Invasion Of Lung Cancer Cells Research Articles

CircHERC1 promotes non-small cell lung cancer cell progression by sequestering FOXO1 in the cytoplasm and regulating the miR-142-3p-HMGB1 axis

BackgroundNoncoding RNAs such as circular RNAs (circRNAs) are abundant in the human body and influence the occurrence and development of various diseases. Non-small cell lung cancer (NSCLC) is one of the most common malignant cancers. Information on the functions and mechanism of circRNAs in lung cancer is limited; thus, the topic needs more exploration. The purpose of this study was to identify aberrantly expressed circRNAs in lung cancer, unravel their roles in NSCLC progression, and provide new targets for lung cancer diagnosis and therapy.MethodsHigh-throughput sequencing was used to analyze differential circRNA expression in patients with lung cancer. qRT‒PCR was used to determine the level of circHERC1 in lung cancer tissues and plasma samples. Gain- and loss-of-function experiments were implemented to observe the impacts of circHERC1 on the growth, invasion, and metastasis of lung cancer cells in vitro and in vivo. Mechanistically, dual luciferase reporter assays, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down experiments were performed to confirm the underlying mechanisms of circHERC1. Nucleocytoplasmic localization of FOXO1 was determined by nucleocytoplasmic isolation and immunofluorescence. The interaction of circHERC1 with FOXO1 was verified by RNA pull-down, RNA immunoprecipitation (RIP) and western blot assays. The proliferation and migration of circHERC1 in vivo were verified by subcutaneous and tail vein injection in nude mice.ResultsCircHERC1 was significantly upregulated in lung cancer tissues and cells, ectopic expression of circHERC1 strikingly facilitated the proliferation, invasion and metastasis, and inhibited the apoptosis of lung cancer cells in vitro and in vivo. However, knockdown of circHERC1 exerted the opposite effects. CircHERC1 was mainly distributed in the cytoplasm. Further mechanistic research indicated that circHERC1 acted as a competing endogenous RNA of miR-142-3p to relieve the repressive effect of miR-142-3p on its target HMGB1, activating the MAPK/ERK and NF-κB pathways and promoting cell migration and invasion. More importantly, we found that circHERC1 could bind FOXO1 and sequester it in the cytoplasm, adjusting the feedback AKT pathway. The accumulation of FOXO1 in the cytosol and nuclear exclusion promoted cell proliferation and inhibited apoptosis. CircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential prognostic biomarker and therapeutic target for NSCLC.ConclusionsCircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential diagnosis biomarker and therapeutic target for NSCLC. Our findings indicate that circHERC1 facilitates the invasion and metastasis of NSCLC cells by regulating the miR-142-3p/HMGB1 axis and activating the MAPK/ERK and NF-κB pathways. In addition, circHERC1 can promote cell proliferation and inhibit apoptosis by sequestering FOXO1 in the cytoplasm to regulate AKT activity and BIM transcription.

LncRNA MIR210HG promotes the proliferation, migration, and invasion of lung cancer cells by inhibiting the transcription of SH3GL3.

Lung cancer (LCa), the most frequent malignancy worldwide, causes millions of mortalities each year. Overexpression of the long noncoding RNA MIR210HG in LCa has been established; however, a more comprehensive investigation into its biological role within LCa is imperative. This study aimed to validate the MIR210H levels in LCa tissues and cells. The expression of indicated genes was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and/or Western blotting. The viability, proliferation, migration, and invasion of LCa cells were measured using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), colony formation, wound healing, and transwell assays, respectively. The methylation levels of LCa cells were determined via methylation-specific PCR; additionally, chromatin immunoprecipitation or RNA immunoprecipitation assays were performed to determine the targeting relationship between DNA methyltransferase 1 (DNMT1) and the SH3-domain containing CRB2 like 3 (SH3GL3) promoters and the interaction between DNMT1 and MIR210HG, respectively. Our findings revealed the upregulation of MIR210HG, coupled with a diminished expression of SH3GL3 in LCa tissues and cells. Knockdown of MIR210HG or overexpression of SH3GL3 suppressed the proliferative, migratory, and invasive capacities of the cells. DNMT1 bound to the SH3GL3 promoter region, and MIR210HG inhibited the transcription of SH3GL3 by recruiting DNMT1. These findings indicate that MIR210HG facilitates LCa cell growth and metastasis by repressing SH3GL3 transcription via the recruitment of DNMT1 to the SH3GL3 promoter region.

Constructing an APOBEC-related gene signature with predictive value in the overall survival and therapeutic sensitivity in lung adenocarcinoma

BackgroundAPOBEC family play an important role in cancer mutagenesis and tumor development. The role of APOBEC family in lung adenocarcinoma (LUAD) has not been studied comprehensively. Materials and methodsThe expression data of pan-cancer as well as LUAD was obtained from public databases. The expression level of APOBEC family genes was analyzed in different normal and cancer tissues. APOBEC mutagenesis enrichment score (AMES) was utilized to evaluate the APOBEC-induced mutations and the relation of APOBEC with genomic instability. Gene set enrichment analysis was used to identify differentially enriched pathways. Univariate Cox regression and Lasso regression were applied to screen key prognostic genes. The immune cell infiltration was estimated by CIBERSORT. RT-qPCR assay, CCK-8 and Transwell assay were conducted to explore gene expression and lung cancer cell invasion. ResultsCancer tissues had significantly altered expression of APOBEC family genes and the expression patterns of APOBEC family were different in different cancer types. APOBEC3B was the most aberrantly expressed in most cancer types. In LUAD, we observed a significantly positive correlation of AMES with intratumor heterogeneity (ITH), tumor neoantigen burden (TNB), and tumor mutation burden (TMB). High AMES group had high mutation counts of DNA damage repair pathways, and high enrichment of cell cycle and DNA repair pathways. We identified four prognostic genes (LYPD3, ANLN, MUC5B, and FOSL1) based on AMES, and constructed an AMES-related gene signature. The expressions of four genes were enhanced and accelerated the invasion ability and viability of lung cancer cells. Furthermore, we found that high group increased oxidative stress level. ConclusionsAPOBEC family was associated with genomic instability, DNA damage-related pathways, and cell cycle in LUAD. The AMES-related gene signature had a great potential to indicate the prognosis and guide immunotherapy/chemotherapy for patients suffering from LUAD.

Exosomal long noncoding RNA MLETA1 promotes tumor progression and metastasis by regulating the miR-186-5p/EGFR and miR-497-5p/IGF1R axes in non-small cell lung cancer

BackgroundLung cancer is the most common and deadliest cancer worldwide, and approximately 90% of all lung cancer deaths are caused by tumor metastasis. Tumor-derived exosomes could potentially promote tumor metastasis through the delivery of metastasis-related molecules. However, the function and underlying mechanism of exosomal long noncoding RNA (lncRNA) in lung cancer metastasis remain largely unclear.MethodsCell exosomes were purified from conditioned media by differential ultracentrifugation and observed using transmission electron microscopy, and the size distributions were determined by nanoparticle tracking analysis. Exosomal lncRNA sequencing (lncRNA-seq) was used to identify long noncoding RNAs. Cell migration and invasion were determined by wound-healing assays, two-chamber transwell invasion assays and cell mobility tracking. Mice orthotopically and subcutaneously xenografted with human cancer cells were used to evaluate tumor metastasis in vivo. Western blot, qRT‒PCR, RNA-seq, and dual-luciferase reporter assays were performed to investigate the potential mechanism. The level of exosomal lncRNA in plasma was examined by qRT‒PCR. MS2-tagged RNA affinity purification (MS2-TRAP) assays were performed to verify lncRNA-bound miRNAs.ResultsExosomes derived from highly metastatic lung cancer cells promoted the migration and invasion of lung cancer cells with low metastatic potential. Using lncRNA-seq, we found that a novel lncRNA, lnc-MLETA1, was upregulated in highly metastatic cells and their secreted exosomes. Overexpression of lnc-MLETA1 augmented cell migration and invasion of lung cancer. Conversely, knockdown of lnc-MLETA1 attenuated the motility and metastasis of lung cancer cells. Interestingly, exosome-transmitted lnc-MLETA1 promoted cell motility and metastasis of lung cancer. Reciprocally, targeting lnc-MLETA1 with an LNA suppressed exosome-induced lung cancer cell motility. Mechanistically, lnc-MLETA1 regulated the expression of EGFR and IGF1R by sponging miR-186-5p and miR-497-5p to facilitate cell motility. The clinical datasets revealed that lnc-MLETA1 is upregulated in tumor tissues and predicts survival in lung cancer patients. Importantly, the levels of exosomal lnc-MLETA1 in plasma were positively correlated with metastasis in lung cancer patients.ConclusionsThis study identifies lnc-MLETA1 as a critical exosomal lncRNA that mediates crosstalk in lung cancer cells to promote cancer metastasis and may serve as a prognostic biomarker and potential therapeutic target for lung cancer diagnosis and treatment.

Effects of cilengitide derivatives on TGF-β1-induced epithelial-to-mesenchymal transition and invasion in gefitinib-resistant non-small cell lung cancer cells.

Long-term administration of tyrosine kinase inhibitors (TKIs) used for the treatment of non-small cell lung cancer (NSCLC) induces TKI resistance in cells. The appearance of resistant cells requires the combined administration of another therapeutic agent and may cause side effects in the gastrointestinal and central nervous system. In previous studies, we found that derivatives of cilengitide, a cyclic Arg-Gly-Asp (RGD) peptide, exert NSCLC apoptotic and anti-epithelial-mesenchymal transition (EMT) effects. In particular, cRGDwV and cRGDyV, which are cyclic peptides containing aromatic amino acids, were found to inhibit NSCLC cell growth, TGF-β1-induced EMT, and invasion. In this study, we confirmed the effects of cRGDwV and cRGDyV on proliferation, TGF-β1-induced EMT marker expression, migration, and invasion in gefitinib-resistant NSCLC A549 (A549GR) cells. In A549GR cells, cRGDwV and cRGDyV showed inhibitory effects on the expression of mesenchymal marker expression, migration, and invasion. These results indicate that cyclic RGD peptides containing aromatic amino acids can be used to inhibit mesenchymal marker expression as well as migration and invasion in gefitinib-resistant cells.

UPK1B promoted the invasion and stem cell characteristics of non-small cell lung cancer cells by modulating c-myc/Sox4 axis

Non-small cell lung cancer (NSCLC) is a malignant tumor with extremely high mortality. Uroplakin1B (UPK1B) promotes the occurrence and development of multiple types of cancer by enhancing the expression of c-myc and Sox4. However, whether UPK1B can modulate the development of NSCLC by regulating c-myc/Sox4 axis is unclear. In this study, UPK1B was overexpressed or knocked down in the non-small cell lung cancer cells (NSCLCs) were. Next, the proliferation and invasion of those cells were detected with the EdU staining and transwell assays. Sphere formation assays was performed to examine the stem cell characteristics of those cells. Then, we overexpressed the Sox4 in UPK1B knockdown cells and determined the proliferation and invasion of those cells. Our results showed that UPK1B promoted the proliferation, invasion and stem cell characteristics of NSCLCs. In addition, UPK1B enhanced the expression of c-myc, Sox4 and stem cell associated proteins in those cells. Overexpression of Sox4 rescued the proliferation and invasion of NSCLCs, which were suppressed by the UPK1B knockdown. In summary, our study suggested that UPK1B enhanced the invasiveness and stem cell characteristics of NSCLCs by activating c-myc/UPK1B axis.

CEP20 promotes invasion and metastasis of non-small cell lung cancer cells by depolymerizing microtubules

Worldwide, Lung cancer is the leading cause of cancer-related death and poses a direct health threat, non-small cell lung cancer (NSCLC) is the most common type. In this study, we demonstrated that centrosomal protein 20 (CEP20) is upregulated in NSCLC tissues and associated with cancer invasion metastasis. Notably, CEP20 depletion inhibited NSCLC cell proliferation, migration, and microtubule polymerization. Mechanistically, we discovered that CEP20 is critical in the development of NSCLC by regulating microtubule dynamics and cell adhesion-related signaling pathways. Furthermore, the knockdown or overexpression of CEP20 affects microtubule polymerization in A549 cell lines. Our research provides a promising therapeutic target for the diagnosis and treatment of lung cancer, as well as a theoretical and experimental basis for clinical application.

LncRNA KCNQ1OT1/miR-496/HMGB1 Signaling Axis Promotes Invasion and Migration of Non-small Cell Lung Cancer Cells.

Enhanced invasion and migration of non-small cell lung cancer (NSCLC) cells is the major cause of metastasis and poor prognosis in NSCLC. This study was conducted to investigate the role and mechanism of lncRNA KCNQ1OT1 in the proliferation, invasion, and migration of NSCLC cells. The expression of KCNQ1OT1 in NSCLC was analyzed in the StarBase database, and the target miRNA of KCNQ1OT1 as well as the target genes of the miRNA was predicted. Then, the mRNA expression levels of KCNQ1OT1, miR-496, and HMGB1 were detected in clinical tissue samples and cells by qRT-PCR assay. Besides, the protein levels of HMGB1 were detected by Western blot. MTT assay, transwell assay, and scratch assay were used to determine the proliferation, invasion, and migration ability of NSCLC cells, respectively. Correlation analysis was performed to assess the correlation between the expression of KCNQ1OT1, miR-496, and HMGB1 in clinical NSCLC samples. Dual-luciferase reporter gene assay was conducted to analyze the interaction between KCNQ1OT1 and miR-496 and between miR-496 and HMGB1. The database results showed that KCNQ1OT1 was highly expressed in NSCLC. Similarly, we found that the expression level of KCNQ1OT1 was significantly higher in NSCLC tissues and cells than that in the corresponding normal tissues and cells. The results of MTT assay, transwell assay, and scratch assay demonstrated that KCNQ1OT1 significantly enhanced the proliferation, invasion, and migration of NSCLC cells. Further mechanism exploration revealed that KCNQ1OT1 could sponge miR-496, and miR-496 directly targeted and regulated the expression of HMGB1. The expression of miR-496 and either KCNQ1OT1 or HMGB1 were negatively correlated in NSCLC, while the expression of KCNQ1OT1 and HMGB1 were positively correlated. Compared with normal paracancer tissues, miR-496 was much lower and HMGB1 was much higher expressed in NSCLC tissues. The results of cotransfection also further demonstrated that miR-496 inhibitor or sh-HMGB1 cotransfected with sh-KCNQ1OT1 could significantly decrease or increase the ability of sh-KCNQ1OT1 to inhibit the proliferation, invasion, and migration of H1299 cells, respectively. In conclusion, lncRNA KCNQ1OT1 promotes the invasion and migration of NSCLC cells through miR-496/HMGB1 signaling axis.

Dissection of paracrine/autocrine interplay in lung tumor microenvironment mimicking cancer cell-monocyte co-culture models reveals proteins that promote inflammation and metastasis

BackgroundTumor cell-monocyte interactions play crucial roles in shaping up the pro-tumorigenic phenotype and functional output of tumor-associated macrophages. Within the tumor microenvironment, such heterotypic cell–cell interactions are known to occur via secretory proteins. Secretory proteins establish a diabolic liaison between tumor cells and monocytes, leading to their recruitment, subsequent polarization and consequent tumor progression.MethodsWe co-cultured model lung adenocarcinoma cell line A549 with model monocytes, THP-1 to delineate the interactions between them. The levels of prototypical pro-inflammatory cytokines like TNF-\U0001d6fc, IL-6 and anti-inflammatory cytokines like IL-10 were measured by ELISA. Migration, invasion and attachment independence of lung cancer cells was assessed by wound healing, transwell invasion and colony formation assays respectively. The status of EMT was evaluated by immunofluorescence. Identification of secretory proteins differentially expressed in monocultures and co-culture was carried out using SILAC LC–MS/MS. Various insilico tools like Cytoscape, Reacfoam, CHAT and Kaplan–Meier plotter were utilized for association studies, pathway analysis, functional classification, cancer hallmark relevance and predicting the prognostic potential of the candidate secretory proteins respectively.ResultsCo-culture of A549 and THP-1 cells in 1:10 ratio showed early release of prototypical pro-inflammatory cytokines TNF-\U0001d6fc and IL-6, however anti-inflammatory cytokine, IL-10 was observed to be released at the highest time point. The conditioned medium obtained from this co-culture ratio promoted the migration, invasion and colony formation as well as the EMT of A549 cells. Co-culturing of A549 with THP-1 cells modulated the secretion of proteins involved in cell proliferation, migration, invasion, EMT, inflammation, angiogenesis and inhibition of apoptosis. Among these proteins Versican, Tetranectin, IGFBP2, TUBB4B, C2 and IFI30 were found to correlate with the inflammatory and pro-metastatic milieu observed in our experimental setup. Furthermore, dysregulated expression of these proteins was found to be associated with poor prognosis and negative disease outcomes in lung adenocarcinoma compared to other cancer types. Pharmacological interventions targeting these proteins may serve as useful therapeutic approaches in lung adenocarcinoma.ConclusionIn this study, we have demonstrated that the lung cancer cell-monocyte cross-talk modulates the secretion of IFI30, RNH1, CLEC3B, VCAN, IGFBP2, C2 and TUBB4B favoring tumor growth and metastasis.

LncRNA RP11-58O9.2 predicts poor prognosis and promotes progression of non-small cell lung cancer.

Long non-coding RNAs (lncRNAs) play a crucial role in non-small cell lung cancer (NSCLC). This study aimed to investigate the novel biomarker, lncRNA RP11-58O9.2, in patients with NSCLC. RP11-58O9.2 expression in NSCLC cells and tissues was detected by reverse transcription-quantitative polymerase chain reaction. Patient survival was analyzed in relation to RP11-58O9.2 expression levels. RP11-58O9.2 expression was knocked down and endogenous expression was verified in two NSCLC cell lines. Cell proliferation was then assessed by Cell Counting Kit-8 and colony-formation assays, and cell invasion and migration were assessed by Transwell and wound-healing assays, respectively. In vivo experiments were performed in mice, and the combination of RP11-58O9.2 and miR-6749-3p was predicted by miRanda. RP11-58O9.2 was highly expressed in NSCLC cell lines and tissues, and was associated with advanced stage, lymphatic metastasis, and differentiation group. High RP11-58O9.2 levels were also associated with shorter survival. RP11-58O9.2 knockdown inhibited the proliferation, invasion, and migration of lung cancer cells, and tumor growth in mouse xenografts in vivo. RP11-58O9.2 may target and regulate miR-6749-3p. LncRNA RP11-58O9.2 is associated with NSCLC prognosis and promotes lung cancer progression. Further studies are needed to investigate the mechanisms and the regulatory association between RP11-58O9.2 and miR-6749-3p.

Heat shock protein B7 (HSPB7) inhibits lung adenocarcinoma progression by inhibiting glycolysis.

In the present study, it was aimed to investigate the effects and potential mechanisms of heat shock protein B7 (HSPB7) on lung adenocarcinoma (LUAD). Bioinformatic analysis was performed to explore the association between HSPB7 expression and patients with LUAD. MTT, colony formation, wound healing and Transwell assays were performed to examine the proliferative, migratory and invasive abilities of H1975 and A549 cells. Western blot analysis was conducted to determine the corresponding protein expression. Co‑Immunoprecipitation and Chromatin immunoprecipitation assays were carried out to reveal the interaction between HSPB7 and myelodysplastic syndrome 1 and ecotropic viral integration site 1 complex locus (MECOM). In addition, an animal model was conducted by the subcutaneous injection of A549 cells into BALB/c nude mice, and tumor weight and size were measured. HSPB7 was downregulated in LUAD tissues and cells, and its expression level correlated with patient prognosis. Cell functional data revealed that silencing of HSPB7 promoted lung cancer cell proliferation, migration, invasion and epithelial mesenchymal transition (EMT); whereas overexpression of HSPB7 led to the opposite results. Furthermore, bioinformatics analysis showed that HSPB7 inhibited glycolysis. HSPB7 decreased glucose consumption, lactic acid production, and lactate dehydrogenase A, hexokinase 2 and pyruvate kinase muscle isoform 2 protein levels. The results demonstrated that MECOM was a transcription factor of HSPB7. Collectively, these results suggested that HSPB7 is regulated by MECOM, and that HSPB7 attenuates LUAD cell proliferation, migration, invasion and EMT by inhibiting glycolysis.

Nickel chloride promotes lung cancer invasion and metastasis by up-regulating the expression of E3 ubiquitin ligase TRIM31 through the IL-6/STAT3 signaling axis

Nickel compounds are widely used in industries and daily life as important industrial products. Long-term exposure to nickel compounds has been associated with increased incidence and poor prognosis of lung cancer. However, the molecular mechanism by which exposure to nickel compounds induces the malignant phenotype of lung cancer cells remains unclear. In this study, we confirmed that nickel chloride (NiCl2) exposure promotes invasion and metastasis through IL-6/STAT3 both in vitro and vivo. Mechanistically, we found that NiCl2 mediated the transcriptional regulation of E3 ubiquitin ligase TRIM31 by SATAT3 phosphorylation, and promoted its up-regulation. Overexpression TRIM31 is an independent risk factor for lung cancer patients, and it promotes the invasion and metastasis of lung cancer cells. In addition, E3 ubiquitination ligase TRIM31 binds to its substrate TP53 protein in the RING region and accelerates TP53 protein ubiquitination and degradation. Functional recovery experiments showed that NiCl2 exposure promotes the invasion and metastasis ability of lung cancer and ubiquitination-mediated degradation of TP53 protein through the STAT3/TRIM31 axis. These findings reveal the role and mechanism of NiCl2 in lung cancer progression, indicating that STAT3 and TRIM31 may be promising targets for the treatment of lung cancer.

LncRNA SLCO4A1-AS1 suppresses lung cancer progression by sequestering the TOX4-NTSR1 signaling axis

BackgroundMetastasis is a multistep process involving the migration and invasion of cancer cells and is a hallmark of cancer malignancy. Long non-coding RNAs (lncRNAs) play critical roles in the regulation of metastasis. This study aims to elucidate the role of the lncRNA solute carrier organic anion transporter family member 4A1-antisense 1 (SLCO4A1-AS1) in metastasis and its underlying regulatory mechanisms.MethodsA comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify metastasis-associated lncRNAs. Transwell migration and invasion assays, and a tail vein-injection mouse model were used to assess the migration and invasion of cancer cells in vitro and in vivo, respectively. High-throughput screening methods, including MASS Spectrometry and RNA sequencing (RNA-seq), were used to identify the downstream targets of SLCO4A1-AS1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA pull-down, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and chromatin immunoprecipitation (ChIp) assays were conducted to identify and validate the underlying regulatory mechanisms of SLCO4A1-AS1.ResultsSLCO4A1-AS1 reduced cancer cell migration and invasion by disrupting cytoskeleton filaments, and was associated with longer overall survival in patients with lung adenocarcinoma. SLCO4A1-AS1 directly interacted with the DNA-binding protein, TOX High Mobility Group Box Family Member 4 (TOX4), to inhibit TOX4-induced migration and invasion. Furthermore, RNA-seq revealed that neurotensin receptor 1 (NTSR1) is a novel and convergent downstream target of SLCO4A1-AS1 and TOX4. Mechanistically, SLCO4A1-AS1 functions as a decoy of TOX4 by interrupting its interaction with the NTSR1 promoter and preventing NTSR1 transcription. Functionally, NTSR1 promotes cancer cell migration and invasion through cytoskeletal remodeling, and knockdown of NTSR1 significantly inhibits TOX4-induced migration and invasion.ConclusionThese findings demonstrated that SLCO4A1-AS1 antagonizes TOX4/NTSR1 signaling, underscoring its pivotal role in lung cancer cell migration and invasion. These findings hold promise for the development of novel therapeutic strategies targeting the SLCO4A1-AS1/TOX4/NTSR1 axis as a potential avenue for effective therapeutic intervention in lung cancer.

Ugonin P inhibits lung cancer motility by suppressing DPP-4 expression via promoting the synthesis of miR-130b-5p

Lung cancer is the leading cause of cancer-related death worldwide, and the survival rate of metastatic lung cancer is exceedingly low. Helminthostatchys Zeylanica (H. Zeylanica) is a Chinese herbal medicine renowned for its anti-inflammatory, immunomodulatory, and anti-cancer activities in various cellular and animal studies. The current study evaluated the effects of H. Zeylanica derivatives on lung cancer cells. We determined that dipeptidyl peptidase-4 (DPP-4) expression levels were higher in lung cancer tissues than in normal tissues. We also determined that DPP-4 expression levels were higher in the metastatic stage and strongly correlated with lung cancer survival rates. An H. Zeylanica derivative (ugonin P) was shown to inhibit DPP-4 mRNA and protein expression in two lung cancer cell lines in a dose-dependent manner. Ugonin P was shown to decrease migration and invasion activities in lung cancer cells while promoting the synthesis of miR-130b-5p, which was found to negatively regulate DPP-4 protein expression and cell motility in lung cancer. We determined that ugonin P suppresses the DPP-4-dependent migration and invasion of lung cancer cells by downregulating the RAF/MEK/ERK signalling pathway and enhancing the expression of miR-130b-5p. This study provides compelling evidence that ugonin P could be used to develop novel therapeutic agents for the treatment of lung cancer.

Integrated Network Pharmacology, Molecular Docking, Molecular Simulation, and In Vitro Validation Revealed the Bioactive Components in Soy-Fermented Food Products and the Underlying Mechanistic Pathways in Lung Cancer.

Globally, lung cancer remains one of the leading causes of cancer-related mortality, warranting the exploration of novel and effective therapeutic approaches. Soy-fermented food products have long been associated with potential health benefits, including anticancer properties. There is still a lack of understanding of the active components of these drugs as well as their underlying mechanistic pathways responsible for their anti-lung cancer effects. In this study, we have undertaken an integrated approach combining network pharmacology and molecular docking to elucidate the mechanism of action of soy-fermented food products against lung cancer through simulation and in vitro validation. Using network pharmacology, we constructed a comprehensive network of interactions between the identified isoflavones in soy-fermented food products and lung cancer-associated targets. Molecular docking was performed to predict the binding affinities of these compounds with key lung cancer-related proteins. Additionally, molecular simulation was utilized to investigate the stability of the compound-target complexes over time, providing insights into their dynamic interactions. Our results identified daidzein as a potential active component in soy-fermented food products with high binding affinities towards critical lung cancer targets. Molecular dynamic simulations confirmed the stability of the daidzein-MMP9 and daidzein-HSP90AA1 complexes, suggesting their potential as effective inhibitors. Additionally, in vitro validation experiments demonstrated that treatment with daidzein significantly inhibited cancer cell proliferation and suppressed cancer cell migration and the invasion of A549 lung cancer cells. Consequently, the estrogen signaling pathway was recognized as the pathway modulated by daidzein against lung cancer. Overall, the findings of the present study highlight the therapeutic potential of soy-fermented food products in lung cancer treatment and provide valuable insights for the development of targeted therapies using the identified bioactive compounds. Further investigation and clinical studies are warranted to validate these findings and translate them into clinical applications for improved lung cancer management.

UBE1C is upregulated and promotes neddylation of p53 in lung cancer.

NEDDylation is a type of protein post-translational modification that has high similarity to ubiquitination. UBE1C encodes NEDDylation E1 enzyme, locates at chromatin region 3p14.1 and shows high gene dosage amplification frequency in both Asian and Caucasian lung cancer patients. However, its NEDDylation substrates and roles in tumorigenesis remain elucidated. In this study, we aim to investigate the oncogenic role of UBE1C and its involvement in how NEDDylation regulates p53 in lung cancer. We found that UBE1C mRNA overexpression and DNA amplification in most of the lung cell lines and cancer patients. Patients with UBE1C overexpression showed poor prognosis. Moreover, we demonstrated that overexpression of UBE1C and NEDD8, a NEDDylation moiety, resulted in the p53 NEDDylation with inhibition of p53 acetylation at K373 residue. Importantly, UBE1C-mediated NEDDylation downregulated the transcriptional activity of p53 by inhibiting p53 ability to target promoter regions of its downstream transcription targets, consequently inhibiting the promoter activities and the expression of mRNA and protein of the p53 downstream genes including p21 and PTEN. In addition, UBE1C and NEDD8 overexpression promoted migration, invasion, and proliferation of lung cancer cells. Our findings suggest that UBE1C acts as an oncogene with prognostic potential and highlight a potential role of UBE1C-mediated NEDDylation in downregulation of p53 transcriptional activity in lung cancer.

(−)-Guaiol inhibit epithelial-mesenchymal transition in lung cancer via suppressing M2 macrophages mediated STAT3 signaling pathway

In the context of cancer expansion, epithelial-mesenchymal transition (EMT) plays an essential role in driving invasion and metastasis potential of cancer cells. Tumor-associated macrophages (TAMs)-derived factors involved in the initiation and progression of EMT. We assess the role of M2 macrophage in suppressing lung tumors of a natural compound (−)-Guaiol by using macrophage depleted model. Bone marrow-derived monocytes (BMDMs) were extracted and induced to M2-like phenotype in vitro. The co-culture of M2 macrophage and lung cancer cells was established to observe that inhibition of lung tumor growth by (−)-Guaiol requires presence of macrophages. This suppressed effect of (−)-Guaiol was alleviated when mice macrophage was depleted. The expression of M2-like macrophages was strongly reduced by (−)-Guaiol treated mice, but not the changes of M1-like macrophages. In vitro studies, we demonstrated that (−)-Guaiol suppressed M2 polarization of BMDMs, as well as migration, invasion, and EMT of lung cancer cells in co-culture. M2 macrophage-derived interleukin 10 (IL-10) was investigated as a critical signaling molecule between M2 macrophage and lung cancer cells. We have also verified that the mechanism of (−)-Guaiol inhibiting the EMT process of lung cancer is related to the activation of IL-10-mediated signal transducer and activator of transcription 3 (STAT3). These results suggested that the suppressive effect role of (−)-Guaiol in M2 macrophage promoting EMT of lung cancer, which was associated with inhibition of IL-10 mediated STAT3 signaling pathway.

Antimetastatic activity of seongsanamide B in γ-irradiated human lung cancer

Lung cancer, which has a high incidence and mortality rates, often metastasizes and exhibits resistance to radiation therapy. Seongsanamide B has conformational features that suggest it has therapeutic potential; however, its antitumor activity has not yet been reported. We evaluated the possibility of seongsanamide B as a radiation therapy efficiency enhancer to suppress γ-irradiation-induced metastasis in non-small cell lung cancer. Seongsanamide B suppressed non-small cell lung cancer cell migration and invasion caused by γ-irradiation. Furthermore, it suppressed γ-irradiation-induced upregulation of Bcl-XL and its downstream signaling molecules, such as superoxide dismutase 2 (SOD2) and phosphorylated Src, by blocking the nuclear translocation of phosphorylated STAT3. Additionally, seongsanamide B markedly modulated the γ-irradiation-induced upregulation of E-cadherin and vimentin. Consistent with the results obtained in vitro, while seongsanamide B did not affect xenograft tumor growth, it significantly suppressed γ-irradiation-induced metastasis by inhibiting Bcl-XL/SOD2/phosphorylated-Src expression and modulating E-cadherin and vimentin expression in a mouse model. Thus, seongsanamide B may demonstrate potential applicability as a radiation therapy efficiency enhancer for lung cancer treatment.

Overexpression of Bruton Tyrosine Kinase Inhibits the Proliferation, Migration, and Invasion of Non-Small Cell Lung Cancer Cells.

Lung cancer is one of the most lethal malignant tumors in the world. Non-small cell lung cancer (NSCLC) is the most common pathological subtype. However, the molecular mechanism of NSCLC progress is still unclear. We extracted the expression data of the Bruton's tyrosine kinase (BTK) gene in NSCLC tissues from the TCGA database. The results of paired t-test showed that the BTK gene was significantly underexpressed in NSCLC tissues. To further verify the above results, we detected the expression of the BTK gene in NSCLC cell lines A549, H1299, and H1650 at the RNA and protein levels by real-time fluorescent quantitative polymerase chain reaction and Western Blot analysis, respectively. The results showed that BTK was low expressed in NSCLC tissues and cells. More importantly, the expression of the BTK gene is also significantly related to the patient's age, gender, tumor range (T), lymph node invasion (N), tumor stage, and prognosis, and its expression level gradually decreases with the progress of the disease. It is speculated that BTK may be an independent prognostic factor of NSCLC. Our experimental results are consistent with the above clinical correlation analysis results. Overexpression of BTK can significantly inhibit the proliferation, migration, and invasion of NSCLC cells and can block the G0/G1 tumor cell cycle, indicating that overexpression of BTK can inhibit the growth, migration, and invasion of NSCLC cells.

Retraction Note: The LMCD1-AS1/miR-526b-3p/OSBPL5 axis promotes cell proliferation, migration and invasion in non-small cell lung cancer

Retraction Note: The LMCD1-AS1/miR-526b-3p/OSBPL5 axis promotes cell proliferation, migration and invasion in non-small cell lung cancer