Migration Of Lung Adenocarcinoma Cells Research Articles

Discriminative and prognostic significance of LINC00623 for lung adenocarcinoma.

This study was conducted to evaluate the diagnostic and prognostic values of LINC00623 in patients with lung adenocarcinoma (LUAD), as well as the promoting role in LUAD progression. LINC00623 levels were identified by RT-qPCR. Using ROC curve analysis, the discrimination value of LINC00623 for LUAD from lung squamous cell carcinoma (LUSC) and the health was assessed. Recurrence-free and overall survival were estimated using the Kaplan-Meier method and multivariate survival analysis. Cell biological properties were analyzed by growth curves, transwell migration, and invasion assays. The downstream miRNA and genes were retrieved and annotated by online databases. LINC00623 was significantly upregulated in the LUAD tissues and cell lines compared to LUSC tissues and the noncancerous tissues. LINC00623 showed a discriminating power for predicting LUAD. LUAD patients with a high level of LINC00623 tend to have poor overall survival and recurrence-free survival. Downregulation of LINC00623 reduced the proliferation, migration, and invasion of LUAD cells. MiR-1207-5p was a target of LINC00623 and its target genes were related to PI3K/Akt signaling pathway. The subtypes, recurrence-free survival, and overall survival of patients with LUAD might be well discriminated by LINC00623 levels. LINC00623 promoted LUAD progression through sponging miR-1207-5p.

Identifying the critical oncogenic mechanism of LDHA based on a prognostic model of T-cell synthetic drivers

BackgroundDespite its early success, immunotherapy focused on removing T-cell inhibition does not achieve the desired effect in most patients. New strategies that target antigen-driven T-cell activation are needed to improve immunotherapy outcomes. However, a comprehensive analysis of synthetic drivers of T-cells is greatly lacking in lung adenocarcinoma (LUAD) and other types of tumors. MethodsWe comprehensively evaluated the patterns of LUAD patients based on T -cell synthetic drivers by unsupervised clustering analysis. A risk model was constructed using Lasso Cox regression analysis. The predicted survival and immunotherapy efficacy of the model was validated by independent cohorts. Finally, single-cell sequencing analysis, and a series of in vitro experiments were conducted to explore the role of lactate dehydrogenase A (LDHA) in the malignant progression of LUAD. ResultsPatients in the high-risk group were characterized by survival disadvantage, a “cold” immune phenotype, and by not having benefitted from immunotherapy. LDHA was shown to promote LUAD cell proliferation, cell cycle, invasion, and migration. Secondly, we found that LDHA induced NF-κB pathway activation, tyrosine kinase inhibitor resistance and immunosuppressant microenvironment. Finally, LDHA was found to be highly expressed in fibroblasts, which may be involved in promoting TKI resistance and mediating the immune escape. ConclusionThis study revealed that the T-cell synthetic driver-associated prognostic model developed herein significantly predicted prognosis and immunotherapy efficacy in LUAD. We further investigated the role of LDHA in the malignant phenotype of tumor cells and tumor microenvironment remodeling, providing a promising and novel therapeutic strategy for LUAD.

Upregulated enhancer of rudimentary homolog promotes epithelial‑mesenchymal transition and cancer cell migration in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the deadliest cancers regarding both mortality rate and number of deaths and warrants greater effort in the development of potential therapeutic targets. The enhancer of rudimentary homolog (ERH) has been implicated in the promotion and progression of certain types of cancer. In the present study, ERH was assessed for its expression pattern and survival association with LUAD in public transcriptomic and proteomic databases. Bioinformatic methods and data from websites, including University of Alabama at Birmingham CANcer data analysis Portal and The Cancer Genome Atlas, were utilized to demonstrate the functional behaviors and corresponding pathways of ERH in LUAD. Human A549 and CL1‑0 cell lines were used to validate the findings via functional assays. It was demonstrated that the expression of ERH, at both the transcriptomic and proteomic levels, was higher in LUAD compared with in adjacent non‑tumor lung tissue and was associated with worse survival prognosis. Moreover, high ERH expression was correlated with more aggressive functional states, such as cell cycle and invasion in LUAD, and the positive ERH‑correlated gene set was associated with worse survival and an immunosuppressive tumor microenvironment. Small nuclear ribonucleoprotein polypeptide G was identified as a molecule that potentially interacted with ERH. Lastly, it was demonstrated that ERH promoted epithelial‑mesenchymal transition and cell migration invitro, but not proliferation. In conclusion, higher expression of ERH in LUAD may facilitate cancer progression and confer worse outcomes. Further deep investigation into the role of ERH in LUAD is needed.

Novel circular RNA circ-0002727 regulates miR-144-3p/KIF14 pathway to promote lung adenocarcinoma progression.

Objective: Circular RNAs (circRNAs) have been shown to participate in various cancers via sponging miRNAs (microRNAs). However, their role in lung adenocarcinoma (LUAD) remains elusive. Methods: The transcriptome data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed genes (DEgenes) were identified and further used to constructed a circRNA-associated competing endogenous RNA (ceRNA) network. Real-Time qPCR analysis was conducted to examine gene expression at transcriptional level. The regulatory mechanisms of circRNA-miRNA-gene were validated by dual-luciferase reporter array and RNA pull-down assay. Cell growth, migration and invasion were evaluated by CCK-8 assay, colony formation assay and transwell assay, respectively. Results: Based on public microarray data, we systematically constructed a circRNA-associated ceRNA network including 11 DEcircRNAs, 8 DEmiRNAs and 49 DEgenes. Among the ceRNA network, we found that circ-0002727 was a key regulatory and was further confirmed to be upregulated in LUAD cancer cells. Subsequently, we found that silencing of circ-0002727 significantly suppressed the LUAD cell proliferation, migration and invasion in vitro. Mechanistically, we showed that circ-0002727 could competitively bind miR-144-3p to enhance the KIF14 expression in LUAD cells. Rescue assays indicated that circ-0002727 could regulate LUAD cell proliferation through modulating miR-144-3p/KIF14 pathway. Besides, KIF14 expression level was positively correlated with TNM stage and metastasis, and patients with high KIF14 expression suffered poor prognosis. Conclusion: Taken together, our study revealed that circ-0002727 could act as a ceRNA to regulate LUAD progression via modulating miR-144-3p/KIF14 pathway, providing a potential therapeutic target for LUAD.

DARS2 promotes the occurrence of lung adenocarcinoma via the ERK/c-Myc signaling pathway.

DARS2 expression is upregulated in lung adenocarcinoma (LUAD) which correlates with tumor patient stage and prognosis. The mechanism of DARS2 involvement in LUAD still needs to be further explored. In this study, we found that DARS2 expression in LUAD tissue was significantly higher than that in normal tissue. At the same time, the Kaplan-Meier curve showed that the survival prognosis of LUAD patients with high expression of DARS2 was significantly worse than low expression of DARS2. The expression of DARS2 was detected in LUAD and adjacent normal tissues by IHC staining, histochemical scoring and a survival curve was generated. In addition, we demonstrated that the knockdown and overexpression of DARS2 significantly affected the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. Finally, western blot and rescue assay were performed on LUAD cells to further explore and verify the signaling pathway. DARS2 expression was significantly upregulated in LUAD tissues and cell lines. What is more, the increased expression of DARS2 was closely related to proliferation, invasion and metastasis. The tumorigenic assay in nude mice further showed that the tumorigenic ability of nude mice was significantly improved with the increase in DARS2 expression. Finally, we determined that DARS2 plays its role in LUAD by targeting the ERK/c-Myc signaling pathway. Our data revealed the oncogenic role of DARS2 in LUAD, indicating that DARS2 may be a predictive biomarker and novel therapeutic target for LUAD.

Targeting PKD2 aggravates ferritinophagy-mediated ferroptosis via promoting autophagosome-lysosome fusion and enhances efficacy of carboplatin in lung adenocarcinoma

Ferroptosis is an iron-dependent cell death and affects efficacies of multiple antitumor regimens, showing a great potential in cancer therapy. Protein kinase D2 (PKD2) plays a crucial role in regulating necrosis and apoptosis. However, the relationship of PKD2 and ferroptosis is still elusive. In this study, we mainly analyzed the roles of PKD2 on ferroptosis and chemotherapy in lung adenocarcinoma (LUAD). We found PKD2 was highly expressed in LUAD and silencing PKD2 could promote erastin-induced reactive oxygen species (ROS), malondialdehyde (MDA) accumulation, intracellular iron content and LUAD cells death. Mechanistically, augmenting PKD2 could prevent autophagic degradation of ferritin, which could be impaired by bafilomycin A1. We further found that PKD2 overexpression would promote LC3B-II, p62/SQSTM1 accumulation and block autophagosome-lysosome fusion in a TFEB-independent manner, which could be impaired by bafilomycin A1. Bafilomycin A1 stimulation could weaken ferroptosis promotion by PKD2 abrogation. Silencing ferritin heavy chain-1 (FTH1) could reverse the resistance to ferroptosis by PKD2 overexpression. Additionally, in vitro and vivo experiments validated PKD2 promoted proliferation, migration and invasion of LUAD cells. PKD2 knockdown or pharmacological inhibition by CRT0066101 could enhance efficacy of carboplatin in LUAD via ferroptosis and apoptosis. Collectively, our study revealed that abrogation of PKD2 could aggravate ferritinophagy-mediated ferroptosis by promoting autophagosome-lysosome fusion and enhance efficacy of carboplatin in LUAD. Targeting PKD2 to induce ferroptosis may be a promising strategy for LUAD therapy.

FUT3 facilitates glucose metabolism of lung adenocarcinoma via activation of NF-κB pathway

ObjectiveFucosyltransferases (FUTs) molecules have been identified to be involved in carcinogenesis of malignant tumors. Nevertheless, the biological function of fucosyltransferases-3 (FUT3) in lung adenocarcinoma (LUAD) malignant phenotype remains unclear. Herein, we investigated the association between FUT3 and LUAD pathological process.MethodsImmunochemistry, RT-qPCR and western blot assays were conducted to evaluate the expression of FUT3 in LUAD and corresponding adjacent tissues. The prognostic value of FUT3 was assessed via Kaplan‑Meier plotter database. The biological process and potential mechanism of FUT3 in LUAD were conducted via GSEA. Additionally, immunofluorescence and metabolite activity detection were performed to determine the potential role of FUT3 in LUAD glucose metabolism. The active biomarkers associated with NF-κB signaling pathway were detected via western blot. Subcutaneous tumor model was conducted to analyze the effect of FUT3 on tumorigenesis of LUAD.ResultsFUT3 was remarkably upregulated in LUAD tissues compared with adjacent tissues from individuals. FUT3 overexpression may predict poor prognosis of LUAD patients. Knockdown of FUT3 significantly inhibited tumor proliferation, migration and glucometabolic alteration in LUAD cells. Moreover, GSEA demonstrated that elevated FUT3 was positively related to NF-κB signaling pathway. Additionally, in vitro and in vivo assays also indicated that downregulation of FUT3 resulted in the suppression of oncogenesis and glucose metabolism via inactivation of NF-κB pathway.ConclusionOur findings demonstrated that FUT3 was involved in glucometabolic process and tumorigenesis of LUAD via NF-κB signaling pathway. FUT3 may be an optimal target for diagnosis and treatment of LUAD patients.

PLEK2 mediates metastasis and invasion via α5-nAChR activation in nicotine-induced lung adenocarcinoma.

Evidence has shown a strong relationship between smoking and epithelial mesenchymal transition (EMT). α5-nicotinic acetylcholine receptor (α5-nAChR) contributes to nicotine-induced lung cancer cell EMT. The cytoskeleton-associated protein PLEK2 is mainly involved in cytoskeletal protein recombination and cell stretch migration regulation, which is closely related to EMT. However, little is known about the link between nicotine/α5-nAChR and PLEK2 in lung adenocarcinoma (LUAD). Here, we identified a link between α5-nAChR and PLEK2 in LUAD. α5-nAChR expression was correlated with PLEK2 expression, smoking status and lower survival in vivo. α5-nAChR mediated nicotine-induced PLEK2 expression via STAT3. α5-nAChR/PLEK2 signaling is involved in LUAD cell migration, invasion and stemness. Moreover, PLEK2 was found to interact with CFL1 in nicotine-induced EMT in LUAD cells. Furthermore, the functional link among α5-nAChR, PLEK2 and CFL1 was confirmed in mouse xenograft tissues and human LUAD tissues. These findings reveal a novel α5-nAChR/PLEK2/CFL1 pathway involved in nicotine-induced LUAD progression.

SOX9 promotes the invasion and migration of lung adenocarcinoma cells by activating the RAP1 signaling pathway

ObjectiveSOX9 has been shown to be related to the metastasis of various cancers. Recently, it has been reported that SOX9 plays a regulatory role in lung adenocarcinoma (LUAD) cell metastasis, but the specific mechanism remains to be explored. Therefore, the objective of this study was to observe the effect and mechanism of SOX9 on the invasion and migration of LUAD cells.MethodsRT-qPCR was applied to observe the expression of SOX9 and RAP1 in tumor tissues and corresponding normal lung tissues collected from LUAD patients. Co-immunoprecipitation and Pearson correlation to analyze the expression correlation of SOX9 with RAP1. To observe the role of SOX9, the invasion and migration levels of LUAD A549 cells in each group were observed by Transwell invasion assay and Scratch migration assay after knocking down or overexpressing SOX9. Besides, the expression levels of RAP1 pathway-related proteins (RAP1, RAP1GAP and RasGRP33) were observed by RT-qCPR or western blot. Subsequently, RAP1 was overexpressed and SOX9 was knocked down in A549 cells, and then the cell invasion/migration level and RAP1 pathway activity were assessed.ResultsThe expression levels of SOX9 and RAP1 in tumor tissues and A549 cells of LUAD patients were significantly increased and positively correlated. Overexpression of SOX9 or RAP1 alone in A549 cells enhanced the invasion and migration ability of cells, as well as up-regulated the expression levels of RAP1, RAP1GAP and RasGRP33. However, knocking down SOX9 decreased cell invasion and migration levels and weakened the activity of RAP1 pathway. Notably, overexpressing RAP1 while knocking down SOX9 significantly activated RAP1 pathway and promoted cell invasion and migration.ConclusionOverexpression of SOX9 in LUAD can significantly activate the RAP1 signaling pathway and promote cell invasion and migration.

Three sesquiterpene lactones suppress lung adenocarcinoma by blocking TMEM16A-mediated Ca2+-activated Cl- channels.

Transmembrane protein TMEM16A, which encodes calcium-activated chloride channel has been implicated in tumorigenesis. Overexpression of TMEM16A is associated with poor prognosis and low overall survival in multiple cancers including lung adenocarcinoma, making it a promising biomarker and therapeutic target. In this study, three structure-related sesquiterpene lactones (mecheliolide, costunolide and dehydrocostus lactone) were extracted from the traditional Chinese medicine Aucklandiae Radix and identified as novel TMEM16A inhibitors with comparable inhibitory effects. Their effects on the proliferation and migration of lung adenocarcinoma cells were examined. Whole-cell patch clamp experiments showed that these sesquiterpene lactones potently inhibited recombinant TMEM16A currents in a concentration-dependent manner. The half-maximal concentration (IC50) values for three tested sesquiterpene lactones were 29.9 ± 1.1 μM, 19.7 ± 0.4 μM, and 24.5 ± 2.1 μM, while the maximal effect (Emax) values were 100.0% ± 2.8%, 85.8% ± 0.9%, and 88.3% ± 4.6%, respectively. These sesquiterpene lactones also significantly inhibited the endogenous TMEM16A currents and proliferation, and migration of LA795 lung cancer cells. These results demonstrate that mecheliolide, costunolide and dehydrocostus lactone are novel TMEM16A inhibitors and potential candidates for lung adenocarcinoma therapy.

Silencing of CD147 inhibits cell proliferation, migration, invasion, lipid metabolism dysregulation and promotes apoptosis in lung adenocarcinoma via blocking the Rap1 signaling pathway

ObjectiveCD147 is an important glycoprotein that participates in the progression of diverse cancers. This study aims to explore the specific function of CD147 in lung adenocarcinoma (LUAD) and to reveal related downstream molecular mechanisms.MethodsFollowed by silencing of CD147, the viability, migration, invasion, and apoptosis of LUAD cells were measured by CCK8, wound healing, transwell assay, and flow cytometer, respectively. The expression of CD147 and two markers of lipid metabolism (FASN and ACOX1) were detected by qRT-PCR. A xenograft tumor model was constructed to investigate the function of CD147 in vivo. Then transcriptome sequencing was performed to explore the potential mechanisms. After measuring the expression of Rap1 and p-p38 MAPK/p38 MAPK by western blot, the changes of CD147 and lipid metabolism markers (FASN, ACOX1) was detected by Immunohistochemistry. Moreover, a Rap1 activator and a Rap1 inhibitor were applied for feedback functional experiments.ResultsCD147 was up-regulated in LUAD cells, and its silencing inhibited cell proliferation, migration, invasion, lipid metabolism dysregulation and promoted apoptosis, while overexpression of CD147 showed the opposite results. Silencing of CD147 also inhibited the growth of tumor xenografts in mice. Transcriptome sequencing revealed 834 up-regulated differentially expressed genes (DEGs) and 602 down-regulated DEGs. After functional enrichment, the Rap1 signaling pathway was selected as a potential target, which was then verified to be blocked by CD147 silencing. In addition, the treatment of Rap1 activator weakened the inhibiting effects of si-CD147 on the proliferation, migration, invasion, and lipid metabolism in LUAD cells, while the intervention of RAP1 inhibitor showed the opposite results.ConclusionsSilencing of CD147 inhibited the proliferation, migration, invasion, lipid metabolism dysregulation and promoted apoptosis of LUAD cells through blocking the Rap1 signaling pathway.

GPR109A partly mediates inhibitory effects of β-hydroxybutyric acid on lung adenocarcinoma cell proliferation, migration and invasion

To explore the mechanism that mediates the inhibitory effects of β-hydroxybutyrate (BHB) on lung adenocarcinoma cells. A549 and LLC cell lines treated with 5 or 10 mmol/L BHB were examined for changes in cell viability, proliferation, migration, and invasion using CCK-8 assay, EdU staining, scratch assay, and Transwell assay. The differential expression of GPR109A in lung adenocarcinoma and normal lung tissue was analyzed using GEPIA database. GPR109A expressions in BHB-treated lung adenocarcinoma cells were determined using RT-PCR and Western blotting. The changes in IC50 of BHB were examined in A549 and LLC cells with GPR109A knockdown. The effect of BHB administered via gavage for 21 days on tumor growth was evaluated in nude mouse and Balb/c mouse models bearing xenografts derived A549 and LLC cells with or without GPR109A knockdown. Treatment with BHB concentration-dependently repressed the viability, proliferation, migration and invasion of A549 and LLC cells. GPR109A expression was significantly decreased in lung adenocarcinoma tissues and A549 and LLC cell lines (P<0.05). Loss of function experiments showed that the inhibitory effects of BHB on A549 and LLC cells were partly mediated by GPR109A, and in the tumor-bearing mouse models, BHB significantly inhibited tumor growth partly by regulating GPR109A expression (P<0.05). BHB can repress the malignant behaviors of A549 and LLC cells and inhibit tumor growth in mice, and these effects are mediated partly by regulating GPR109A expression.

LncRNA ARAP1-AS1 contributes to lung adenocarcinoma development by targeting miR-8068 to upregulate CEACAM5.

It has been discovered that lncRNA ARAP1-AS1 is upregulated and operates as a tumor promoter in many cancers. However, its pattern of expression and potential mechanism in lung adenocarcinoma (LUAD) is still unknown. The levels of lncRNA ARAP1-AS1, miR-8068, and CEACAM5 expressions in LUAD cell lines and tissues were assessed by conducting western blot and RT-qPCR analyses. MiR-8068's potential targeting relationships with lncRNA ARAP1-AS1 and CEACAM5 were ascertained by performing bioinformatics analysis. The interaction of lncRNA ARAP1-AS1 with miR-8068 was validated by means of by RIP and luciferase reporter experiments. CCK-8, cell adhesion, and Transwell migration experiments were conducted to study how lncRNA ARAP1-AS1 affects LUAD cell migration, adhesion, and proliferation. To confirm the function of lncRNA ARAP1-AS1 in vivo, a tumor formation experiment was executed. An elevated expression of lncRNA ARAP1-AS1 was observed among the LUAD cells and tissues. The overexpression of lncRNA ARAP1-AS boosted cell proliferation, adhesion, and migration in LUAD and also favored in vivo tumor growth. MiR-8068 was found to be lncRNA ARAP1-AS1's target gene. MiR-8068 overexpression partially antagonized lncRNA ARAP1-AS1's promotive effect on proliferation, viability, and adhesion. Meanwhile CEACAM5 could alleviate the miR-8068-induced inhibition of tumor growth. The negative correlation of miR-8068 with lncRNA ARAP1-AS1 or CEACAM5 was also revealed. To upregulate CEACAM5 expression lncRNA ARAP1-AS1 targeted miR-8068, thus promoting the progression of LUAD. This indicates that the lncRNA ARAP1-AS1/miR-8068/CEACAM5 axis has potential as a therapeutic target in LUAD treatment.

Effects of TRAF3 on the proliferation and migration of lung adenocarcinoma depend partly on pyroptosis

BackgroundTumor necrosis factor receptor-associated factor 3 (TRAF3) has specific regulatory effects on a wide range of diseases, including tumors. However, the effect and mechanism of TRAF3 on lung adenocarcinoma (LUAD) are still unknown. The aim of the present study was to make clear the role and potential mechanism of TRAF3 in LUAD.MethodsTIMER2.0 database and western blot were applied to detect the expression of TRAF3 in lung adenocarcinoma tissue. Kaplan-Meier Plotter database was utilized to explore the effect of TRAF3 on the clinical prognosis of lung adenocarcinoma patients. Specific siRNA was used to inhibit the expression of TRAF3 in LUAD cells (A549 and H1299). CCK-8 and EdU assays were performed for assessing LUAD cells proliferation. Wound healing assay and transwell assay were performed for determining cells migration. CCK-8 assay was used to assess the response of the LUAD cells to paclitaxel. TIMER2.0 bioinformatics and western blot were employed to detect the effects of TRAF3 on pyroptosis in LUAD.ResultsTRAF3 was highly expressed in lung adenocarcinoma tissues and cell lines. Patients with TRAF3 hyperexpression had a good prognosis compared to those with lower expression. TRAF3 inhibition notably induced proliferation and migration of LUAD cells. Inhibition of TRAF3 also weakened the sensitivity of LUAD cells to paclitaxel. Moreover, bioinformatics results showed that TRAF3 was positively correlated with the expression of pyroptosis-related genes in LUAD. Western blot assays showed that TRAF3 inhibition visibly decreased the expression of apoptosis-associated speck-like protein (ASC), cleaved caspase-1 and matured- IL-1β.ConclusionsInhibition of TRAF3 promotes the proliferation and migration of LUAD cells, and reduces the sensitivity of LUAD cells to paclitaxel. The effects of TRAF3 on LUAD cells were mediated in part by caspase-1-dependent pyroptosis.

MiR-30a-3p/IGF2BP1 affect the proliferation and migration of lung adenocarcinoma cells

Background: IGF2BP1 is a carcinomatous fetal protein associated with proliferation, migration and invasion of tumor cells. The different roles of miR-30a-3p as a tumor suppressor or an oncogene depend on the target genes it regulates. Methods: Downloading the relevant data of lung adenocarcinoma from the TCGA database for bioinformatics analysis to determine the key gene IGF2BP1 and its miRNA that affect the progression of lung adenocarcinoma, and using qPCR to verify their expression and correlation in lung adenocarcinoma. Gene enrichment analysis of IGF2BP1 related pathways, and the function of miR-30a-3p/IGF2BP1 axis in lung adenoma was verified by CCK-8 detection, MTT assay, double luciferase gene reporting assay, cell cloning assay and wound healing assay. Results: As predicted, IGF2BP1 was highly expressed in lung adenocarcinoma tissues, affecting TNM stage and survival status. In addition, IGF2BP1 was negatively correlated with the expression of miR-30a-3p, and the low expression of miR-30a-3p had a poor survival period. Luciferase result confirmed the existence of a targeting relationship between miR-30a-3p and IGF2BP1. Gene enrichment analysis showed that the high expression of IGF2BP1 was correlated with the proliferation of lung adenocarcinoma cells. The experimental results of this study showed that cell viability, proliferation and migration of cells were decreased in the si-IGF2BP1 group and miR-30a-3p-mimics group. In the wound healing assay, compared with the mimics group, the migration ability of cells in the mimics+oe-IGF2BP1 group was improved, which was consistent with the results in the control group. Conclusion: miR-30a-3p can affect the activity of lung adenocarcinoma cells and promote cell proliferation via regulating IGF2BP1. The miR-30a-3p/IGF2BP

Immune Cell Infiltration and Clinical Significance of Angiogenesis-related Genes in Lung Adenocarcinoma.

Angiogenesis is one of the hallmarks of cancer. However, the role of molecular subtypes of angiogenesis-associated genes (AAGs) in the tumor immune microenvironment (TIME) of lung adenocarcinoma (LUAD) remains unclear. The expression of AAGs in patients with LUAD were studied. Consensus clustering was performed to identify new AAG-associated molecular subgroups. The TIME and immune status of the subgroups were analyzed. Functional enrichment analysis was performed on the differentially expression genes among the clustered subgroups to analyze their relationship with AAGs. Furthermore, a prognostic risk model and clinical nomogram associated with survival time were constructed. Risk scores of drug sensitivity, immune checkpoint molecules, tumor mutational burden, and tumor cell stemness were analyzed. Finally, a series of in vitro experiments were performed to investigate the role of dickkopf WNT signaling pathway inhibitor 1 (DKK1) in LUAD. Two molecular subgroups with significantly different survival rates and TIME were identified. Immune checkpoint scores were higher in the subgroup with a worse prognosis. Moreover, differentially expressed genes were enriched in cell-cycle regulation, protein metabolism, and the immune microenvironment. The risk model and clinical nomogram constructed based on AAGs accurately predicted the prognosis of patients with LUAD. Patients with high-risk scores were less sensitive to chemotherapy but more sensitive to immunotherapy. DKK1 was highly expressed in basal cells and luminal cells. In addition, the knockdown of DKK1 reduced LUAD cell proliferation, invasion, and migration. Models based on AAGs can play an important role in predicting LUAD prognosis and immunotherapy effects. We further characterized the angiogenesis of TIME and studied the AAG DKK1. Our findings provide a theoretical basis for antitumor strategies targeting angiogenesis.

UBE2V2 promotes metastasis by regulating EMT and predicts a poor prognosis in lung adenocarcinoma.

As a member of the ubiquitin-conjugating enzyme (E2) family, UBE2V2 demonstrates significant tumorigenicity in many cancers. However, the relationship between UBE2V2 expression and the morbidity of lung adenocarcinoma (LUAD) is still unknown. We detected the mRNA and protein expression of UBE2V2 and analyzed its relationship with clinical parameters as well as survival prognosis based on bioinformatic and immunohistochemistry (IHC) in LUAD. The signaling pathway of UBE2V2 in the development of LUAD was obtained by GSEA. The TIMER database was used to investigate the association between UBE2V2 expression and the level of infiltration of different immune cells. Finally, we explored the effects of UBE2V2 knockdown on the proliferation, apoptosis, and migration of LUAD cells. The results showed that UBE2V2 was a potential oncogene and might be considered an independent prognostic molecule for LUAD patients based on TCGA prediction (HR: 1.497 p = 0.012) and IHC (HR:1.864 p = 0.044). IHC showed that UBE2V2 was related to the following clinicopathological factors: gender (p = 0.043), stage (p = 0.042), and lymph node metastasis (p = 0.002). Finally, knockdown of UBE2V2 reduced the migration of LUAD cells by regulating EMT-related proteins. Knockdown of UBE2V2 induced LUAD cells to arrest in the G1 phase. Knockdown of UBE2V2 increased LUAD cell apoptosis and decreased proliferation, which might be related to the downregulation of PCNA and upregulation of P53 and ƳH2AX expression. Interestingly, UBE2V2 is negatively correlated with B cells, CD4+ T cells, macrophages, and dendritic cells. UBE2V2 may be a valuable therapeutic target for lung cancer.

A novel risk model of three gefitinib-related genes FBP1, SBK1 and AURKA is related to the immune microenvironment and is predicting prognosis of lung adenocarcinoma patients.

Gefitinib, an anticancer drug, has been reported to potentially improve the prognosis of patients with lung adenocarcinoma (LUAD). This study aims to investigate the roles and mechanisms of Gefitinib. The effects of Gefitinib on the growth and migration of LUAD cells were assessed using various methods, including CCK-8, flow cytometry, wound healing, and Transwell assays. To analyze the function and mechanisms of the differentially expressed Gefitinib target genes (GTGs), data from the TCGA database were utilized. Kaplan-Meier survival and ROC analysis identified prognostic-related GTGs and constructed a prognostic nomogram in LUAD. Consensus clustering, COX analysis and survival analysis evaluated the relationship between GTGs and the prognosis of LUAD patients. The mechanisms of the risk model involved LUAD progression, and the relationship between the risk model and immune microenvironment were investigated. Gefitinib could inhibit proliferation, migration and invasion and promote cell apoptosis. 84 DEGTGs were involved in RAS, MAPK, ERBB pathways. The DEGTGs (FBP1, SBK1, and AURKA) were the independent risk factors for dismal prognosis of LUAD patients and were used to establish risk model and nomogram. Gefitinib could promote the expression of FBP1 and inhibit the expression of SBK1 and AURKA. High-risk LUAD patients had the dismal prognosis, and the high-risk score group was significantly associated with the immune microenvironment. FBP1, SBK1, and AURKA are prognostic risk factors, and the risk model and nomogram of FBP1, SBK1 and AURKA are associated with dismal prognosis and immune cell infiltration, and have huge prospects for application in evaluating the prognosis in LUAD.

CBX8 promotes lung adenocarcinoma growth and metastasis through transcriptional repression of CDKN2C and SCEL.

Dysregulation of polycomb group (PcG) proteins that mediate epigenetic gene silencing contributes to tumorigenesis. As core components of the polycomb repressive complex 1 (PRC1), chromobox (CBX) proteins recognize H3K27me3 to recruit PRC1 to maintain a repressive transcriptional state. However, the individual biological functions of these CBX proteins in tumorigenesis warrant in-depth investigation. In this study, we analyzed the mRNA expression of CBX family genes across multiple cancers using The Cancer Genome Atlas data and found different expression patterns of the five CBX genes in different types of cancer. This analyses together with the result of immunohistochemistry indicated that CBX8 expression was significantly higher in lung adenocarcinoma (LUAD) tissues compared to adjacent nontumor tissues. Overexpression approaches demonstrated that CBX8 facilitated LUAD cell proliferation and migration in vitro. Consistently, CBX8 knockdown reduced LUAD cell proliferation and migration in both cell culture and mouse models. RNA sequencing combined with real-time RT-PCR assays revealed CDKN2C and SCEL as target genes of CBX8. Furthermore, chromatin immunoprecipitation assays indicated that CBX8 directly bound to the promoters of CDKN2C and SCEL to establish H2AK119ub. CBX8 depletion reduced the enrichment of H2AK119ub on CDKN2C and SCEL promoters. Moreover, depletion of CDKN2C and SCEL restored the repressed growth and invasion ability of LUAD cells caused by CBX8 knockdown. These findings demonstrate that CBX8 promotes LUAD growth and metastasis through the transcriptional repression of CDKN2C and SCEL. Our study uncovers the oncogenic role of CBX8 in LUAD progression and provides a new target for the diagnosis and therapy of LUAD.

CXXC finger protein 1 (CFP1) bridges the reshaping of genomic H3K4me3 signature to the advancement of lung adenocarcinoma

Histone H3 lysine 4 trimethylation (H3K4me3) is a canonical chromatin modification associated with active gene transcription, playing a pivotal role in regulating various cellular functions. Components of the H3K4me3 methyltransferase complex, known as the proteins associated with SET1 (COMPASS), have been implicated in exerting cancer-protective or cancer-inhibitory effects through inducive H3K4me3 modification. However, the role of the indispensable non-catalytic component of COMPASS CXXC-type zinc finger protein 1 (CFP1) in malignant progression remains unclear. We have unveiled that CFP1 promote lung adenocarcinoma (LUAD) cell proliferation, migration, and invasion while impairing cell apoptosis through in vitro and in vivo models. In addition, high CFP1 expression was identified as emerged as an adverse prognostic indicator across multiple public and in-house LUAD datasets. Notably, CFP1 deficiency led to dual effects on cancer cell transcriptome including extensive inactivation of cancer-promoting as well as activation of cancer repressors. Combining this with the chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we showed that CFP1 ablation reshaped the genomic H3K4me3 distribution signature, with prominent effects on TGF-β and WNT signaling pathways. Collectively, our study proposes that CFP1 mediates tumorigenesis by genomic histone methylation reprogramming, offering insights for future investigations into epigenetic modifications in cancer progression and potential therapeutic advancements.