Lung Adenocarcinoma Growth Research Articles

The impact of BTK knockdown on lung adenocarcinoma growth and immune response.

This study explores the molecular role of the BTK gene in lung adenocarcinoma (LUAD) progression and patient prognosis. Using a radiomics model based on BTK expression and PET-CT data analyzed through DeeplabV3, alongside transcriptomic and clinical data from TCGA, we established a strong predictive relationship between BTK levels and LUAD outcomes. Our findings demonstrate that low BTK expression is linked to poorer prognoses. Experimental models, including cell lines and invivo mouse studies, revealed that BTK deficiency leads to increased LUAD cell proliferation, invasion, and metastasis. Furthermore, invivo models indicated that BTK knockdown results in enhanced tumor growth and diminished CD8+ T cell activity. These results suggest that BTK plays a crucial role in modulating LUAD progression and the tumor immune environment, highlighting its potential as a therapeutic target.

HIF1A/PCDH7 axis mediates fatty acid synthesis and metabolism to inhibit lung adenocarcinoma anoikis.

Aberrantly expressed PCDH7 participates in the malignant progression of many cancers. PCDH7 has been newly discovered as a risk factor in lung cancer, but its functional study in lung adenocarcinoma (LUAD) has not been conducted yet. This study aimed to investigate the functional role of PCDH7 in LUAD. Bioinformatics analyzed the expression of PCDH7 and HIF1A in LUAD tissues, predicted the binding sites between the two, analyzed the clinicopathological relevance of PCDH7 and examined the pathway enrichment of PCDH7. Expression of PCDH7 and HIF1A in LUAD cells was analyzed by RT-qPCR. A nude mouse transplantation tumor model was constructed to analyze the effect of PCDH7 on tumor growth in vivo. The binding relationship between PCDH7 and HIF1A was confirmed by chromatin immunoprecipitation experiments and the dual-luciferase assay. Cell viability was detected with Cell Counting Kit-8. Triglyceride content and Caspase3 activity were measured using corresponding reagent kits. FASN and ACC1 expression was determined utilizing western blot. PCDH7 was highly expressed in LUAD and correlated with patients' overall survival time and N stage. In vitro and in vivo experiments confirmed that PCDH7 could promote LUAD growth and anoikis resistance. Moreover, overexpression of PCDH7 markedly increased the content of triglycerides in cells and promoted the expression of FASN and ACC1 proteins to inhibit LUAD cell anoikis. Cell rescue experiment confirmed that HIF1A activated PCDH7 to suppress LUAD anoikis by promoting fatty acid (FA) synthesis and metabolism. Our findings demonstrated that the HIF1A/PCDH7 axis suppressed LUAD anoikis by promoting FA synthesis and metabolism. The FA synthesis pathway might be a key pathway regulated by PCDH7 in LUAD anoikis.

Activin A inhibits the migration of human lung adenocarcinoma A549 cells induced by EGF

Activin A, a member of the transforming growth factor β (TGF-β) superfamily, is involved in tumorigenesis and tumor progression. However, it remains unclear whether activin A can affect the migration of lung adenocarcinoma (LUAD) cells. In this study, the results of differentially expressed genes (DEGs) identification revealed that lung adenocarcinoma tissues exhibited lower expression of activin βA mRNA, but higher expression of epidermal growth factor (EGF) and MMP9 mRNA compared to nontumor tissues. Moreover, we found that activin A inhibited human LUAD A549 cell proliferation promoted by EGF. Additionally, EGF induced A549 cell migration in microfluidic device, while activin A attenuated EGF actions. Simultaneously, EGF increased the levels of migration-related proteins, but activin A played the opposite role. Furthermore, the study revealed that EGF upregulated the ratio of p-ERK/ERK in A549 cells, which was weakened by activin A, and A549 cell migration regulated by activin A was not related to calcium signaling. In addition, the inhibitory effect of activin A on EGF-induced A549 cell migration was attenuated by the ERK inhibitor FR180204. These findings demonstrate that activin A effectively hinders the migration of A549 cells induced by EGF through ERK1/2 signaling, suggesting that targeting activin A may hold promise in the treatment of EGF-dependent LUAD growth and metastasis.

Design and Synthesis of New Aminothiazole‐Benzazole Based Ureas: Antiproliferative and Antimigration Activity Studies

AbstractIn our quest to develop new treatments for cancer, we synthesized and tested a series of urea‐functionalized aminothiazole‐benzazole analogs. Our primary focus was assessing their ability to inhibit the growth of breast cancer (MCF‐7) and lung adenocarcinoma (A549) cells. Using 1H NMR, 13C NMR spectra, and high resolution mass spectrometry (HRMS), we confirmed the chemical structures of these compounds. Among them, compound 8a demonstrated significant cytotoxicity against MCF‐7 cells, achieving an IC50 value of 9.6±0.6 μM. Similarly, compound 8e exhibited potent cytotoxicity against A549 cells, with an IC50 value of 9.2±1.1 μM. We further investigated the antimigration properties of all compounds that showed promising antiproliferative effects in both MCF‐7 and A549 cells. Additionally, we evaluated how these compounds impact key apoptosis‐related proteins: Caspase‐7, PARP‐1, BAX, and Bcl‐2. These proteins play crucial roles in the regulation of programmed cell death. Overall, our findings suggest that these urea‐functionalized aminothiazole‐benzazole analogs hold promise as potential anticancer agents, warranting further exploration into their mechanisms of action and therapeutic potential.

Expression Profile and Prognostic Values of IRX Family Members in Lung Adenocarcinoma.

The potential role of the iroquois homeobox (IRX) genes in tumorigenesis is a subject of interest, yet their specific involvement in lung adenocarcinoma (LUAD) has not been extensively examined. This research endeavored to explore the impact of the IRX genes on the onset and progression of LUAD. Utilizing data from The Cancer Genome Atlas (TCGA), samples of LUAD were selected for analysis. The influence of the IRX genes was scrutinized through various tools, including Kaplan-Meier Plotter, cBioPortal, and the R programming language (version 3.6.3), with gene expression levels being confirmed in cellular models via quantitative real-time polymerase chain reaction (qRT-PCR). It was observed that the levels of IRX1/2/3/6 were notably diminished in LUAD tissues when juxtaposed with healthy lung tissue. Conversely, the expression of IRX4 was found to be elevated in LUAD. Correlations were identified between IRX gene expression and several clinical parameters such as T stage, smoking history quantified in pack-years, lymph node involvement, patient gender, initial treatment responses, and smoking status. The diminished expression of IRX2/5 emerged as a significant indicator of an unfavorable prognosis in LUAD. The study also highlighted the potential of various IRX genes as diagnostic indicators for LUAD. These genes were implicated in the facilitation of LUAD's growth and spread through a range of biological pathways, encompassing the Ras signaling and more. Additionally, a pronounced link was discovered between the infiltration of immune cells and the expression patterns of the IRX genes. IRX genes were abnormally expressed in LUAD cell lines. IRX gene family could serve not only as indicators of LUAD prognosis but also as therapeutic targets for LUAD.

KIS, a target of SOX4, regulates the ID1-mediated enhancement of β-catenin to facilitate lung adenocarcinoma cell proliferation and metastasis

PurposeKinase interacting with stathmin (KIS) is a serine/threonine kinase involved in RNA processing and protein phosphorylation. Increasing evidence has suggested its involvement in cancer progression. The aim of this study was to investigate the role of KIS in the development of lung adenocarcinoma (LUAD). Dual luciferase assay was used to explore the relationship between KIS and SOX4, and its effect on ID1/β-catenin pathway.MethodsReal-time qPCR and western blot were used to assess the levels of KIS and other factors. Cell proliferation, migration, and invasion were monitored, and xenograft animal model were established to investigate the biological functions of KIS in vitro and in vivo.ResultsIn the present study, KIS was found to be highly expressed in LUAD tissues and cell lines. KIS accelerated the proliferative, migratory and invasive abilities of LUAD cells in vitro, and promoted the growth of LUAD in a mouse tumor xenograft model in vivo. Mechanistically, KIS activated the β-catenin signaling pathway by modulating the inhibitor of DNA binding 1 (ID1) and was transcriptionally regulated by SOX4 in LUAD cells.ConclusionKIS, a target of SOX4, regulates the ID1-mediated enhancement of β-catenin to facilitate LUAD cell invasion and metastasis.

Spinosad blocks CHRNA5 mediated EGFR signaling pathway activation to inhibit lung adenocarcinoma proliferation

Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, with high incidence and low survival rates. Nicotinic acetylcholine receptors play an important role in the progression of LUAD. In this study, a screening of 17 nicotinic acetylcholine receptor allosteric agents revealed that spinosad effectively suppressed the proliferation of LUAD cells. The experiments demonstrated that spinosad induced cell cycle arrest in the G1 phase and stimulated apoptosis, thereby impeding the growth of LUAD and enhancing the responsiveness to gefitinib in vitro and vivo. Mechanistic insights obtained through transcriptome sequencing, Co-IP, and protein immunoblots indicated that spinosad disrupted the interaction between CHRNA5 and EGFR, thereby inhibiting the formation of downstream complexes and activation of the EGFR signaling pathway. The supplementation of exogenous acetylcholine showed to mitigate the inhibition of LUAD cell proliferation induced by spinosad. This study elucidates the therapeutic effects and mechanisms of spinosad in LUAD, and offers a theoretical and experimental foundation for novel LUAD treatments.

Antibody MYH9 and Antibiotic Lidamycin Inhibit the Growth and Proliferation of Lung Cancer Cells and Induce Their Apoptosis.

The aim of this study was to investigate the impact of the antibiotic lidamycin (LDM) and the targeted therapy with the antibody Myosin heavy chain 9 (MYH9) on cancer cells, aiming to provide insights for cancer treatment. In this study, antibiotics and targeted antibodies were used in cancer cells, and then their effects on cell growth, proliferation, apoptosis regulation, and related proteins were measured, and comparative analysis was conducted on the effects of different drug concentrations on the growth of cancer cells. In H460, the apoptotic effect of 2nM LDM on cells reached 70%. LDM had a downward trend on the levels of B-cell lymphoma-2 (Bcl-2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in cells. The inhibitory effects of LDM at different concentrations on human large cell lung cancer H460 transplanted tumor in nude mice reached 53.20% and 69.80%, and the inhibitory effects on the growth of lung adenocarcinoma transplanted tumor in nude mice reached 40.20% and 58.30%. The expression of MYH9 (myosin, heavy polypeptide 9, non-muscle) in human lung cancer tissues and adjacent tissues reached more than 80%. At the concentration of 300μM, antibody MYH9 inhibited cell growth by 30%, and the migration rate was also reduced by 25%. The inhibitory effect of siRNA after knocking out the MYH9 gene on cancer cells reached 70%. Antibiotic LDM and targeted antibody MYH9 can inhibit the growth, proliferation, and migration of cancer cells, promote cancer cell apoptosis, and have certain clinical significance for the treatment of cancer patients.

The Novel Fusion Protein Melittin-MIL-2 Exhibits Strong Antitumor Immune Effect in Lung Adenocarcinoma Cell A549.

In previous studies, we developed a novel fusion protein named "melittin-MIL-2" which exhibited more anti-tumor activity. However, it remains unclear whether melittin-MIL-2 possesses antitumor immune effect on lung adenocarcinoma. In this study, the immune effect and mechanism of melittin-MIL-2 inhibiting the growth and invasion of lung adenocarcinoma will be investigated, in order to provide novel perspectives for the immunotherapy of lung cancer. The results indicated that melittin-MIL-2 promoted T cell proliferation, enhanced NK cell cytotoxicity, and boosted IFN-γ secretion in PBMCs. After melittin-MIL-2 stimulation, perforin expression and LAK/NK-like killing activities of human PBMCs and NK cells were significantly enhanced. Melittin-MIL-2 is capable of hampering the development and proliferation of lung adenocarcinoma cell A549. ICAM-1 and Fas expression in A549 cells exposed to melittin-MIL-2 rose significantly. The expression levels of TLR8 and VEGF in A549 cells decreased significantly after melittin-MIL-2 stimulation. Invivo, melittin-MIL-2 substantially impeded the growth of lung adenocarcinoma and formed an immune-stimulating microenvironment locally in tumor tissues. In conclusion, the novel fusion protein melittin-MIL-2 exhibits strong anti-tumor immune effect in lung adenocarcinoma cell A549 via activating the LFA-1/ICAM-1 and Fas/FasL pathways to enhance cytolytic activity, upregulating the secretion of IFN-γ and perforin, and boosting LAK/NK-like killing activities. Immuno-effector cells and their secreted cytokines can form immune stimulation microenvironment locally in lung adenocarcinoma Lewis mice tissue.

Dipeptidyl peptidase 4-positive cancer-associated fibroblasts enhance lung adenocarcinoma growth

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer progression through cell–cell interactions in various types of malignancies, including lung adenocarcinoma (LUAD). Dipeptidyl peptidase 4 (DPP4) is a transmembrane protein with serine protease activity and is involved in the progression of tumors, metabolic diseases, and autoimmune diseases. In the present study, we focused on the role of DPP4-positive CAFs in LUAD. Immunohistochemistry revealed that 38 of 89 LUAD patients showed DPP4 expression in the fibrous stroma, and patients harboring DPP4-positive CAFs were more often male, had a higher Brinkman index, and had a higher Ki-67 labeling index of tumor cells than those with DPP4-negative CAFs. DPP4-positivity was associated with the expression of other CAF markers, α-SMA, periostin, and podoplanin, as well as a cellular senescence marker, p16. In the in vitro study, conditioned media collected from pulmonary fibroblast (OUS-11, HPF, and HPF-C)-induced overexpression of DPP4 significantly promoted the proliferation of LUAD cells (A549 and PC-9) and increased the expression levels of MCP-1, IL-8, IL-6, and GCSF in the media compared to those in controls. In addition, OUS-11 overexpression in DPP4 overexpression increased periostin expression. In conclusion, DPP4-positive CAFs could promote lung adenocarcinoma cell growth by producing soluble factors, and DPP4 inhibition may inhibit cancer progression.

Correlation of CT features of lung adenocarcinoma with sex and age

This study aimed to retrospectively examine the computed tomography (CT) features of lung adenocarcinoma across different demographic groups. Preoperative chest CT findings from 1266 surgically resected lung adenocarcinoma cases were retrospectively analyzed. Lung adenocarcinomas were categorized based on CT characteristics into pure ground glass (pGGO), nodule-containing ground glass opacity (mGGO), and pure solid without containing ground glass opacity (pSD). These categories were correlated with sex, age, EGFR status, and five histopathological subtypes. The diameters of pGGO, mGGO, and pSD significantly increased across all patient groups (P < 0.05). Males exhibited a significantly higher proportion of pSD than females (P = 0.002). The mean diameters of pGGO and pSD were significantly larger in males than in females (P = 0.0017 and P = 0.043, respectively). The frequency of pGGO was higher in the younger age group (≤ 60 years) compared to the older group (> 60 years) for both males (P = 0.002) and females (P = 0.027). The frequency of pSD was higher in the older age group for both sexes. A linear correlation between age and diameter was observed in the entire cohort as well as in the male and female groups (P < 0.0001 for all groups). EGFR mutations were less frequent in pSD compared to pGGO (P = 0.0002) and mGGO (P < 0.0001). The frequency of lesions containing micropapillary components increased from pGGO to mGGO and pSD (P < 0.0001 for all). The frequency of lesions containing solid components also increased from pGGO to mGGO and pSD (P = 0.045, P < 0.0001, and P < 0.0001, respectively). The CT features of lung adenocarcinoma exhibit differences across genders and age groups. Male gender and older age are risk factors for lung adenocarcinoma growth.

IL-17A-induced cancer-associated fibroblasts releases CXCL12 to promote lung adenocarcinoma progression via Wnt/β-Catenin signaling pathway

BackgroundCancer-associated fibroblasts (CAFs) and their secretion, C-X-C motif chemokine ligand 12 (CXCL12), play an important role in the development of lung adenocarcinoma (LUAD). Interleukin 17A (IL-17A) is also crucial in regulating tumor progression. Herein, we explored the specific relationships between these two factors and their mechanisms in the progression of LUAD. MethodsImmunohistochemistry was utilized to assess the differential expression levels of IL-17A and CXCL12 in tumor versus normal tissues of LUAD patients, followed by gene correlation analysis. Cell counting kit-8 (CCK8), wound-healing and transwell assays were performed to investigate the effect of IL-17A on the function of LUAD cells. qPCR, immunofluorescence, immunohistochemistry and western blot analyses were conducted to elucidate the potential mechanism by which IL-17A facilitates the development of LUAD via CXCL12. Male BALB-C nude mice were used to explore the role of IL-17A in subcutaneous LUAD mouse models. ResultsElevated expression levels of IL-17A and CXCL12 were observed in LUAD tissues, exhibiting a positive correlation. Further studies revealed that IL-17A could stimulate CAFs to enhance the release of CXCL12, thereby facilitating the growth, proliferation, and metastasis of LUAD. The binding of CXCL12 to its specific receptor influences the activation of the Wnt/β-Catenin pathway, which in turn affects the progression of LUAD. In vivo experiments have demonstrated that IL-17A enhances the growth of LUAD tumors by facilitating the secretion of CXCL12. Conversely, inhibiting CXCL12 has been demonstrated to impede tumor growth. ConclusionsWe discovered that IL-17A promotes the release of CAFs-derived CXCL12, which in turn facilitates the development of LUAD via the Wnt/β-Catenin signaling pathway.

Prediction of the stage shift growth of early-stage lung adenocarcinomas by volume-doubling time

Prediction of the stage shift growth of early-stage lung adenocarcinomas by volume-doubling time

Transcription Factor E2F8 Activates PDK1-Mediated DNA Damage Repair to Enhance Cisplatin Resistance in Lung Adenocarcinoma

Introduction: Cisplatin (DDP) is the commonest chemo drug in lung adenocarcinoma (LUAD) treatment, and DDP resistance is a significant barrier to therapeutic therapy. This study attempted to elucidate the impact of PDK1 on DDP resistance in LUAD and its mechanism. Methods: Bioinformatics analysis was used to determine the expression and enriched pathways of PDK1 in LUAD tissue. Subsequently, E2F8, the upstream transcription factor of PDK1, was predicted, and the binding relationship between the two was analyzed using dual-luciferase and ChIP experiments. PDK1 and E2F8 levels in LUAD tissues and cells were detected via qRT-PCR. Cell viability, proliferation, and apoptosis levels were assayed by CCK-8, EdU, and flow cytometry experiments, respectively. Comet assay was used to assess DNA damage, and immunofluorescence was used to assess the expression of γ-H2AX. NHEJ reporter assay was to assess DNA repair efficiency. Western blot tested levels of DNA damage repair (DDR)-related proteins. Immunohistochemistry assessed the expression of relevant genes. Finally, an animal model was constructed to investigate the influence of PDK1 expression on LUAD growth. Results: PDK1 was found to be upregulated in LUAD and enhanced DDP resistance by mediating DDR. E2F8 was identified as an upstream transcription factor of PDK1 and was highly expressed in LUAD. Rescue experiments presented that knocking down E2F8 could weaken the promotion of PDK1 overexpression on DDR-mediated DDP resistance in LUAD. In vivo experiments showed that knocking down PDK1 plus DDP significantly reduced the growth of xenograft tumors. Conclusion: Our results indicated that the E2F8/PDK1 axis mediated DDR to promote DDP resistance in LUAD. Our findings lead to an improved treatment strategy after drug resistance.

Combined cryoablation and PD-1 inhibitor synergistically enhance antitumor immune responses in Lewis lung adenocarcinoma mice via the PI3K/AKT/mTOR pathway

Cryoablation is a therapeutic modality for lung adenocarcinoma that destroys target tumors using lethal levels of cold, resulting in the release of large amounts of specific antigens that activate immune responses. However, tumor immune checkpoint escape mechanisms prevent these released self-antigens from inducing effective anti-tumor immune responses. To overcome this challenge, we propose the use of immune checkpoint inhibitors to relieve T cell inhibition by immune checkpoints and enhance the anti-tumor immune response mediated by cryoablation. We used bilateral tumor-bearing mouse models and a specific cryoablation instrument to study the efficacy of cryoablation combined with PD-1 inhibitors in Lewis lung adenocarcinoma model mice. We found that cryoablation combined with PD-1 inhibitors significantly inhibited the growth of mouse lung adenocarcinoma, prolonged mouse survival, and enhanced the anti-tumor immune response. Moreover, this combined regimen could synergistically promote the activation and proliferation of T cells via the PI3K/AKT/mTOR pathway. The present study provides a strong theoretical basis for the clinical combination of cryoablation and PD-1 inhibitors.

Integrated analysis reveals critical cisplatin-resistance regulators E2F7 contributed to tumor progression and metastasis in lung adenocarcinoma

BackgroundDrug resistance poses a significant challenge in cancer treatment, particularly as a leading cause of therapy failure. Cisplatin, the primary drug for lung adenocarcinoma (LUAD) chemotherapy, shows effective treatment outcomes. However, the development of resistance against cisplatin is a major obstacle. Therefore, identifying genes resistant to cisplatin and adopting personalized treatment could significantly improve patient outcomes.MethodsBy examining transcriptome data of cisplatin-resistant LUAD cells from the GEO database, 181 genes associated with cisplatin resistance were identified. Using univariate regression analysis, random forest and multivariate regression analyses, two prognostic genes, E2F7 and FAM83A, were identified. This study developed a prognostic model utilizing E2F7 and FAM83A as key indicators. The Cell Counting Kit 8 assay, Transwell assay, and flow cytometry were used to detect the effects of E2F7 on the proliferation, migration, invasiveness and apoptosis of A549/PC9 cells. Western blotting was used to determine the effect of E2F7 on AKT/mTOR signaling pathway.ResultsThis study has pinpointed two crucial genes associated with cisplatin resistance, E2F7 and FAM83A, and developed a comprehensive model to assist in the diagnosis, prognosis, and evaluation of relapse risk in LUAD. Analysis revealed that patients at higher risk, according to these genetic markers, had elevated levels of immune checkpoints (PD-L1 and PD-L2). The prognostic and diagnosis values of E2F7 and FAM83A were further confirmed in clinical data. Furthermore, inhibiting E2F7 in lung cancer cells markedly reduced their proliferation, migration, invasion, and increased apoptosis. In vivo experiments corroborated these findings, showing reduced tumor growth and lung metastasis upon E2F7 suppression in lung cancer models.ConclusionOur study affirms the prognostic value of a model based on two DEGs, offering a reliable method for predicting the success of tumor immunotherapy in patients with LUAD. The diagnostic and predictive model based on these genes demonstrates excellent performance. In vitro, reducing E2F7 levels shows antitumor effects by blocking LUAD growth and progression. Further investigation into the molecular mechanisms has highlighted E2F7’s effect on the AKT/mTOR signaling pathway, underscoring its therapeutic potential. In the era of personalized medicine, this DEG-based model promises to guide clinical practice.

MiR-301b-3p can be used as a Potential Marker for the Diagnosis of Lung Adenocarcinoma.

The involvement of aberrantly expressed miR-301b-3p has been discovered in diverse human tumors. Our study was primarily centered around the role of miR-301b-3p in diagnosing lung adenocarcinoma (LUAD). We used the TCGA database to download the TCGA-LUAD dataset and selected miR- 301b-3p as the object of our study by differential expression analysis of miRNAs combined with previous studies. The LUAD diagnostic model was constructed utilizing machine learning based on miR-301b-3p expression. The predictive performance of the diagnostic model was found to be excellent by ROC curves combined with the clinical information of the dataset samples. GSEA, GO, and KEGG enrichment analyses demonstrated that miR-301b-3p may mediate the cell cycle by regulating the expression of hormones. Subsequently, combined with tumor immunity and mutation analysis, it was found that patients in the low-expression group had better immune infiltration, indicating that their response rate to immunotherapy may be relatively high. Finally, a mouse xenograft model was constructed to verify how miR-301b-3p affected LUAD progression in mice. The results illustrated that overexpressed miR-301b-3p could cause faster tumor growth in mice. On the contrary, the growth of LUAD could be impeded by the downregulated miR-301b-3p expression. It was suggested that miR-301b-3p had a crucial part in LUAD progression. Overall, the diagnostic performance of the LUAD diagnostic model constructed based on miR-301b-3p is great, and the model can be used as a potential diagnostic marker for LUAD to provide new ideas for clinical diagnosis.

WTAP-mediated N6-methyladenine Modification of circEEF2 Promotes Lung Adenocarcinoma Tumorigenesis by Stabilizing CANT1 in an IGF2BP2-dependent Manner.

N6-methyladenosine (m6A) is a common posttranscriptional RNA modification and plays an important role in cancer biology. Circular RNAs (circRNAs) are also reported to participate in lung adenocarcinoma (LUAD) progression. Here, we aimed to investigate the functions of Wilms tumor 1-associating protein (WTAP) methyltransferase and circEEF2 in LUAD cell tumorigenesis, and probe whether circEEF2 functioned through WTAP-induced m6A modification and its potential mechanisms. Functional analyses were conducted by tube formation, sphere formation, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, and transwell assays in vitro as well as tumor formation experiments in mice, respectively. The N6-methyladenine (m6A) modification in circEEF2 mRNA was determined by RNA immunoprecipitation (Me-RIP) assay. The interaction between IGF2BP2 (Insulin Like Growth Factor 2 MRNA-Binding Protein 2) and circEEF2 or Calcium-activated nucleotidase 1 (CANT1) mRNA was confirmed using RIP assay. LUAD tissues and cells showed high circEEF2 expression, and the deficiency of circEEF2 suppressed LUAD cell angiogenesis, stemness, proliferation, migration, and invasion. WTAP induced circEEF2 m6A modification. WTAP silencing repressed the oncogenic phenotypes of LUAD cells via stabilizing circEEF2 in an m6A-dependent manner. IGF2BP2 interacted with circEEF2 and CANT1, and WTAP and circEEF2 could regulate CANT1 expression through IGF2BP2. The inhibition of LUAD cell oncogenic phenotypes caused by circEEF2 deficiency was abolished by CANT1 overexpression. In addition, WTAP silencing impeded LUAD growth via modulating circEEF2 and CANT1 in vivo. WTAP-mediated m6A modification of circEEF2 promotes lung adenocarcinoma growth and tumorigenesis by stabilizing CANT1 through IGF2BP2.

MELK aggravates lung adenocarcinoma by regulating EZH2 ubiquitination and H3K27me3 histone methylation of LATS2.

We tried to elucidate the possible roles of maternal embryonic leucine pull chain kinase (MELK) in lung adenocarcinoma (LUAD) growth and metastasis. Differentially expressed genes in LUAD samples were analysed by the GEPIA database. Clinical tissue samples and cells were collected for MELK, EZH2 and LATS2 expression determination. Co-IP assay was used to verify the interaction between EZH2 and MELK; CHX tracking assay and ubiquitination assay detected the degradation of MELK on EZH2 ubiquitination. ChIP assay detected the enrichment of EZH2 and H3K27me3 on the LATS2 promoter region. LUAD cells were selected for invitro validation, and the tumorigenic ability of LUAD cells was also observed in a transplantation tumour model of LUAD nude mice. MELK and EZH2 were highly expressed in LUAD samples, while LATS2 was lowly expressed. MELK interacted with EZH2 to inhibit its ubiquitination degradation; EZH2 elevated H3K27me3 modification in the LATS2 promoter to lower LATS2 expression. Silencing MELK or EZH2 or overexpressing LATS2 restrained LUAD cell proliferation and invasion, and facilitated their apoptosis. Silencing MELK or EZH2 or overexpressing LATS2 suppressed tumour formation in nude mice. This study demonstrated that MELK aggravated LUAD by upregulating EZH2 and downregulating LATS2.

Silencing of circ_0088036 inhibits growth and invasion of lung adenocarcinoma through miR-203/SP1 axis.

Lung cancer is the leading cause of cancer-related deaths worldwide. Circular RNA (circRNA) circ_0088036 is a recently discovered circRNA known for its roles in rheumatoid arthritis. The study aimed to study the function of circ_0088036 in lung adenocarcinoma (LUAD).Circ_0088036 expressions were analyzed in the Gene Expression Omnibus (GEO) database. The relationship between circ_0088036 expressions and clinicopathological data of LUAD was assessed. The messenger RNAand protein levels were analyzed by quantitative real-time polymerase chain reaction and Western blot. Cell viability, apoptosis, and invasion were tested by Cell Counting Kit-8, flow cytometry, and transwell assay. The direct interaction between microRNA-203 (miR-203) and circ_0088036 or specificity protein 1 (SP1) was confirmed by dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation assays. Circ_0088036 was overexpressed in LUAD from the analysis of the GEO database. The poor prognosis was found in the patients with high expressions of circ_0088036. The level of Circ_0088036 was increased in LUAD tissues and cells. In terms of function, the deletion of circ_0088036 inhibited LUAD tumorigenesis in vitro by repressing cell growth, invasion, and epithelial-mesenchymal transition (EMT). In mechanism, circ_0088036 could competitively sponge miR-203, thereby affecting the expressions of the target gene SP1. In addition, lessening of miR-203 and enlarging of SP1 could eliminate the anticancer effect of short hairpin RNA-circ_0088036 on LUAD cells. Besides, the knockout of circ_0088036 hindered the growth of xenografted tumors in vivo.Circ_0088036 promoted the LUAD cell growth, invasion, and EMT via modulating the miR-203/SP1 axis in LUAD.