significance and biological role in glioma remain unknown. Herein, we found that SMC4 expression at both mRNA and protein level was markedly increased in glioma cells and clinical tissues and that it correlated with poor prognosis. SMC4 overexpression markedly promoted the glioma cell proliferation rate and migration and invasive capability in vitro and in vivo, whereas SMC4 downregulation reduced it. Moreover, the transforming growth factor β (TGFβ)/Smad signaling pathway, which was activated in SMC4-transduced glioma cells and inhibited in SMC4-silenced glioma cells, contributed to SMC4-mediated glioma cell aggressiveness. Our results provide new insight into the oncofunction of SMC4 and the mechanism by which the TGFβ/Smad pathway is hyperactivated in gliomas, indicating that SMC4 is a valuable prognostic factor and a potential therapeutic target in gliomas.

/pdf/overexpression-of-smc4-activates-tgfb-smad-signaling-and-4c2c3z710z.pdf

Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells

Approved COVID-19 vaccines to date have limited effectiveness in protecting infection and blocking transmission. A nasal spray of broad-spectrum antibody against COVID-19 (SA58 Nasal Spray) has recently been developed by Sinovac Life Sciences Co., Ltd.. From October 31 to November 30, 2022, an open-label, blank controlled study on the SA58 Nasal Spray against COVID-19 infection was conducted with the medical personnel working in the designated COVID-19 hospitals and Fangcang shelter hospitals (alternate care sites) of COVID-19 cases in Hohhot city, the Inner Mongolia Autonomous Region. A total of 6662 medical personnel were involved in this study: 3368 used SA58 Nasal Spray from the drug group, and 3294 not used from blank control group. The medication was self-administered intranasally 1~2 times per day with an interval of 6 hours for 30 days.. The safety results indicated that the SA58 Nasal Spray was well tolerant. The incidence of adverse events (AEs) was 28.6% (497/1736), and the majority of the AEs were mild and from administrative site. 135 COVID-19 cases were identified for SARS-CoV-2 by RT-PCR during the 30-day observation. The cumulative incidence of COVID-19 in the drug group and the control group were 0.026% and 0.116%, respectively. The effectiveness of the SA58 Nasal Spray for preventing COVID-19 infection among medical personnel was evaluated as 77.7% (95% CI: 52.2% - 89.6%). In conclusion, the SA58 Nasal Spray is well-tolerant and highly effective against COVID-19 infection.

/pdf/safety-and-effectiveness-of-sa58-nasal-spray-against-covid-1kzqvb5w.pdf

Safety and Effectiveness of SA58 Nasal Spray against COVID-19 Infection in Medical Personnelï¼An Open-label, Blank-controlled Study

Background: A better understanding of the T cells in lung cancer and their distribution across tumor-adjacent lungs and the peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients. Methods: Here, we performed CDR3{beta} TCR sequencing of 143 samples from 21 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumor, tumor edges (<1cm from tumor), as well as adjacent lungs 1cm, 2cm, 5cm, and 10cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4 and CD8 expression was assessed by immunohistochemical staining and genomic features were derived by targeted sequencing of 1,021 cancer related genes. Results: Our study reveals a decreasing gradient in TIL homology with the tumor-edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression. Conclusions: The exclusion in T cells at play across the lungs of patients with NSCLC may be potentially the mechanism for lung cancer occurrence.

/pdf/spatial-heterogeneity-of-t-cell-repertoire-across-nsclc-2jt3owng.pdf

Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues

Cystic fibrosis (CF) is a life-shortening genetic disorder, caused by mutations in the gene that encodes Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride and bicarbonate channel. Although multiple organ systems can be affected, CF lung disease claims the most morbidity and mortality due to chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite the clear predominance of neutrophils in these pathologies, how CFTR loss-of-function affects these cells per se remains incompletely understood. Here, we report the profiling and comparing of transcriptional signatures of peripheral blood neutrophils from CF participants and healthy human controls (HC) at the single-cell level. Circulating CF neutrophils had an aberrant basal state with significantly higher scores for activation, chemotaxis, immune signaling, and pattern recognition, suggesting that CF neutrophils in blood are prematurely primed. Such an abnormal basal state was also observed in neutrophils derived from an F508del-CF HL-60 cell line, indicating an innate characteristic of the phenotype. LPS stimulation drastically shifted the transcriptional landscape of HC circulating neutrophils towards a robust immune response, however, CF neutrophils were immune-exhausted. Moreover, CF blood neutrophils differed significantly from CF sputum neutrophils in gene programming with respect to energy use, immune signaling, and phagocytic function, highlighting additional environmental influences on the neutrophils in CF lungs. Taken together, loss of CFTR function has intrinsic effects on neutrophil immune programming that leads to premature priming and dysregulated response to challenge.

Aberrant immune programming in neutrophils in cystic fibrosis

432 Molecular signatures of human neutrophils from healthy subjects and people with cystic fibrosis

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Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells

Safety and Effectiveness of SA58 Nasal Spray against COVID-19 Infection in Medical Personnelï¼An Open-label, Blank-controlled Study

Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues

Aberrant immune programming in neutrophils in cystic fibrosis

432 Molecular signatures of human neutrophils from healthy subjects and people with cystic fibrosis

Y Hu

Author Tools

Chat about Author

Papers

Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells

Safety and Effectiveness of SA58 Nasal Spray against COVID-19 Infection in Medical Personnelï¼An Open-label, Blank-controlled Study

Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues

Aberrant immune programming in neutrophils in cystic fibrosis

432 Molecular signatures of human neutrophils from healthy subjects and people with cystic fibrosis

Safety and Effectiveness of SA58 Nasal Spray against COVID-19 Infection in Medical Personnelï¼An Open-label, Blank-controlled Study