Inhibited Lung Cancer Cell Proliferation Research Articles

ERH is a prognostic biomarker associated with immune cell infiltration in lung cancer

Introduction The enhancer of rudimentary homolog (ERH) is significant in cancers, but its role in lung cancer is understudied. We divided lung cancer patients into high and low ERH expression groups based on tumor tissue levels. Methods Using the log-rank test, we analyzed the correlation between ERH expression and patient prognosis. The effects of high ERH expression on lung cancer cell proliferation, migration, and invasion were assessed using CCK8, EDU, transwell, and wound healing assays. Results ERH expression was significantly higher in cancerous versus normal lung tissue (p < 0.05), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Patients with high ERH expression had worse overall survival (HR = 1.37, p = 2.5 × 10−7) and first progression survival (HR = 1.38, p = 0.00065) in lung cancer. However, while high ERH expression predicts an unfavorable prognosis in LUAD, it does not hold true for LUSC. Furthermore, knockdown of ERH inhibited lung cancer cell proliferation, migration, and invasion. ERH expression was linked to immune cell infiltration. High ERH expression in LUAD and LUSC samples correlated with higher CD8 T cell, T cells CD4 memory activated, and M1 macrophages abundance, while low ERH expression correlated with higher T cells CD4 memory resting abundance. Conclusion Upregulation of ERH in lung cancer tissue is associated with poor prognosis and immune cell infiltration.

Glutathione-dependent degradation of SMARCA2/4 for targeted lung cancer therapy with improved selectivity

SMARCA2 and SMARCA4 are the mutually exclusive catalytic subunits of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, and have recently been considered as attractive synthetic lethal targets for PROTAC-based cancer therapy. However, the potential off-tissue toxicity towards normal tissues remains a concern. Here, we optimize a GSH-inducible SMARCA2/4-based PROTAC precursor with selective antitumor activity towards lung cancer cells and negligible cytotoxicity towards normal cells in both in vitro and in vivo studies. The precursor is not bioactive or cytotoxic, but preferentially responds to endogenous GSH in GSH-rich lung cancer cells, releasing active PROTAC to degrade SMARCA2/4 via PROTAC-mediated proteasome pathway. Subsequent xenograft model study reveals that selective SMARCA2/4 degradation in lung tumors triggers DNA damage and apoptosis, which significantly inhibits lung cancer cell proliferation without obvious adverse events towards normal tissues. This study exemplifies the targeted degradation of SMARCA2/4 in lung cancer cells by the GSH-responsive PROTAC precursor, highlighting its potential as an encouraging cancer therapeutic strategy.

Oridonin represses lung cancer cell proliferation and migration by modulating AFAP1-AS1/IGF2BP1.

Oridonin belongs to a small molecule from the Chinese herb Rabdosia rubescens with potent anticancer activity. In spite of the lncRNA AFAP1-AS1 has been proven to exert promoting function in lung cancer, its relationship with oridonin in lung cancer is obscure. Therefore, our study planned to explore the potential of oridonin in lung cancer as well as unveil the regulatory mechanism of oridonin on AFAP1-AS1 in lung cancer cells. In the present study, oridonin inhibited lung cancer cell proliferation, migration, as well as invasion, as evidenced by MTT, wound healing, as well as transwell assays. Besides, we observed that oridonin could downregulate AFAP1-AS1 expression, and overexpressed AFAP1-AS1 could reverse the repressive effects of oridonin on lung cancer cell proliferation, migration, as well as invasion. More importantly, we found that AFAP1-AS1 could bind to IGF2BP1 through starBase prediction and RIP assay. The expression level of IGF2BP1 was also reduced by oridonin treatment but reversed after AFAP1-AS1 overexpression. Additionally, we proved that overexpressed IGF2BP1 could reverse the repressive impacts of oridonin on lung cancer cell proliferation, migration, as well as invasion. Further, in vivo experiments validated the repressive role of oridonin on tumor growth of lung cancer. Together, oridonin inhibits lung cancer cell proliferation as well as migration by modulating AFAP1-AS1/IGF2BP1, and AFAP1-AS1/IGF2BP1 possesses the potential to be a promising therapy targeting for lung cancer, especially in oridonin treatment.

Retraction: Knockdown of TRIM65 inhibits lung cancer cell proliferation, migration and invasion: A therapeutic target in human lung cancer.

Retraction: Knockdown of TRIM65 inhibits lung cancer cell proliferation, migration and invasion: A therapeutic target in human lung cancer.

Ethaverine and Papaverine Target Cyclin-Dependent Kinase 5 and Inhibit Lung Cancer Cell Proliferation and Migration.

CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more recently with several human cancers, in particular lung cancer. However, ATP-competitive inhibitors targeting CDK5 are poorly selective and suffer limitations, calling for new classes of inhibitors. In a screen for allosteric modulators of CDK5, we identified ethaverine and closely related derivative papaverine and showed that they inhibit cell proliferation and migration of non small cell lung cancer cell lines. Moreover the efficacy of these compounds is significantly enhanced when combined with the ATP-competitive inhibitor roscovitine, suggesting an additive dual mechanism of inhibition targeting CDK5. These compounds do not affect CDK5 stability, but thermodenaturation studies performed with A549 cell extracts infer that they interact with CDK5 in cellulo. Furthermore, the inhibitory potentials of ethaverine and papaverine are reduced in A549 cells treated with siRNA directed against CDK5. Taken together, our results provide unexpected and novel evidence that ethaverine and papaverine constitute promising leads that can be repurposed for targeting CDK5 in lung cancer.

Diosbulbin C, a novel active ingredient in Dioscorea bulbifera L. extract, inhibits lung cancer cell proliferation by inducing G0/G1 phase cell cycle arrest

BackgroundDespite the critical progress of non-small cell lung cancer (NSCLC) therapeutic approaches, the clinical outcomes remain considerably poor. The requirement of developing novel therapeutic interventions is still urgent. In this study, we showed for the first time that diosbulbin C, a natural diterpene lactone component extracted from traditional Chinese medicine Dioscorea bulbifera L., possesses high anticancer activity in NSCLC.MethodsA549 and NCI-H1299 cells were used. The inhibitory effects of the diosbulbin C on NSCLC cell proliferation were evaluated using cytotoxicity, clone formation, EdU assay, and flow cytometry. Network pharmacology methods were used to explore the targets through which the diosbulbin C inhibited NSCLC cell proliferation. Molecular docking, qRT-PCR, and western blotting were used to validate the molecular targets and regulated molecules of diosbulbin C in NSCLC.ResultsDiosbulbin C treatment in NSCLC cells results in a remarkable reduction in cell proliferation and induces significant G0/G1 phase cell cycle arrest. AKT1, DHFR, and TYMS were identified as the potential targets of diosbulbin C. Diosbulbin C may inhibit NSCLC cell proliferation by downregulating the expression/activation of AKT, DHFR, and TYMS. In addition, diosbulbin C was predicted to exhibit high drug-likeness properties with good water solubility and intestinal absorption, highlighting its potential value in the discovery and development of anti-lung cancer drugs.ConclusionsDiosbulbin C induces cell cycle arrest and inhibits the proliferation of NSCLC cells, possibly by downregulating the expression/activation of AKT, DHFR, and TYMS.

NSUN6 Regulates NM23-H1 Expression in an m5C Manner to Affect Epithelial-Mesenchymal Transition in Lung Cancer

Purpose: The expression and regulatory mechanism of NSUN6 in lung cancer are still unclear. Our study explored whether NSUN6 mediates progression of lung cancer by affecting NM23-H1 expression in an m5C-dependent manner. Methods: qRT-PCR, CCK-8, colony formation, transwell, and Western blot analysis were employed to probe the impact of NSUN6 on lung cancer cell proliferation, migration, and epithelial-mesenchymal transition (EMT). RMVar database was utilized to forecast the downstream genes of NSUN6. The mode of interaction between NSUN6 and NM23-H1 was determined by dot blot, luciferase assay, m5C RIP, and cell function assays. The effect of NSUN6 expression on tumor growth was verified in vivo. Results: Expression of NSUN6 was reduced in lung cancer cells, and over-expression of NSUN6 restricted the proliferation of lung cancer cells, migration, and EMT. NSUN6 regulated NM23-H1 expression by modifying the 3′-UTR of NM23-H1 mRNA through m5C and inhibited lung cancer cell proliferation, migration, and EMT. In vivo experiments also showed that over-expression of NSUN6 inhibited the occurrence of lung cancer. Conclusion: NSUN6 regulates NM23-H1 expression in an m5C-dependent manner to affect EMT in lung cancer. Thus, NSUN6 may be considered as a potential therapeutic target for lung cancer.

Deciphering the Role of Fatty Acid-Metabolizing CYP4F11 in Lung Cancer and Its Potential As a Drug Target.

Lung cancer is the leading cause of cancer deaths worldwide. We found that the cytochrome P450 isoform CYP4F11 is significantly overexpressed in patients with lung squamous cell carcinoma. CYP4F11 is a fatty acid ω-hydroxylase and catalyzes the production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. 20-HETE promotes cell proliferation and migration in cancer. Inhibition of 20-HETE-generating cytochrome P450 enzymes has been implicated as novel cancer therapy for more than a decade. However, the exact role of CYP4F11 and its potential as drug target for lung cancer therapy has not been established yet. Thus, we performed a transient knockdown of CYP4F11 in the lung cancer cell line NCI-H460. Knockdown of CYP4F11 significantly inhibits lung cancer cell proliferation and migration while the 20-HETE production is significantly reduced. For biochemical characterization of CYP4F11-inhibitor interactions, we generated recombinant human CYP4F11. Spectroscopic ligand binding assays were conducted to evaluate CYP4F11 binding to the unselective CYP4A/F inhibitor HET0016. HET0016 shows high affinity to recombinant CYP4F11 and inhibits CYP4F11-mediated 20-HETE production in vitro with a nanomolar IC 50 Cross evaluation of HET0016 in NCI-H460 cells shows that lung cancer cell proliferation is significantly reduced together with 20-HETE production. However, HET0016 also displays antiproliferative effects that are not 20-HETE mediated. Future studies aim to establish the role of CYP4F11 in lung cancer and the underlying mechanism and investigate the potential of CYP4F11 as a therapeutic target for lung cancer. SIGNIFICANCE STATEMENT: Lung cancer is a deadly cancer with limited treatment options. Cytochrome P450 4F11 (CYP4F11) is significantly upregulated in lung squamous cell carcinoma. Knockdown of CYP4F11 in a lung cancer cell line significantly attenuates cell proliferation and migration with reduced production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE). Studies with the unselective inhibitor HET0016 show a high inhibitory potency of CYP4F11-mediated 20-HETE production using recombinant enzyme. Overall, our studies demonstrate the potential of targeting CYP4F11 for new transformative lung cancer treatment.

Identification of the Key Active Pharmaceutical Ingredients of Yishen Qutong Granule, A Chinese Medicine Formula, In The Treatment of Primary Lung Cancer.

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Traditional Chinese medicine (TCM) reportedly has potential therapeutic effects against LC. This study aimed to investigate the antitumor efficacy of Yishen Qutong granule (YSQTG) in primary LC treatment, to identify its key active pharmaceutical ingredients (APIs), and to explore its possible mechanism of action. The antitumor role of YSQTG was validated via cell function assays and a xenograft tumor model. Then, high-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed to determine the objective precipitation components of YSQTG, followed by target prediction through reference to databases. Subsequently, the proportion of the predicted targets that underwent actual changes was identified via RNA-sequencing. Enrichment analysis was performed to explore the possible mechanisms of action. Hub genes were screened, and western blotting was used to verify their protein expression levels to identify the core target. Molecular docking between the active compounds and the verified core target was performed, combined with an evaluation of the potential efficacy of candidate compounds using meta-analysis to screen the candidate key APIs. Experiments confirmed that YSQTG could inhibit LC cell proliferation, induce apoptosis in vitro, and inhibit lung tumor growth in vivo. HPLC-MS, RNA-seq, and enrichment analysis showed that oxidative stress-related pathways were the possible mechanism of YSQTG in primary LC treatment. Western blot verification indicated that heme oxygenase 1 (HMOX1, HO-1) could be the core target. Molecular docking and meta-analysis suggested that genistein and quercetin were the candidate key APIs. YSQTG and its active ingredients, genistein and quercetin, may have therapeutic effects against LC through their action on the downregulation of oxidative stress-related HMOX1 protein expression.

Antiproliferative and apoptotic effect of tuna blood on human lung cancer A549 cells via p38 MAPKs and Akt pathway

Tuna blood has been reported the anti-inflammatory properties. However, the anticancer effects of tuna blood remain unelucidated. Therefore, this study investigated the anticancer effects of tuna blood against human non-small cell lung cancer (NSCLC) A549 cells and its potential mechanism of action. The amino acid profile presented in tuna whole blood freeze-dried (TWBF) and tuna blood cell freeze-dried (TRBF) were analyzed, and the antiproliferative effect was assessed by MTT assay. The nuclear staining, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP) were examined by Hoechst/PI staining, DCFHDA assay, and JC-1 staining. The expression of apoptosis-related proteins and the involvement of p38 MAPKs and Akt signaling were evaluated by western blotting. TWBF and TRBF inhibited the proliferation of lung cancer A549 cells with IC50 values of 354.97, 141.31 µg/mL, respectively. TRBF revealed more efficacy of cell proliferation inhibition than that of TWBF. The percentage of apoptotic cell death after treatment with 100 µg/mL TRBF was 35.95%. The increase in the ROS production and the disruption of MMP were also detected. At a mechanistic level, the exposure of TRBF to A549 cells showed an increase of the Bax/Bcl2 ratio and subsequently activated the proteolytic activity of caspase-3. TRBF administration induced apoptosis through the downregulation of protein kinase B (Akt) and upregulation of p38 MAPK. These findings indicate TRBF inhibits lung cancer cell proliferation and mediates apoptosis signaling, suggesting a promising chemotherapeutic candidate target NSCLC.

Abstract 5054: The study of synergy mechanism between surufatinib and vinorelbine in the treatment of non-small cell lung cancer

Abstract Background: The incidence and mortality rate of lung cancer ranks first among malignant tumors. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. Combined use of targeted therapy can enhance the efficacy of chemotherapy drugs while reduce the related side effects in clinical practice. Surufatinib is a potent, small-molecule tyrosine kinase inhibitor (TKI), selectively targeting VEGF receptors (VEGFR) 1, 2, and 3, Fibroblast growth factor receptor 1 (FGFR1), and CSF-1R, which simultaneously prevents tumor angiogenesis and tumor immune evasion. Our clinical study (NCT04922658) has showed the promising effect and safety of surufatinib plus vinorelbine in NSCLC patients, but the potential mechanism is still to be revealed. Herein, tumor-bearing models and cancer cell culture platform would be established for further studying, which may shed light on the synergy mechanism between surufatinib and vinorelbine, and guide the clinical treatment ultimately. Methods: Subcutaneous tumorigenesis in nude mice were successfully established, and then treated with related experimental drugs. The tumor size was observed and CD31 expression of tumor tissue was measured using immunohistochemical analysis. In vitro study, the A549 and PC9 cell multiplication capacities were measured by CCK8 assay and plate cloning assay. The abilities of cancer cell migration and apoptosis were detected using cell scratch assay and flow cytometry kit, respectively. Results: Monotherapy with surufatinib or vinorelbine showed a moderate tumor suppression, whereas the combination therapy of surufatinib and vinorelbine showed the remarkable inhibition of tumor growth in vivo. Surufatinib and the combination therapy obviously decreased the expression of CD31 in tumor issue which might cause the anti-angiogenesis. Monotherapy with surufatinib or vinorelbine significantly inhibited the proliferation of lung cancer cells (A549 cells and PC9 cells) in a concentration-dependent manner, and surufatinib could memorably promote the anti-proliferation activity of vinorelbine. As a result, combination therapy of surufatinib and vinorelbine distinctly inhibited lung cancer cell proliferation when compared with monotherapy with vinorelbine. Consistently, the synergistic effects of surufatinib plus vinorelbine were also observed in cell migration and apoptosis analysis. Conclusions: Synergistic effect of surufatinib and vinorelbine resulted in a conspicuous tumor regression, which is consistent with the clinical observation. In a depth data analysis, surufatinib enhanced the antitumor activity of vinorelbine probably by inhibiting tumor cell proliferation and migration, suppressing tumor angiogenesis and promoting tumor apoptosis in NSCLC patients. Citation Format: Xiaoran Wu, Yanfang Zheng, Lingyu Qin, Ying Li, Zhongjian Yu, Xiongjie Zhu, Rui Cai, Feiyu Niu, Yan Yuan, Peng Jiang, Shaoshi Wen, Xing Lv, Jiancai Zhou. The study of synergy mechanism between surufatinib and vinorelbine in the treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5054.

In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma

Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains unknown. Here we show, using an orthotopic murine lung cancer model and human carcinoma samples, that AMs support cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of activin A, a homodimer of INHBA. Accordingly, follistatin, an antagonist of activin A is able to inhibit lung cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBA/activin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts.

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long-chain acyl-coenzyme A synthase 5.

Lung cancer is a widespread malignancy with a high death rate and disorder of lipid metabolism. Lysophosphatidylcholine (lysoPC) has anti-tumour effects, although the underlying mechanism is not entirely known. The purpose of this study aims at defining changes in lysoPC in lung cancer patients, the effects of lysoPC on lung cancer cells and molecular mechanisms. Lung cancer cell sensitivity to lysoPC was evaluated and decisive roles of long-chain acyl-coenzyme A synthase 5 (ACSL5) in lysoPC regulation were defined by comprehensively evaluating transcriptomic changes of ACSL5-downregulated epithelia. ACSL5 over-expressed in ciliated, club and Goblet cells in lung cancer patients, different from other lung diseases. LysoPC inhibited lung cancer cell proliferation, by inducing mitochondrial dysfunction, altering lipid metabolisms, increasing fatty acid oxidation and reprograming ACSL5/phosphoinositide 3-kinase/extracellular signal-regulated kinase-regulated triacylglycerol-lysoPC balance. Thus, this study provides a general new basis for the discovery of reprogramming metabolisms and metabolites as a new strategy of lung cancer precision medicine.

RBMS3, a downstream target of AMPK, Exerts Inhibitory Effects on Invasion and Metastasis of Lung Cancer.

Background: Lung cancer is a highly malignant disease, primarily due to its propensity for metastasis. AMP-activated protein kinase (AMPK), the principal downstream effector of Liver Kinase B1 (LKB1), orchestrates a broad spectrum of molecular targets, thereby constraining tumor invasion and metastasis. In parallel, the RNA-binding protein RBMS3 (RNA-binding motif, single-stranded-interacting protein 3) plays a pivotal role in the epithelial-mesenchymal transition (EMT), a pivotal process in tumorigenesis. Therefore, our research aims to clarify the important role of RBMS3 as a mediator in the LKB1/AMPK inhibition of tumor invasion and metastasis. Methods: We investigated the expression and correlation between RBMS3 and LKB1 in lung cancer tissues utilizing immunohistochemistry and TCGA-LUAD data, respectively. The relationship between RBMS3 and clinical pathological features and prognosis of lung cancer was also analyzed. The functions of RBMS3 in lung cancer cell proliferation, invasion, and migration were investigated in real-time in vitro. Additionally, we investigated the effects of AMPK agonists and inhibitors to explore the mediating role of RBMS3 in AMPK-induced inhibition of lung cancer invasion and migration. Results: The IHC and TCGA data both revealed low expression of RBMS3 in lung cancer. Moreover, we found that low expression of RBMS3 was positively associated with lung cancer's histological grade, clinical stage, and N stage. Additionally, low RBMS3 expression was associated with poor overall survival. Cox regression analysis revealed that RBMS3 was an independent prognostic factor for lung cancer patients. In vitro experiments verified that RBMS3 inhibited lung cancer cell proliferation, invasion, and migration. Furthermore, our findings suggested that RBMS3 played an essential role in mediating AMPK's inhibitory effect on lung cancer invasion and migration. Conclusion: Our study highlights a novel mechanism by which LKB1/AMPK pathway activation inhibits lung cancer invasion and metastasis by promoting RBMS3 expression, offering insights in developing innovative lung cancer therapies.

Preventive and therapeutic effects of green tea on lung cancer: a narrative review of evidence from clinical and basic research.

Green tea is a popular beverage worldwide and has numerous health-promoting properties. Accumulating evidence indicates that green tea has preventive and therapeutic effects on lung cancer. This study aimed to investigate the association between green tea consumption and lung cancer. We performed a narrative review to summarized the association between green tea consumption and lung cancer. Green tea consumption is known to decrease lung cancer risk in the general population, as indicated by meta-analyses of observational studies. Two active components of green tea, theabrownin and (-)-epigallocatechin gallate (EGCG), mediate the antitumor activity of green tea. Theabrownin promotes apoptosis, induces cell cycle arrest, and inhibits the migration, clone formation, and proliferation of lung cancer cell lines in vitro and in vivo. EGCG inhibits lung cancer cell proliferation and promotes apoptosis, agenesis, and epithelial-mesenchymal transition (EMT). In addition, EGCG sensitizes lung cancer cells to cisplatin and tyrosine kinase inhibitors (TKIs). The possible molecular mechanisms underlying the antitumor activity of EGCG and theabrownin were reviewed. Observational studies have indicated that green tea has preventive effects on lung cancer. In vitro and animal studies have indicated that green tea has therapeutic effects on lung cancer. Further clinical trials are needed to illustrate the therapeutic effects of green tea or its active components (i.e., theabrownin, EGCG) on lung cancer.

PELP1 is overexpressed in lung cancer and promotes tumor cell malignancy and resistance to tyrosine kinase inhibitor drug

Proline, glutamate, and leucine-rich protein 1 (PELP1) are involved in several cancers, but little is known about PELP1 in lung cancer. In this study, PELP1 expression was evaluated in 305 lung cancer (NSCLC) specimens to explore the role of PELP1 in lung cancer. After silencing PELP1, the proliferation, migration, invasion of tumor cells, PELP1 in relation to cell cycle and signaling pathways were evaluated, and whole-genome exons were analyzed. PELP1 is overexpressed in lung cancer, PELP1 expression correlated with squamous carcinoma, smoking, and wild-type EGFR status (all Ps<0.001) but associated with lung cancer-specific survival (P > 0.05). Silencing significantly inhibited lung cancer cell proliferation, migration, and invasion (P < 0.05) and promoted high sensitivity of lung cancer cells to tyrosine kinase inhibitor (TKI) gefitinib. PELP1-silenced cells showed downregulated phosphorylated MAPK, cyclinD1, CDK2, and upregulated RB (P < 0.05) but no change in AKT. In PELP1-silenced lung cancer cells, 140 genes were upregulated, and 143 genes were downregulated. Furthermore, the number of T regulatory cell was higher in lung adenocarcinoma with pelp1 high-expression and pelp1 expression was negatively correlated with CD274 (PDL-1) and CTLA4. Therefore, PELP1 plays an important role in the malignant behavior of NSCLC and could be a potential therapeutic target.

Treatment of malignant pleural effusion in non-small cell lung cancer with VEGF-directed therapy

Background Vascular endothelial growth factor (VEGF) is a critical regulator of malignant pleural effusion (MPE) in non-small-cell lung cancer (NSCLC). Bevacizumab (BEV) and apatinib (APA) are novel VEGF blockers that inhibit lung cancer cell proliferation and the development of pleural effusion. Methods In this study, we established Lewis lung cancer (LLC) xenograft mouse models to compare the therapeutic effect of APA and BEV in combination with cisplatin (CDDP) against MPE. The anti-tumour and anti-angiogenic effects of this combination therapy were evaluated by 18F-FDG PET/CT imaging, TUNEL assay and Immunohistochemistry. Results The triple drug combination significantly prolonged the overall survival of the tumour-bearing mice by reducing MPE and glucose metabolism and was more effective in lowering VEGF/soluble VEGFR-2 levels in the serum and pleural exudates compared to either of the monotherapies. Furthermore, CDDP + APA + BEV promoted in vivo apoptosis and decreased microvessel density. Conclusions Mechanistically, LLC-induced MPE was inhibited by targeting the VEGF-MEK/ERK pathways. Further studies are needed to establish the synergistic therapeutic effect of these drugs in NSCLC patients with MPE. KEY MESSAGES Combined treatment of MPE with apatinib, bevacizumab and cisplatin can prolong the survival time of mice, reduce the content of MPE, decrease the SUVmax of thoracic tumour tissue, down-regulate the content of VEGF and sVEGFR-2 in serum and pleural fluid, and promote the apoptosis of tumour cells. Angiogenesis and MPE formation can be inhibited by down-regulation of HIF-1α, VEGF, VEGFR-2, MEK1 and MMP-2 molecular signalling pathway proteins.

Molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and potential treatment strategies.

Isocitrate dehydrogenase (IDH) is an appealing target for anticancer therapy, and IDH (IDH1/2) inhibitors have been approved for targeted therapy of acute myeloid leukemia (AML) and Cholangiocarcinoma. The therapeutic potential of IDH inhibitors for non-small-cell lung cancer (NSCLC) patients is under active clinical investigation. Thus, it would be necessary and meaningful to study the molecular and clinical characteristics of IDH mutation in NSCLC patients, especially in the Chinese population. A total of 17,978 Chinese patients with NSCLC who underwent next -generation sequencing (NGS) testing were retrospectively reviewed. We identified 161 unique IDH mutations in 361 of 17,978 patients (2.01%). Common active-site mutations, including IDH1R100 , IDH1R132 , IDH2R140 , and IDH2R172 , were detected in 154 patients (0.86%) and were associated with male sex (p=0.004) and older age (p=0.02). The IDH mutation spectra observed in NSCLC were quite different from those in glioma or AML. Patients with IDH active-site mutations exhibited significantly higher coalterations in KRAS (p. G12/13/61, 22.1% vs. 8.2%, p < 0.001) or BRAF (p. V600E, 6.5% vs. 1.0%, p < 0.001), but significantly lower coalterations in activating EGFR (e18-e20, 22.7 vs. 37.9%, p < 0.001) than IDH wild-type patients. Furthermore, we found that active-site IDH mutations were correlated with a short PFS (2-5.6 months) and short OS (2-9.5 months), which may arise as a resistance mechanism against common targeted drugs. In vitro, we experimentally observed that the combination of an IDH inhibitor and EGFR TKI could better inhibit lung cancer cell proliferation than an EGFR TKI alone. Taken together, this study reveals the molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and provides a theoretical basis for IDH-directed treatment. The potential of IDH mutations as response markers for targeted therapy warrants further investigation.

Long non-coding RNA LSAMP-1 is down-regulated in non-small cell lung cancer and predicts a poor prognosis

BackgroundLong noncoding RNAs (lncRNAs) are emerging as master regulators for gene expression and thus play a vital role in human tumorigenesis and progression. But the involvement of novel lncRNAs in non-small cell lung cancer (NSCLC) remains largely unelucidated.MethodsA total of 170 NSCLC and their adjacent non-tumor tissues were enrolled to detect the expression of Lnc-LSAMP-1 by RT-qPCR. The effects of Lnc-LSAMP-1 on cell proliferation, migration, invasion and drug-sensitivity were determined by in vitro and in vivo experiments. The proteins that interact with Lnc-LSAMP-1were confirmed by RNA pull-down assay. RNA-sequencing were used to identify the potential targets of Lnc-LSAMP-1 in NSCLC.ResultsWe found that Lnc-LSAMP-1 was significantly down-regulated in 170 cases of NSCLC tissues when compared to their adjacent non-cancerous tissues. Loss expression of Lnc-LSAMP-1 was notably correlated with unfavorable prognosis of NSCLC patients. The ectopic expression of Lnc-LSAMP-1 drastically inhibited lung cancer cell proliferation, viability, invasion and migration ability, arrested cell cycle and facilitated apoptosis. Chemotherapy sensitization experiments showed that over-expressed Lnc-LSAMP-1 enhanced the inhibition of cell proliferation induced by TKI. Mechanistically, Lnc-LSAMP-1-LSAMP formed a complex which could protect the degradation of LSAMP gene, and thus exerted crucial roles in NSCLC progression and TKI targeted treatment.ConclusionsConsequently, our findings highlight the function and prognostic value of Lnc-LSAMP-1 in NSCLC and provide potential novel therapeutic targets and prognostic biomarkers for patients with NSCLC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12935-022-02592-0.

Mxi1 participates in the progression of lung cancer via the microRNA-300/KLF9/GADD34 Axis

The purpose of the current study was to define the role of MAX interactor 1 (Mxi1) in the pathogenesis of lung cancer and its underlying molecular mechanism. Bioinformatics analysis was performed to identify important regulatory pathway related to lung cancer. Dual luciferase reporter and ChIP assays were adopted to validate the interaction among Mxi1, miR-300 and KLF9. Loss- and gain-of-function studies were conducted to determine the roles of Mxi1, miR-300, and KLF9 in cell proliferation, migration, and invasion in vitro and their effects on myeloid-derived suppressor cell (MDSC) recruitment in vivo. Mxi1 was poorly expressed in lung cancer tissues and cells and its poor expression was associated with poor prognosis. Mxi1 inhibited miR-300 by suppressing its transcription. miR-300 suppressed the expression of KLF9, and KLF9 negatively regulated GADD34 expression in lung cancer cells. Mxi1 or KLF9 elevation or miR-300 repression inhibited lung cancer cell proliferation, as evidenced by reduced Ki67 and PCNA expression, and lowered invasion and migration. In vivo findings revealed that silencing KLF9 induced tumor growth by enhancing MDSC-mediated immunosuppression through upregulation of GADD34. Collectively, these findings suggest that Mxi1 can inhibit lung cancer progression by regulating the miR-300/KLF9 axis and GADD34-mediated immunosuppression.