STMN1 Promotes Tumor Metastasis in Non-small Cell Lung Cancer Through Microtubule-dependent And Nonmicrotubule-dependent Pathways.

The relationship between STMN1 and cancer metastasis is controversial. The purpose of this study was to explore the role and mechanism of STMN1 in NSCLC metastasis. In this study, we reported that STMN1 was highly expressed in NSCLC tissues and associated with poor prognosis. Both in vivo and in vitro functional assays confirmed that STMN1 promoted NSCLC metastasis. Further studies confirmed that STMN1 promoted cell migration by regulating microtubule stability. The results of Co-IP and LC‒MS/MS illustrated that STMN1 interacts with HMGA1. HMGA1 decreases microtubule stability by regulating the phosphorylation level of STMN1 at Ser16 and Ser38 after interacting with STMN1. This result suggested that STMN1 could be activated by HMGA1 to further promote NSCLC metastasis. Meanwhile, it has been found that STMN1 could promote cell migration by activating the p38MAPK/STAT1 signaling pathway, which is not dependent on microtubule stability. However, activating p38MAPK can decrease microtubule stability by promoting the dephosphorylation of STMN1 at ser16. A positive feedback loop was formed between STMN1 and p38MAPK to synergistically promote cell migration. In summary, our study demonstrated that STMN1 could promote NSCLC metastasis through microtubule-dependent and nonmicrotubule-dependent mechanisms. STMN1 has the potential to be a therapeutic target to inhibit metastasis.

Identification and validation of LINC01322 as a potential prognostic biomarker and oncogene promoting tumor progression in lung adenocarcinoma.

Our study identified a novel long noncoding RNA, LINC01322, that acts as an oncogene in lung adenocarcinoma progression. Cytoplasmic and nuclear RNA purification assays indicated that LINC01322 was localized in the cytoplasm and nucleus. Gene set enrichment analysis revealed the involvement of LINC01322 in the regulation of cell proliferation, migration, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. LINC01322 may promote lung adenocarcinoma proliferation and migration through the Janus kinase/signal transducer and activator of transcription signaling pathway. In vitro experiments demonstrated that the knockdown of LINC01322 significantly suppressed lung adenocarcinoma cell proliferation, migration, and activation of the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, whereas overexpression had the opposite effects. Inhibition of the Janus kinase 2/signal transducer and activator of transcription 3 pathway activity partially reversed the enhancement of cell proliferation and migration caused by LINC01322 overexpression. In vivo experiments further verified the oncogene role of LINC01322. Altogether, our findings suggest that LINC01322 promotes lung adenocarcinoma progression by activating the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway and that it could be a therapeutic target.

DHX38 enhances proliferation, metastasis, and EMT progression in NSCLC through the G3BP1-mediated MAPK pathway.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a prevalent and aggressive malignancy with limited therapeutic options. Despite advances in treatment, NSCLC remains a major cause of cancer-related death worldwide. Tumor heterogeneity and therapy resistance present challenges in achieving remission. Research is needed to provide molecular insights, identify new targets, and develop personalized therapies to improve outcomes. METHODS: The protein expression level and prognostic value of DHX38 in NSCLC were explored in public databases and NSCLC tissue microarrays. DHX38 knockdown and overexpression cell lines were established to evaluate the role of DHX38 in NSCLC. In vitro and in vivo functional experiments were conducted to assess proliferation and metastasis. To determine the underlying molecular mechanism of DHX38 in human NSCLC, proteins that interact with DHX38 were isolated by IP and identified by LC-MS. KEGG analysis of DHX38-interacting proteins revealed the molecular pathway of DHX38 in human NSCLC. Abnormal pathway activation was verified by Western blot analysis and immunohistochemical (IHC) staining. A molecule-specific inhibitor was further used to explore potential therapeutic targets for NSCLC. The pathway-related target that interacted with DHX38 was verified by co-immunoprecipitation(co-IP) experiments. In cell lines with stable DHX38 overexpression, the target protein was knocked down to explore its complementary effect on DHX38 overexpression-induced tumor promotion. RESULTS: The protein expression of DHX38 was increased in NSCLC, and patients with high DHX38 expression levels had a poor prognosis. In vitro and in vivo experiments showed that DHX38 promoted the proliferation, migration and invasion of human NSCLC cells. DHX38 overexpression caused abnormal activation of the MAPK pathway and promoted epithelial-mesenchymal transition (EMT) in tumours. SCH772984, a novel specific ERK1/2 inhibitor, significantly reduced the increases in cell proliferation, migration and invasion caused by DHX38 overexpression. The co-IP experiments confirmed that DHX38 interacted with the Ras GTPase-activating protein-binding protein G3BP1. DHX38 regulated the expression of G3BP1. Knocking down G3BP1 in cells with stable DHX38 overexpression prevented DHX38-induced tumor cell proliferation, migration and invasion. Silencing G3BP1 reversed the MAPK pathway activation and EMT induced by DHX38 overexpression. CONCLUSION: In NSCLC, DHX38 functions as a tumor promoter. DHX38 modulates G3BP1 expression, leading to the activation of the MAPK signaling pathway, thus promoting tumor cell proliferation, metastasis, and the progression of epithelial-mesenchymal transition (EMT) in non-small cell lung cancer.

Integrative Analysis of Single-Cell and Bulk RNA Sequencing Reveals Prognostic Characteristics of Macrophage Polarization-Related Genes in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is a group of cancers with poor prognosis. The combination of single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) can identify important genes involved in cancer development and progression from a broader perspective. Methods: The scRNA-seq data and bulk RNA-seq data of LUAD were downloaded from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. Analyzing scRNA-seq for core cells in the GSE131907 dataset, and the uniform manifold approximation and projection (UMAP) was used for dimensionality reduction and cluster identification. Macrophage polarization-associated subtypes were acquired from the TCGA-LUAD dataset after analysis, followed by further identification of differentially expressed genes (DEGs) in the TCGA-LUAD dataset (normal/LUAD tissue samples, two subtypes). Venn diagrams were utilized to visualize differentially expressed and highly variable macrophage polarization-related genes. Subsequently, a prognostic risk model for LUAD patients was constructed by univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO), and the model was investigated for stability in the external data GSE72094. After analyzing the correlation between the trait genes and significantly mutated genes, the immune infiltration between the high/low-risk groups was then examined. The Monocle package was applied to analyze the pseudo-temporal trajectory analysis of different cell clusters in macrophage clusters. Subsequently, cell clusters of data macrophages were selected as key cell clusters to explore the role of characteristic genes in different cell populations and to identify transcription factors (TFs) that affect signature genes. Finally, qPCR were employed to validate the expression levels of prognosis signature genes in LUAD. Results: 424 macrophage highly variable genes, 3920 DEGs, and 9561 DEGs were obtained from macrophage clusters, the macrophage polarization-related subtypes, and normal/LUAD tissue samples, respectively. Twenty-eight differentially expressed and highly mutated MPRGs were obtained. A prognostic risk model with 7 DE-MPRGs (RGS13, ADRB2, DDIT4, MS4A2, ALDH2, CTSH, and PKM) was constructed. This prognostic model still has a good prediction effect in the GSE72094 dataset. ZNF536 and DNAH9 were mutated in the low-risk group, while COL11A1 was mutated in the high-risk group, and they were highly correlated with the characteristic genes. A total of 11 immune cells were significantly different in the high/low-risk groups. Five cell types were again identified in the macrophage cluster, and then NK cells: CD56hiCD62L+ differentiated earlier and were present mainly on 2 branches. While macrophages were present on 2 branches and differentiated later. It was found that the expression levels of BCLAF1 and MAX were higher in cluster 1, which might be the TFs affecting the expression of the characteristic genes. Moreover, qPCR confirmed that the expression of the prognosis genes was generally consistent with the results of the bioinformatic analysis. Conclusion: Seven MPRGs (RGS13, ADRB2, DDIT4, MS4A2, ALDH2, CTSH, and PKM) were identified as prognostic genes for LUAD and revealed the mechanisms of MPRGs at the single-cell level.

A bionic "Trojan horse"-like gene delivery system hybridized with tumor and macrophage cell membrane for cancer therapy.

MiRNA-based gene therapy as a novel targeted therapy has yielded promising results in experimental cancer treatment, however, the inefficient delivery of miRNA to target tissues has limited its application in vivo. Here a unique dual-membrane-camouflaged miRNA21 antagomir delivery nanoplatform (M@NPs/miR21) with immune escape and homologous targeting properties was constructed by cancer cell membrane and macrophage membrane. Different from the single-cell membrane camouflage strategy, the dual-membrane camouflage miRNA21 antagomir delivery nanoplatform based on modification of CD47 protein with immune escape signal and galectin-3 protein with tumor cell aggregation enables efficient, safe and targeted therapy for colon cancer and lung metastases. Camouflaged with the dual-cell membrane, the "Trojan horse" like "pseudo-tumor cell" and/or "pseudo-macrophage" (M@NPs/miR21) carried the target gene miR21 antagomir to the tumor site and showed significant anti-tumor properties at the periphery and the core of subcutaneous tumor tissues. In addition, M@NPs/miR21 was more likely to penetrate dense tumor tissues and function within the tumor mass than NPs/miR21 without membrane coating. M@NPs/miR21 can deliver miR21 antagomir into MC38 cancer cells and tumor tissues, promote tumor apoptosis, and regulate the expression of Bcl2 and Ki67. Moreover, the M@NPs/miR21 gene delivery system not only can effectively inhibit the progression of subcutaneous tumors and lung metastases, but also showed minimal toxicity and good biosafety, making this delivery system particularly attractive for future translational research.

6-Methoxydihydrosanguinarine induces apoptosis and autophagy in breast cancer MCF-7 cells by accumulating ROS to suppress the PI3K/AKT/mTOR signaling pathway.

6-Methoxydihydrosanguinarine (6-MDS) is a natural benzophenanthridine alkaloid extracted from Hylomecon japonica (Thunb.) Prantl. It is the first time to explore the effect and mechanism of 6-MDS in breast cancer. Network pharmacology, molecular docking, and molecular dynamics simulation technology were adopted to identify the potential targets and pathways of 6-MDS in breast cancer. Besides, cell proliferation, apoptosis, and western blotting assays were conducted to investigate the effect of 6-MDS on MCF-7 cells. Network pharmacology, molecular docking, and molecular dynamics simulation results confirmed the effect of 6-MDS on resisting breast cancer via the PI3K/AKT/mTOR signaling pathway. In addition, the functional experiments results demonstrated that 6-MDS inhibited proliferation and induced apoptosis and autophagy. The autophagy inhibitor chloroquine and the silence of Atg5 augmented the effect of 6-MDS on promoting apoptosis. Furthermore, 6-MDS suppressed the PI3K/AKT/mTOR signaling pathway, and the PI3K inhibitor LY294002 enhanced these changes and promoted the 6-MDS pro-apoptotic and autophagy effects. 6-MDS triggered the generation of reactive oxygen species. The pretreatment with antioxidant N-acetyl-L-cysteine reversed the changes induced by 6-MDS, including increases in apoptosis and autophagy and inhibition of the PI3K/AKT/mTOR pathway. In conclusion, 6-MDS induces the apoptosis and autophagy of MCF-7 cells by ROS accumulation to suppress the PI3K/AKT/mTOR signaling pathway.

Astragalin mitigates inflammatory osteolysis by negatively modulating osteoclastogenesis via ROS and MAPK signaling pathway.

Inflammatory bone destruction has gradually attracted attention worldwide and has been observed in several kinds of pathological bone diseases, such as osteoarthritis, osteomyelitis, rheumatic arthritis, and other infectious clinical trials in the skeletal system. In this regard, excessive osteoclasts and bone resorption activity participate in osteolytic processes. Thus, negatively modulating osteoclast differentiation and bone erosion has been considered an effective therapeutic strategy to limit the poor progression of inflammatory osteolysis. Astragalin (AST) is a bioactive component of traditional Chinese drugs, such as Rosa agrestis, which presents anti-inflammatory and antioxidant effects. However, it is unclear how AST may play an essential role in regulating the dynamic balance of the bone matrix by affecting osteoclastogenesis. This study found that AST could inhibit osteoclastic formation and bone resorption activity in a dose-dependent manner without cytotoxicity. Administration of AST also inhibited the expression of cathepsin K, c-Fos, NFATc1, and TRAP at different stages of mRNA and protein levels during osteoclastogenesis. Reactive oxygen species (ROS) signalling could also be modulated by treatment with AST during RANKL-induced osteoclast differentiation through the Nrf2-HO1 signalling pathway. Additionally, AST could negatively regulate mitogen-activated protein kinase (MAPK) signalling in this process. In vivo, AST significantly reduced lipopolysaccharide (LPS)-induced bone loss in an osteolytic mouse model. AST might be a promising therapeutic candidate for treating osteolytic bone diseases in the future.

Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib.

BACKGROUND: The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. METHODS: The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment. RESULTS: Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment. CONCLUSIONS: Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment.

DDX47 promotes cell proliferation and migration in lung adenocarcinoma.

This study aimed to investigate the role of DEAD-box helicase 47 (DDX47) in lung adenocarcinoma (LUAD). Our results demonstrated that DDX47 was highly expressed in LUAD tissues, and its high expression predicted a poor prognosis. Bioinformatics analysis indicated that DDX47 involved RNA processing and cell division. Furthermore, knockdown of DDX47 reduced cell proliferation and migration in vitro. In sum, our data confirmed the cancer-promoting effect of DDX47.

[LINC00668 is Highly Expressed in Lung Squamous Cell Carcinoma and 
Promotes Tumor Cell Migration and Invasion].

BACKGROUND: A lack of effective treatment for lung squamous cell carcinoma (LUSC) makes it an important factor restricting the 5-year survival rate of non-small cell lung cancer (NSCLC). Long non-coding RNA 00668 (LINC00668) was reported to play crucial regulatory roles in the tumorigenesis and progression of various cancers; however, its role in LUSC is unclear. The aim of this study was to investigate the prognosis value and biological function of LINC00668 in NSCLC, especially in LUSC. METHODS: The expression pattern of LINC00668 and its relationship with clinical characteristics and prognosis of patients were investigated in the NSCLC especially LUSC based on The Cancer Genome Altas (TCGA) database. Its function in LUSC cells was explored in vitro. RESULTS: LINC00668 expression was significantly up-regulated in LUSC patients and high expression level of LINC00668 was associated with advanced tumor-node-metastasis (TMN) stage. Moreover, the expression of LINC00668 significantly increased in smoking patients, and was a prognostic indicator for overall survival (OS) of smoking patients with LUSC. In vitro experiments showed that LINC00668 has significantly higher expression level in LUSC cell lines and tissues compared to normal bronchial epithelial cell and para-tumor tissues; meanwhile, functional assay indicated knockdown of LINC00668 effectively inhibited the migration and invasion of LUSC cells. CONCLUSIONS: LINC00668 might closely relate to the development of LUSC, and inhibition of LINC00668 may reduce the metastasis of LUSC.

Pretreatment HDL-C and ApoA1 are predictive biomarkers of progression-free survival in patients with EGFR mutated advanced non-small cell lung cancer treated with TKI.

BACKGROUND: We aimed to explore the correlation between blood lipids (high density lipoprotein cholesterol [HDL-C] and apolipoprotein A1 [ApoA1]) and epidermal growth factor receptor (EGFR) T790M mutation, as well as its predictive role in clinical efficacy and progression-free survial (PFS) in advanced non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKI). METHODS: We retrospectively collected information of 153 patients with advanced NSCLC harboring exon EGFR mutation and receiving EGFR-TKI. RESULTS: The best cutoff value for HDL-C and ApoA1 was determined to be 1.15 and 1.14 mmol/l. The overall response rate (ORR) was 67.7% in the high HDL-C group and 46.6% in the low HDL-C group, respectively. The ORR of the high ApoA1 group showed a significant increase than that of the low ApoA1 group (68.1% vs. 38.5%). The mean ApoA1 level of the EGFR T790M mutation-positive group was significantly higher than that of the EGFR T790M mutation-negative group (1.13 g/l vs. 1.01 g/l). Patients with high ApoA1 levels were related to the EGFR T790M mutation (r = 0.324). (3) The median progression-free survival (PFS) of the high HDL-C group and low HDL-C group were 13.00 months and 10.20 months. The median PFS of the high ApoA1 group and the low ApoA1 group were 12.10 and 10.00 months, respectively. Multivariate Cox stepwise regression model analysis demonstrated ECOG PS, pathological type and HDL-C were confirmed as critical and independent predictors of PFS. CONCLUSIONS: Patients with EGFR T790M mutations often show higher ApoA1 levels. Peripheral serum HDL-C and ApoA1 before treatment can be used as potential significant factors for predicting clinical efficacy and PFS in advanced NSCLC patients treated with EGFR-TKI.

3-Epipachysamine B suppresses proliferation and induces apoptosis of breast cancer cell via PI3K/AKT/mTOR signaling pathway.

3-Epipachysamine B is a natural steroidal alkaloid isolated from Pachysandra terminalis Sieb. et Zucc. (known locally as Kunxianqi). Kunxianqi contains numerous compounds with demonstrated activity against breast cancer (BRCA). However, it is unknown whether 3-epipachysamine B also has anti-BRCA efficacy. In the present study, we employed network pharmacology technology to search and find potential molecular targets of 3-epipachysamine B. We applied cell proliferation, apoptosis, and western blotting assays to test the predicted key targets and the effects of 3-epipachysamine B against BRCA. Network pharmacology disclosed 80 potential BRCA-related targets of 3-epipachysamine B and assigned them to 75 signaling pathways. Of these, the most highly enriched was the PI3K/AKT signaling pathway. PIK3R1, AKT1, and mTOR had high degrees and betweenness centrality in protein-protein interaction network and are associated with PI3K/AKT signaling. Molecular docking and molecular dynamics simulation indicated strong binding between 3-epipachysamine B and PIK3R1, AKT1, and mTOR. 3-Epipachysamine B repressed the proliferation and induced the apoptosis of BRCA cells, as well as downregulated P-AKT/AKT, P-mTOR/mTOR, and P-PI3K/PI3K in the cells. The PI3K inhibitor LY294002 augmented these changes. Hence, 3-epipachysamine could also prove effective as an anticancer agent in future animal tumor model and human clinical breast cancer trials. Successful validation results could lead to a safe and effective new breast cancer treatment that improves patient prognosis and quality of life.

Overexpression of BCCIP predicts an unfavorable prognosis and promotes the proliferation and migration of lung adenocarcinoma.

BACKGROUND: Lung cancer accounts for the highest rate of cancer-related diagnosis and mortality. Lung adenocarcinoma (LUAD) is the most common histopathological type. BCCIP was originally identified as a BRCA2 and CDKN1A interacting protein. In different cancers, BCCIP plays different roles. The role of BCCIP in LUAD is still unknown. METHODS: The expression and prognostic value of BCCIP was analyzed using public databases, including LCE, GEPIA, TCGA, and clinical specimens. Bioinformatic analysis and vitro experiments were conducted to explore the biological functions of BCCIP in LUAD. By using the GEPIA and TIMER databases, we investigated the correlations between LUAD expression and immune infiltration in LUAD. RESULTS: Compared with normal tissue, LUAD tissue had a higher expression level of BCCIP and high expression level of BCCIP was detrimental to LUAD patient survival. The suppression of BCCIP inhibited LUAD cell proliferation, migration and resulted in G1/S phase arrest in vitro. Bioinformatic analysis demonstrated that BCCIP could be associated with cell cycle, DNA repair and E2F transcription factor family. There were significant correlations between BCCIP expression and immune infiltrates, including B cell, CD4+ T cell, macrophage, neutrophil and dendritic cells. Furthermore, BCCIP expression showed strong correlations with diverse immune marker sets in LUAD, such as B cell, macrophage and DC. CONCLUSIONS: Overexpression of BCCIP predicts an unfavorable prognosis and promotes the proliferation and migration of lung adenocarcinoma cells. BCCIP is correlated with immune infiltration in LUAD. Suppression of BCCIP may be a potential approach in the prevention and treatment of LUAD.

CircPVT1 promotes proliferation of lung squamous cell carcinoma by binding to miR-30d/e.

BACKGROUND: Circular RNAs (circRNAs) are a new type of extensive non-coding RNAs that regulate the activation and progression of different human diseases, including cancer. However, information on the underlying mechanisms and clinical significance of circRNAs in lung squamous cell carcinoma (LUSC) remains scant. METHODS: The expression profile of RNAs in 8 LUSC tissues, and 9 healthy lung tissues were assayed using RNA sequencing (RNA-seq) techniques. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to profile the expression of circPVT1 and its relationship with the prognosis of LUSC, i.e., survival analysis. Moreover, in vitro and in vivo experiments were performed to evaluate the impacts of circPVT1 on the growth of tumors. RNA pull-down tests, mass spectrometry, dual-luciferase reporter assessment, and RNA immune-precipitation tests were further conducted to interrogate the cross-talk between circPVT1, HuR, or miR-30d/e in LUSC. RESULTS: Our data showed that circPVT1 was upregulated in LUSC tissues, serum, and cell lines. LUSC patients with higher circPVT1 expression exhibited shorter survival rates. The in vivo and in vitro data revealed that circPVT1 promotes the proliferation of LUSC cells. Additionally, mechanistic analysis showed that HuR regulated circPVT1. On the other hand, circPVT1 acted as a competing endogenous RNA (ceRNA) of miR-30d and miR-30e in alleviating the suppressive influences of miR-30d and miR-30e on its target cyclin F (CCNF). CONCLUSION: CircPVT1 promotes LUSC progression via HuR/circPVT1/miR-30d and miR-30e/CCNF cascade. Also, it acts as a novel diagnostic biomarker or treatment target of individuals diagnosed with LUSC.

Erratum: Long non-coding RNA LINC01116 is overexpressed in lung adenocarcinoma and promotes tumor proliferation and metastasis.

[This corrects the article on p. 4302 in vol. 12, PMID: 32913506.].

Long noncoding RNA LMO7DN inhibits cell proliferation by regulating the cell cycle in lung adenocarcinoma.

In our previous study, we reported that the long noncoding RNA, LMO7 downstream neighbor (LMO7DN), has a strong prognostic value in lung adenocarcinoma (LUAD). In this study, we further investigated the role of LMO7DN in LUAD progression. LMO7DN was found to be expressed at low levels in LUAD tissues, and its high expression predicted good prognosis. Bioinformatics analysis indicated that LMO7DN was closely associated with the cell cycle. Furthermore, we found that cell proliferation was significantly enhanced following knockdown of LMO7DN, and the number of cells in the G2/M phase was markedly decreased, whereas there was no change in apoptosis. Thus, LMO7DN inhibits cell proliferation by affecting the cell cycle and is of significant prognostic value in LUAD.

Exploring the mechanism of Cremastra Appendiculata (SUANPANQI) against breast cancer by network pharmacology and molecular docking.

BACKGROUND: SUANPANQI, the pseudo phosphorous stem of Cremastra appendiculata, is one of the most well-known traditional Chinese medicine, which has been shown to inhibit tumorigenesis in various human cancers. However, the underlying mechanism of SUANPANQI treatment against breast cancer (BRCA) remains unclear. In this study. we aim to investigate the bioactive compounds and mechanisms of SUANPANQI in the treatment of BRCA based on network pharmacology and molecular docking. METHODS: The compounds were collected from previous research. SwissADME was used to screen bioactive compounds. The targets corresponding to SUANPANQI and BRCA were obtained using MalaCards and SwissTargetPrediction. SUANPANQI-related and BRCA-related targets were found and then overlapped to get intersections, which represented potential anti-BRCA targets of SUANPANQI. The Cytoscape software was used to construct bioactive compounds targeting the BRCA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the targets was extracted from the metascape database, then conducted using the Cluster Profiler package in R software. Protein-Protein interaction (PPI) network was constructed using the STRING online database and analyzed using Cytoscape software. Pivotal genes were screened using the topological analysis, survival analysis, and pathological stage analysis. Molecular docking analysis was used to verify whether the bioactive compounds had a definite affinity with the pivotal targets. RESULTS: Sixty-five bioactive compounds of SUANPANQI were involved with 225 predicted BRCA targets. Then, a compound-target network and a PPI network were constructed. The GO analysis and KEGG enrichment analysis suggested that SUANPANQI worked against BRCA via PI3K-Akt, Ras, FoxO, Rap1, and ErbB signaling pathways, etc. After topological analysis, survival analysis, and pathological stage analysis of the SUANPANQI potential targets against BRCA, 6 pivotal target genes (AR, HSP90AA1, MMP9, PGR, PTGS2, TNF) that were highly responsible for the therapeutic effects of SUANPANQI against BRCA were obtained. Molecular docking results showed that 6 bioactive compounds of SUANPANQI had strong binding efficiency with the 6 pivotal genes. CONCLUSIONS: The present study clarifies the mechanism of SUANPANQI against BRCA through multiple targets and pathways, and provides evidence to support its clinical use.

GALNT2 promotes cell proliferation, migration, and invasion by activating the Notch/Hes1-PTEN-PI3K/Akt signaling pathway in lung adenocarcinoma.

AIMS: Our study aimed to investigate the function of GALNT2 in lung adenocarcinoma (LUAD). MAIN METHODS: We used network tools and tissue microarray immunohistochemistry to measure the expression levels of GALNT2 in LUAD. Kaplan-Meier curves and Cox regression methods were used in survival analysis. We detected the role of GALNT2 in cell lines by Cell Counting Kit-8, colony formation, transwell, and wound healing assays. We performed Western blotting to evaluate downstream protein levels. KEY FINDINGS: GALNT2 was highly expressed in LUAD samples and indicated a poor prognosis. Knockdown of GALNT2 suppressed cell line proliferation, migration, and invasion abilities, while overexpression of GALNT2 enhanced those phenotypes. Moreover, GALNT2 activated Notch/Hes1-PTEN-PI3K/Akt signaling axis. SIGNIFICANCE: Our data confirmed the cancer-promoting effect of GALNT2, and might provide a new approach for LUAD therapy.

Association Between Neutrophil-Lymphocyte Ratio and All-Cause Mortality and Cause-Specific Mortality in US Adults, 1999-2014.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) is a novel marker of inflammation. Emerging studies have evaluated the relationship of NLR with cardiovascular diseases and malignant conditions. However, rare studies regarded the association between NLR and long-term health status. This study aimed to evaluate the association of NLR with all-cause mortality and cause-specific mortality among adults in the United States. METHODS: We obtained eight cycles data of National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2014, and enrolled 32328 participants after certain screening. By weighted chi-square test and linear regression analysis, we analyzed the correlation between NLR and baseline characteristics of the participants. Kaplan-Meier curves and Cox regression models were used to assess the survival relevance of NLR. We conducted stratified analysis, interaction analysis, and sensitivity analysis to robustness of our results. RESULTS: Participants with high NLR levels had a higher risk of death. After adjustment for baseline characteristics, the hazard ratio comparing the higher vs lower NLR levels was 1.43 (95% CI, 1.18-1.73) for all-cause mortality, 1.27 (95% CI, 0.84-1.92) for cancer mortality, and 1.44 (95% CI, 0.96-2.16) for cardiovascular disease mortality. Stratified analysis found that the observed associations between NLR levels and mortality did not differ significantly. CONCLUSION: In this nationally representative cohort of US adults, higher NLR was significantly associated with an increased risk of all-cause mortality.

Long non-coding RNA LINC01116 is overexpressed in lung adenocarcinoma and promotes tumor proliferation and metastasis.

Long non-coding RNA LINC01116 is involved in the occurrence and progression of a variety of cancers. However, the specific role of LINC01116 in lung adenocarcinoma (LUAD) remains unclear. In this work, we found that LINC01116 was overexpressed in LUAD tissues and cell lines and that increased expression was significantly associated with worse prognoses in patients with LUAD. Univariate and multivariate Cox regression analyses indicated that LINC01116 was an independent risk factor for the prognosis of patients with LUAD. Downregulation of LINC01116 significantly inhibited cell proliferation and migration, promoted cell apoptosis, and prevented cell progression from G1 to S phase. In addition, downregulation of LINC01116 significantly inhibited the epithelial-mesenchymal transition, leading to an increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. In summary, our results suggest that LINC01116 may act as an oncogene in LUAD and may be a valuable prognostic biomarker for patients with LUAD.