Explore the vast range of titles available.

Viruses are widely recognized to be intricately associated with both solid and hematological malignancies in humans. The primary goal of this research is to elucidate the interplay of genes between SARS‐CoV‐2 infection and lung adenocarcinoma (LUAD), with a preliminary investigation into their clinical significance and underlying molecular mechanisms. Transcriptome data for SARS‐CoV‐2 infection and LUAD were sourced from public databases. Differentially expressed genes (DEGs) associated with SARS‐CoV‐2 infection were identified and subsequently overlapped with TCGA‐LUAD DEGs to discern the crosstalk genes (CGs). In addition, CGs pertaining to both diseases were further refined using LUAD TCGA and GEO datasets. Univariate Cox regression was conducted to identify genes associated with LUAD prognosis, and these genes were subsequently incorporated into the construction of a prognosis signature using 10 different machine learning algorithms. Additional investigations, including tumor mutation burden assessment, TME landscape, immunotherapy response assessment, as well as analysis of sensitivity to antitumor drugs, were also undertaken. We discovered the risk stratification based on the prognostic signature revealed that the low‐risk group demonstrated superior clinical outcomes (p < 0.001). Gene set enrichment analysis results predominantly exhibited enrichment in pathways related to cell cycle. Our analyses also indicated that the low‐risk group displayed elevated levels of infiltration by immunocytes (p < 0.001) and superior immunotherapy response (p < 0.001). In our study, we reveal a close association between CGs and the immune microenvironment of LUAD. This provides preliminary insight for further exploring the mechanism and interaction between the two diseases. The primary goal of this research is to elucidate the interplay of genes between SARS‐CoV‐2 infection and lung adenocarcinoma, with a preliminary investigation into their clinical significance and underlying molecular mechanisms.

Editor's Note on use of BGC-823 cell line.BackgroundTumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for tumors. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, yet the underlying mechanism on how lncRNAs manipulate the polarization states of TAMs is still unclear and remains to be further investigated.MethodsMicroarray analyses were employed to characterize the lncRNA profile involved in THP-1-induced M0, M1 and M2-like macrophage. Among those differentially expressed lncRNAs, NR_109 was further studied, for its function in M2-like macrophage polarization and the effects of the condition medium or macrophages mediated by NR_109 on tumor proliferation, metastasis and TME remodeling both in vitro and in vivo. Moreover, we revealed how NR_109 interacted with far upstream element-binding protein 1 (FUBP1) to regulate the protein stability through hindering ubiquitination modification by competitively binding with JVT-1. Finally, we examined sections of tumor patients to probe the correlation among the expression of NR_109 and related proteins, showing the clinical significance of NR_109.ResultsWe found that lncRNA NR_109 was highly expressed in M2-like macrophages. Knockdown NR_109 impeded IL-4 induced M2-like macrophage polarization and significantly reduced the activity of M2-like macrophages to support the proliferation and metastasis of tumor cells in vitro and in vivo. Mechanistically, NR_109 competed with JVT-1 to bind FUBP1 at its C-terminus domain, impeded the ubiquitin-mediated degradation of FUBP1, activated c-Myc transcription and thus promoted M2-like macrophages polarization. Meanwhile, as a transcription factor, c-Myc could bind to the promoter of NR_109 and enhance the transcription of NR_109. Clinically, high NR_109 expression was found in CD163+ TAMs from tumor tissues and was positively correlated with poor clinical stages of patients with gastric cancer and breast cancer.ConclusionsOur work revealed for the first time that NR_109 exerted a crucial role in regulating the phenotype-remodeling and function of M2-like macrophages via a NR_109/FUBP1/c-Myc positive feedback loop. Thus, NR_109 has great translational potentials in the diagnosis, prognosis and immunotherapy of cancer.

Exosomal microRNAs (miRNAs) have been recently shown to play vital regulatory and communication roles in cancers. In this study, we showed that the expression levels of miR-652-5p in tumour tissues and serum samples of oesophageal squamous cell carcinoma (OSCC) patients were lower compared to non-tumorous tissues and serum samples from healthy subjects, respectively. Decreased expression of miR-652-5p was correlated with TNM stages, lymph node metastasis, and short overall survival (OS). More frequent CpG sites hypermethylation in the upstream of miR-652-5p was found in OSCC tissues compared to adjacent normal tissues. Subsequently, miR-652-5p downregulation promoted the proliferation and metastasis of OSCC, and regulated cell cycle both in cells and in vivo. The dual-luciferase reporter assay confirmed that poly (ADP-ribose) glycohydrolase (PARG) and vascular endothelial growth factor A (VEGFA) were the direct targets of miR-652-5p. Moreover, the delivery of miR-652-5p agomir suppressed tumour growth and metastasis, and inhibited the protein expressions of PARG and VEGFA in nude mice. Taken together, our findings provide novel insight into the molecular mechanism underlying OSCC pathogenesis.

Early detection of esophageal cancer (EC) remains a major challenge due to the limited understanding of its initial molecular alterations. Therefore, this study aimed to identify the key molecular drivers involved in EC carcinogenesis. Human normal esophageal epithelial cells were subjected to chronic malignant transformation, followed by assessment of their morphological changes, proliferative capacity, clonogenic potential, migration, and invasion abilities. To elucidate the molecular mechanisms underlying tumorigenesis, transcriptome sequencing was performed and integrated with clinical datasets from two independent EC cohorts. Machine learning algorithms were then applied to pinpoint diagnostic and prognostic gene signatures, which were further validated through comprehensive in vitro and in vivo experiments. Differential expression analysis and machine learning identified RIB43A domain with coiled-coils 2 (RIBC2) as a strong diagnostic and prognostic biomarker for EC. RIBC2 expression was markedly upregulated in chronically transformed epithelial cells, established EC cell lines, and clinical tumor specimens, and its elevation was associated with unfavorable clinicopathological characteristics. Functional studies revealed that silencing RIBC2 significantly inhibited cell proliferation, migration, and invasion in both transformed and EC cells. Moreover, immune profiling indicated that high RIBC2 expression was linked to an immune-excluded tumor microenvironment, implying a potential role in modulating responsiveness to immunotherapy. These findings reveal RIBC2 as a novel driver of EC initiation and progression, highlighting its potential as a biomarker for early diagnosis and as a promising target for therapeutic intervention.

Studies have demonstrated that sialylation changes play a vital part in lung adenocarcinoma (LUAD), yet the specific mechanism is uncertain. Hence, in the present research, we screened sialylation-related biomarkers in LUAD using the bioinformatic strategy, predicted the drugs and performed relevant experiments to explore their role in regulating LUAD. The TCGA-LUAD, GSE31210, and GSE13213 datasets were combined to form LUAD ensemble. The sialylation-related genes (SRGs) linked with LUAD prognosis were determined by univariate Cox regression analysis, and their expressions and mutations in LUAD were analyzed in GSCA database. Then, depending on the consistent clustering of prognostic SRGs, LUAD patients were divided into sialylation-related subgroups, followed by the investigation of survival, immunity, and clinical characteristics in the subgroups. LASSO regression analysis was further employed to identify prognostic gene signatures and to build a sialylation-related model to predict the prognosis of LUAD patients. The gene signature were validated using RT-qPCR and used for predicting target medicines using molecular docking to further investigate the potential therapies for LUAD patients. A total of 26 SRGs in LUAD ensemble were associated with prognosis, and LUAD samples were classified into two sialylation-related subgroups based on these SRGs. Intergroup comparisons revealed that patients in Cluster A had greater survival rates, as well as higher immune infiltration. The risk prognostic model built based on 6 prognostic gene signature was able to effectively predict the survival of LUAD patients. Finally, the experimental findings indicated that Troxerutin exhibits a strong binding energy to the sialylation-related gene EGLN3, which could greatly reduce the growth of LUAD by inhibiting the expression of EGLN3, thus limiting the capacity of LUAD cells in the proliferation, migration, and invasion. Troxerutin could target and lower the expression of sialylation-related gene EGLN3, reducing LUAD cells’ ability to proliferate, migrate, and invade, making it an essential reference for LUAD prevention and treatment.

Accumulating evidence indicates that miRNAs can be promising diagnostic and/or prognostic markers for various cancers. In this study, we identified a novel miRNA, miR-3607-3p, and its targets in non-small cell lung cancer (NSCLC). The expression of miR-3607-3p was measured and its correlation with patient prognosis was determined. Ectopic expression in NSCLC cells, xenografts, and metastasis models was used to evaluate the effects of miR-3607-3p on proliferation and migration of NSCLC. Luciferase assay and western blotting were performed to validate the potential targets of miR-3607-3p after preliminary screening by microarray analysis and computer-aided algorithms. We demonstrated that miR-3607-3p was downregulated in NSCLC tissues and that miR-3607-3p might act as an independent predictor for overall survival in NSCLC. Moreover, serum miR-3607-3p may be a novel and stable marker for NSCLC. We found that overexpression of miR-3607-3p inhibited cell proliferation, colony formation, migration and invasion, and hampered the cell cycle of NSCLC cell lines in vitro. Our results suggested that miR-3607-3p directly targets TGFBR1 and CCNE2. In accordance with in vitro studies, we confirmed that miR-3607-3p functions as a potent suppressor miRNA of NSCLC. We showed that miR-3607-3p agomir could reduce tumor growth and inhibit TGFBR1 and CCNE2 protein expression. Taken together, our findings indicate that miR-3607-3p can inhibit NSCLC cell growth and metastasis by targeting TGFBR1 and CCNE2 protein expression, and provide new evidence of miR-3607-3p as a potential non-invasive biomarker and therapeutic target for NSCLC.

Background Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. Methods Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan–Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. Results Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6–5.4%), and DCR was 35.8% (95% CI, 33.7–38.0%). The median PFS was 2.7 months (95% CI 2.2–2.8), and the median OS was 5.8 months (95% CI 5.4–6.1). Conclusions The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. Trial registration This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

During the last several years, a growing number of studies have shown that microRNAs (miRNAs) participate in cancer metastasis. Brain metastasis (BM) is a frequent complication of lung adenocarcinoma (LAD), and the incidence of locally advanced LAD with BM can be as high as 30–50%. This study was performed to identify the miRNA expression patterns of LAD with BM and to determine the biological role that miRNAs play in tumorigenesis. To this end, we conducted microarray and quantitative PCR analyses to evaluate BM-related miRNAs independently validated from a total of 155 patients with LAD. A series of in vivo and in vitro assays were also conducted to verify the impact of miRNAs on BM. We found significantly increased expression of miR-423-5p, and BM was predicted in non-small cell lung cancer when compared to LAD without BM. We next examined the function of miR-423-5p and discovered that it significantly promoted colony formation, cell motility, migration, and invasion in vitro. We computationally and experimentally confirmed that metastasis suppressor 1 ( MTSS1 ) was a direct miR-423-5p target. Through a combination of image, histological, and molecular analyses, we found that miR-423-5p overexpression significantly increased tumor burden, local invasion, and distant BM. The level of MTSS1 expression was inversely correlated with miR-423-5p upregulation in the LAD specimens and was associated with survival of patients with BM. MiR-423-5p promoted BM in LAD and inhibited MTSS1 expression. Together, these results show that MiR-423-5p has the potential to be a marker of BM and/or a therapeutic target in LAD.

Brain metastasis (BM) is a major complication of lung adenocarcinoma (LAD). An investigation of the pathogenic mechanisms of BM, as well as the identification of appropriate molecular markers, is necessary. The aim of this study was to determine the expression patterns of microRNAs (miRNAs) in LAD with BM, and to investigate the biological role of these miRNAs during tumorigenesis. miRNA array profiles were used to identify BM-associated miRNAs. These miRNAs were independently validated in 155 LAD patients. Several in vivo and in vitro assays were performed to verify the effects of miRNAs on BM. We identified six miRNAs differentially expressed in patients with BM as compared to patients with BM. Of these, miR-4270 and miR-423-3p were further investigated. miR-4270 and miR-423-3p directly targeted MMP19 and P21, respectively, to influence cell viability, migration, and colony formation in vitro. miR-4270 downregulation and miR-423-3p upregulation was associated with an increased risk of BM in LAD patients. Thus, our results suggested that miR-4270 and miR-423-3p might play an important role in BM pathogenesis in LAD patients, and that these miRNAs might be useful prognostic and clinical treatment targets.

Mitochondria Sirtuins including SIRT4 erase a variety of posttranslational modifications from mitochondria proteins, leading to metabolic reprogramming that acts as a tumor suppressor, oncogenic promotor, or both. However, the factors and the underlying mechanisms that stimulate and relay such a signaling cascade are poorly understood. Here, we reveal that the voltage‐gated calcium channel subunit α2δ1‐mediated calcium signaling can upregulate the expression of SIRT4, which is highly expressed in α2δ1‐positive pancreatic tumor‐initiating cells (TICs). Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties of pancreatic cancer cells by directly deacetylating ENO1 at K358, leading to attenuated ENO1's RNA‐binding capacity, enhanced glycolytic substrate 2‐PG affinity, and subsequently robust catalytic activity with boosted glycolytic ability and increased production of lactate acid. Interestingly, both SIRT4 and deacetylated mimetic of ENO1‐K358 can increase the lactylation of histones at multiple sites including H3K9 and H3K18 sites, which resulted in epigenetic reprogramming to directly activate a variety of pathways that are essential for stemness. Hence, the study links α2δ1‐mediated calcium signaling to SIRT4‐mediated histone lactylation epigenetic reprogramming in promoting the stem cell‐like properties of pancreatic cancer, which holds significant potential for the development of novel therapeutic strategies by targeting TICs of pancreatic cancer. As a downstream target of α2δ1‐mediated calcium signaling, SIRT4 serves as an oncogene to promote the stemness of pancreatic cancer via deacetylating ENO1 directly at K358, leading to attenuated ENO1's RNA‐binding capacity, enhanced glycolytic substrate 2‐PG binding and robust glycolytic activity to increase the level of lactate that induce histone lactylation to epigenetically regulate signaling pathways essential for stemness.