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Non‑small cell lung cancer (NSCLC) is a highly prevalent lung malignancy characterized by insidious onset, rapid progression and advanced stage at the time of diagnosis, making radical surgery impossible. Sirtuin (SIRT) is a histone deacetylase that relies on NAD+ for its function, regulating the aging process through modifications in protein activity and stability. It is intricately linked to various processes, including glycolipid metabolism, inflammation, lifespan regulation, tumor formation and stress response. An increasing number of studies indicate that SIRTs significantly contribute to the progression of NSCLC by regulating pathophysiological processes such as energy metabolism, autophagy and apoptosis in tumor cells through the deacetylation of histones or non‑histone proteins. The present review elaborates on the roles of different SIRTs and their mechanisms in NSCLC, while also summarizing novel therapeutic agents based on SIRTs. It aims to present new ideas and a theoretical basis for NSCLC treatment.

Cisplatin resistance is common in non‑small cell lung cancer (NSCLC); however, the molecular mechanisms remain unclear. The present study aimed to identify a new function of Golgi phosphoprotein 3 (GOLPH3) in NSCLC‑associated cisplatin resistance. Using A549 human NSCLC cells and the cisplatin‑resistant variant, stable cell lines with GOLPH3 knockdown or overexpression were established using lentiviral vectors. Through Cell Counting Kit‑8 and EdU assays, it was revealed that knockdown of GOLPH3 significantly enhanced cisplatin sensitivity in NSCLC cells. Specifically, flow cytometric analysis showed that GOLPH3 knockdown promoted apoptosis and G 2 ‑phase cell cycle arrest in A549 cells. Mechanistically, intracellular reactive oxygen species (ROS) and glutathione (GSH) levels were measured using assay kits, and it was demonstrated that GOLPH3 knockdown decreased intracellular GSH levels, and further attenuated intracellular cisplatin efflux and GSH/ROS imbalance. In addition, tumor‑sphere formation assays verified that GOLPH3 knockdown mitigated the stem cell‑like phenotype of NSCLC cells. In conclusion, the present findings indicated the relevance of GOLPH3 in NSCLC‑associated cisplatin resistance, and thus targeting GOLPH3 may be developed into a combination therapy to overcome cisplatin resistance.

Non‑small cell lung cancer (NSCLC) is one of the major causes of cancer‑related death worldwide. Cisplatin is a front‑line chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatin‑mediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcription‑quantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROS‑mediated endoplasmic reticulum stress, and the C‑Jun‑amino‑terminal kinase and p38 mitogen‑activated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROS‑mediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.

The prognosis for patients with non‑small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5‑year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5‑30 mm, or whole‑brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial‑to‑mesenchymal transition, overexpression of programmed cell death‑ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes‑associated protein‑1, on cerebral metastases originating from lung cancer.

Ferroptosis, a recently discovered type of programmed cell death triggered by excessive accumulation of iron‑dependent lipid peroxidation, is linked to several malignancies, including non‑small cell lung cancer. Long non‑coding RNAs (lncRNAs) are involved in ferroptosis; however, data on their role and mechanism in cancer therapy remains limited. Therefore, the aim of the present study was to identify ferroptosis‑associated mRNAs and lncRNAs in A549 lung cancer cells treated with RAS‑selective lethal 3 (RSL3) and ferrostatin‑1 (Fer‑1) using RNA sequencing. The results demonstrated that lncRNA lung cancer‑associated transcript 1 (LUCAT1) was significantly upregulated in lung adenocarcinoma and lung squamous cell carcinoma tissues. Co‑expression analysis of differentially expressed mRNAs and lncRNAs suggested that LUCAT1 has a crucial role in ferroptosis. LUCAT1 expression was markedly elevated in A549 cells treated with RSL3, which was prevented by co‑incubation with Fer‑1. Functionally, overexpression of LUCAT1 facilitated cell proliferation and reduced the occurrence of ferroptosis induced by RSL3 and Erastin, while inhibition of LUCAT1 expression reduced cell proliferation and increased ferroptosis. Mechanistically, downregulation of LUCAT1 resulted in the downregulation of both GTP cyclohydrolase 1 (GCH1) and ferroptosis suppressor protein 1 (FSP1). Furthermore, inhibition of LUCAT1 expression upregulated microRNA (miR)‑34a‑5p and then downregulated GCH1. These results indicated that inhibition of LUCAT1 expression promoted ferroptosis by modulating the downregulation of GCH1, mediated by miR‑34a‑5p. Therefore, the combination of knocking down LUCAT1 expression with ferroptosis inducers may be a promising strategy for lung cancer treatment.

It was recently reported that netrin‑4 (Ntn‑4), a component of the extracellular matrix, when downregulated, is involved in the progression of several types of cancer, including breast cancer, colorectal tumours, neuroblastoma and gastric cancer. In the present study, the level of Ntn‑4 was examined in a public non‑small cell lung cancer (NSCLC) dataset from the Netherlands Cancer Institute. This analysis revealed that the mRNA expression level of Ntn‑4 was lower in the samples of patients with NSCLC compared with that in the control samples. Consistent with the mRNA level, the protein level of Ntn‑4 was also found to be decreased in NSCLC cells. However, both the function of Ntn‑4 and the underlying mechanisms of Ntn‑4 downregulation in NSCLC have yet to be fully elucidated. As was anticipated, the overexpression of Ntn‑4 led to a marked decrease in the proliferation, migration and invasion of NSCLC cells. Notably, RNA‑binding protein quaking 5 (Qki‑5) was found to exhibit antitumor activity in lung cancer, not only by enhancing the level of Ntn‑4 by binding to Ntn‑4 mRNA, but also by suppressing the proliferation, invasion and migration of NSCLC cells. However, Qki‑5 is known to be frequently downregulated in NSCLC. Moreover, the knockdown of Ntn‑4 was found to reverse the suppressive effects of Qki‑5 on NSCLC progression both in vitro and in vivo . Taken together, the findings of the present study demonstrate that Ntn‑4 is able to suppress the progression of NSCLC, and that the level of Ntn‑4 can be regulated by Qki‑5. Therefore, Ntn‑4 may be a novel diagnostic and therapeutic target for the treatment of NSCLC.

Lung cancer is the leading cause of cancer‑related mortality worldwide. Non‑small cell lung cancer (NSCLC) is the most common pathological subtype of lung cancer and is associated with low 5‑year overall survival rates. Therefore, novel and effective chemotherapeutic drugs are urgently required for improving the survival outcomes of patients with lung cancer. Cyclovirobuxine D (CVB‑D) is a natural steroidal alkaloid, used for the treatment of cardiovascular diseases in Traditional Chinese Medicine. Several studies have also demonstrated the antitumor effects of CVB‑D. Therefore, in the present study, the therapeutic effects of CVB‑D in lung cancer and the underlying mechanisms were investigated using the in vivo xenograft model of NSCLC in nude mice and in vitro experiments with the NSCLC cell lines. Bioinformatics analyses of RNA‑sequencing data, and cell‑based functional assays demonstrated that CVB‑D treatment significantly inhibited in vitro and in vivo NSCLC cell proliferation, survival, invasion, migration, angiogenesis, epithelial‑to‑mesenchymal transition and G 2 /M phase cell cycle. CVB‑D exerted its antitumor effects by inhibiting the KIF11‑CDK1‑CDC25C‑cyclinB1 G 2 /M phase transition regulatory oncogenic network and the NF‑κB/JNK signaling pathway. CVB‑D treatment significantly reduced the sizes and weights and malignancy of xenograft NSCLC tumors in the nude mice. In conclusion, the present study demonstrated that CVB‑D inhibited the growth and progression of NSCLC cells by inhibiting the KIF11‑CDK1‑CDC25C‑CyclinB1 G 2 /M phase transition regulatory network and the NF‑κB/JNK signaling pathway. Therefore, CVB‑D is a promising drug for the treatment of NSCLC patients.

Kirsten rat sarcoma viral oncogene homolog (KRAS) aberrations frequently occur in patients with lung cancer. Oncogenic KRAS is characterized by excessive reactive oxygen species (ROS) accumulation, thus, ROS detoxification may contribute to KRAS‑driven lung tumorigenesis. In the present study, the influence of glutathione peroxidase 2 (GPX2) on malignant progression and cisplatin resistance of KRAS‑driven lung cancer was explored. The RNA sequencing data from TCGA lung cancer samples and GEO database were downloaded and analyzed. The effects of GPX2 on KRAS‑driven lung tumorigenesis were evaluated by western blotting, cell viability assay, soft agar assay, Transwell assay, tumor xenograft model, flow cytometry, BrdU incorporation assay, transcriptome RNA sequencing, luciferase reporter assay and RNA immunoprecipitation. In the present study, GPX2 was upregulated in patients with non‑small cell lung carcinoma (NSCLC), and positively correlated with poor overall survival. Ectopic GPX2 expression facilitated malignant progression of KRAS G12C ‑transformed BEAS‑2B cells. Moreover, GPX2 overexpression promoted growth, migration, invasion, tumor xenograft growth and cisplatin resistance of KRAS‑mutated NSCLC cells, while GPX2 knockdown exhibited the opposite effects. GPX2 overexpression reduced ROS accumulation and increased matrix metalloproteinase‑1 (MMP1) expression in KRAS‑mutated NSCLC cells. In addition, GPX2 was directly targeted by miR‑325‑3p, while MMP1 knockdown or miR‑325‑3p overexpression partially abrogated the effects of GPX2 in NSCLC cells. In conclusion, the results indicated that GPX2 facilitated malignant progression and cisplatin resistance of KRAS‑driven lung cancer, and inhibition of GPX2 may be a feasible strategy for lung cancer treatment, particularly in patients with active KRAS mutations.

Adjuvant cisplatin‑vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP‑binding cassette (ABC) sub‑family B member 1 (ABCB1) and phosphorylated Fyn (p‑Fyn) overexpression. However, the underlying mechanisms remain unclear. NF‑E2‑related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p‑Fyn/ABCB1 axis in vinorelbine‑resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH‑DA assay. The total and subcellular expression of Nrf2, ABCB1 and p‑Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p‑Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin‑vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p‑Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease‑free survival, and p‑Fyn was associated with overall survival (P<0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p‑Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non‑small cell lung cancer.

Schizandrin A (SchA) can be extracted from the vine plant Schisandra chinensis and has been reported to confer various biologically active properties. However, its potential biological effects on non‑small cell lung cancer (NSCLC) remain unknown. Therefore, the present study aims to address this issue. NSCLC and normal lung epithelial cell lines were first treated with SchA. Cell viability and proliferation were measured using CellTiter‑Glo Assay and colony formation assays, respectively. PI staining was used to measure cell cycle distribution. Cell cycle‑related proteins p53, p21, cyclin D1, CDK4, CDK6, cyclin E1, cyclin E2, CDK2 and DNA damage‑related protein SOX4 were detected by western blot analysis. Annexin V‑FITC/PI staining, DNA electrophoresis and Hoechst 33342/PI dual staining were used to detect apoptosis. JC‑1 and DCFH‑DA fluorescent dyes were used to measure the mitochondrial membrane potential and reactive oxygen species concentrations, respectively. Apoptosis‑related proteins caspase‑3, cleaved caspase‑3, poly(ADP‑ribose) polymerase (PARP), cleaved PARP, BimEL, BimL, BimS, Bcl2, Bax, caspase‑9 and cleaved caspas‑9 were measured by western blot analysis. Dansylcadaverine was used to detect the presence of the acidic lysosomal vesicles. The expression levels of the autophagy‑related proteins LC3‑I/II, p62/SQSTM and AMPKα activation were measured using western blot analysis. In addition, the autophagy inhibitor 3‑methyladenine was used to inhibit autophagy. SchA treatment was found to reduce NSCLC cell viability whilst inhibiting cell proliferation. Low concentrations of SchA (10‑20 µM) mainly induced G 1 /S‑phase cell cycle arrest. By contrast, as the concentration of SchA used increases (20‑50 µM), cells underwent apoptosis and G 2 /M‑phase cell cycle a13rrest. As the treatment concentration of SchA increased from 0 to 50 µM, the expression of p53 and SOX4 protein also concomitantly increased, but the expression of p21 protein was increased by 10 µM SchA and decreased by higher concentrations (20‑50 µM). In addition, the mRNA and protein expression levels of Bcl‑like 11 (Bim)EL, BimL and BimS increased following SchA application. SchA induced the accumulation of acidic vesicles and induced a marked increase in the expression of LC3‑II protein, suggsting that SchA activated the autophagy pathway. However, the expression of the p62 protein was found to be increased by SchA, suggesting that p62 was not degraded during the autophagic flux. The 3‑methyladenine exerted no notable effects on SchA‑induced apoptosis. Taken together, results from the present study suggest that SchA exerted inhibitory effects on NSCLC physiology by inducing cell cycle arrest and apoptosis. In addition, SchA partially induced autophagy, which did not result in any cytoprotective effects.

Accumulating evidence indicates that circular (circ)RNAs exhibit complex functions in diverse malignant tumors, including non‑small cell lung cancer (NSCLC). The role of the circRNA transcription adaptor 2A (circTADA2A) in NSCLC remains unclear. The expression, function and mechanism of circTADA2A in NSCLC development were investigated in the present study. The results revealed that circTADA2A was upregulated in NSCLC, and that knockdown of circTADA2A inhibited cell proliferation and migration in the NSCLC cell lines A549 and H1299. Functional assays demonstrated that circTADA2A promoted proliferation and migration via interacting with microRNA (miR)‑638. Bioinformatics and reverse transcription‑quantitative PCR assay confirmed that miR‑638 was expressed at low levels in NSCLC. In addition, it was found that miR‑638 served a tumor‑suppressive role and suppressed proliferation and migration via PCNA clamp associated factor (KIAA0101) inhibition in A549 and H1299 cells. Lastly, it was verified that circTADA2A promoted cell proliferation and migration, at least partially, via miR‑638/KIAA0101 signaling in A549 and H1299 cells. In summary, the present study showed that circTADA2A promoted NSCLC cell proliferation and migration via modulating miR‑638/KIAA0101 signaling.

Lung cancer is the most common malignant tumor type and it is associated with poor prognosis. The identification of potential biomarkers is of great significance for the early diagnosis and treatment of lung cancer. Non‑small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The present study aimed to investigate the mechanism via which thyroid hormone receptor‑interacting protein 13 (TRIP13) participates in the malignant progression of NSCLC. Immunohistochemistry, reverse transcription‑quantitative PCR and western blotting were used to assess the expression level of TRIP13. According to The Cancer Genome Atlas database, TRIP13 was upregulated in NSCLC tissues compared with adjacent normal tissues. Moreover, TRIP13 knockdown increased apoptosis, induced cell cycle arrest in the S phase and inhibited the proliferation, invasion and migration of H1299 cells in vitro . Furthermore, TRIP13 upregulation was closely associated with tumor metastasis via epithelial‑mesenchymal transformation. In conclusion, TRIP13 could promote the malignant progression of lung cancer, and TRIP13 may be a potential biomarker for the early diagnosis and treatment of NSCLC.

Transmembrane protein 229A (TMEM229A) is a member of the TMEM family that plays an important role in tooth differentiation and development. However, the expression level and biological role of TMEM229A in cancer remains unknown. The present study aimed to investigate the expression level of TMEM229A in non‑small cell lung cancer (NSCLC), as well as its effect and mechanism on NSCLC progression. Clinical specimens from patients with NSCLC were enrolled from the First People's Hospital of Huzhou (Huzhou, China). TMEM229A expression was detected using reverse transcription‑quantitative PCR (RT‑qPCR), western blotting and immunohistochemical analysis. The relationship between TMEM229A expression and the survival rate of patients with NSCLC was analyzed using Kaplan‑Meier Plotter datasets. The effects of TMEM229A on cell proliferation, migration and invasion were detected using Cell Counting Kit‑8, colony formation, soft agar, real‑time cellular analysis and Transwell assays. The expression levels of epithelial‑mesenchymal transition (EMT)‑related proteins, as well as ERK and AKT phosphorylation were determined via RT‑qPCR and western blot analysis. The results demonstrated that TMEM229A expression was significantly downregulated in human NSCLC tissues and in several cell lines compared with adjacent normal lung tissues and BEAS‑2B cells, respectively. Survival analysis of lung adenocarcinoma and squamous cell lung carcinoma cases identified that low TMEM229A expression was associated with a poor prognosis. The in vitro assays indicated that overexpressing TMEM229A significantly inhibited cell proliferation, migration and invasion, while TMEM229A knockdown had the opposite effect. Mechanistically, TMEM229A overexpression effectively increased E‑cadherin expression and reduced N‑cadherin, snail family transcriptional repressor 1 and MMP2 expression, indicating that EMT was suppressed. In addition, overexpression of TMEM229A reduced the expression levels of phosphorylated (p)‑ERK and p‑AKT, and this effect was partially suppressed by the incorporation of specific ERK inhibitor PD98059. Collectively, the results of the present study demonstrated that the effects of TMEM229A on inhibiting cell proliferation, migration and invasion were partially mediated by inactivating the ERK signaling pathway, thereby providing a potential therapeutic target for the treatment of NSCLC.

Non‑small cell lung cancer (NSCLC) is a common malignant tumour. Nevertheless, the 5‑year survival rate of NSCLC patients remains poor. Thus, identifying critical factors involved in regulating the progression of NSCLC is important for providing potential treatment targets. In the present study, it was observed that transmembrane protein 100 (TMEM100) was significantly downregulated in NSCLC tissues compared with paired peritumoral tissues. Decreased TMEM100 expression was associated with poor clinical outcomes in NSCLC patients. Moreover, TMEM100 overexpression inhibited colony formation and facilitated apoptosis by suppressing survivin expression in NSCLC cells, whereas TMEM100 knockdown had the opposite effect. In addition, microRNA (miR)‑106b, a miR with controversial roles in different human cancers, was upregulated in NSCLC and directly downregulated TMEM100 expression. The roles of miR‑106b in cell survival were mitigated by the restoration of TMEM100. The aforementioned results indicated that TMEM100 induced cell apoptosis and inhibited cell survival by serving as a tumour suppressor and that miR‑106b‑mitigatedTMEM100 expression defined a potentially oncogenic pathway in NSCLC.

Lung cancer is the most frequent cause of cancer‑associated mortality worldwide. Upregulation of heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) has been reported in non‑small cell lung cancer (NSCLC) cells, but its contribution to NSCLC remains poorly understood. hnRNPA2/B1 is involved in carcinogenesis by interacting with a number of proteins; however, little is known about its interaction with p53. The results of the present study revealed that hnRNPA2/B1 expression levels were upregulated in NSCLC cells under tumorsphere culture conditions and cisplatin treatment compared with those in cells under the adherent condition and dimethyl sulfoxide treatment, respectively, suggesting that hnRNPA2/B1 expression is induced under stress conditions. hnRNPA2/B1 knockdown decreased the number and size of NSCLC cell colonies in a clonogenic survival assay and led to a decreased migratory potential of NSCLC cells, suggesting that hnRNPA2/B1 may promote the survival, proliferation and migration of NSCLC cells. hnRNPA2/B1 knockdown induced G 0 /G 1  phase arrest in NSCLC cells through cyclin E degradation and phosphorylation of cyclin‑dependent kinase 2. In addition, hnRNPA2/B1 knockdown inhibited extracellular signal‑regulated kinase (ERK)1/2 phosphorylation, suggesting that hnRNPA2/B1 may promote the G 1 /S phase transition in NSCLC cells through ERK signaling. hnRNPA2/B1 knockdown resulted in increased expression levels of p21 and p27 in NSCLC cells, as well as p53 induction and phosphorylation. Additionally, hnRNPA2/B1 knockdown inhibited human double minute 2 protein (HDM2) stability and phosphorylation, whereas overexpression of hnRNPA2 induced the opposite effects. These results suggested that hnRNPA2/B1 may promote the survival, proliferation and migration of NSCLC cells through preventing the activation of p53, which is induced by ERK‑mediated HDM2 activation. The results of the present study also indicated that the components of the hnRNPA2/B1/ERK/p53/HDM2 signaling pathway may be novel potential molecular targets for the treatment of patients with NSCLC.

The aim of the present study was to identify the function of long non‑coding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) and examine its effects on non‑small cell lung cancer (NSCLC). A series of in vitro experiments were employed to evaluate the effects of SNHG3 on the progression of NSCLC, including Cell Counting Kit‑8, 5‑Ethynyl‑2'‑deoxyuridine, flow cytometry, wound healing, Transwell, western blotting and reverse transcription‑quantitative PCR assays. Bioinformatics analyses and a luciferase reporter assay were performed to identify the target gene of SNHG3 and microRNA (miR)‑1343‑3p. Finally, recuse experiments were conducted to verify the effect of SNHG3 and its target gene on proliferation, apoptosis, migration and invasion. The findings indicated that lncRNA SNHG3 was highly expressed in NSCLC tissues and cell lines. Knockdown of lncRNA SNHG3 inhibited cell proliferation, migration and invasion, and accelerated cell apoptosis in NSCLC cell lines. The results of the bioinformatics analysis and the luciferase reporter assay indicated that lncRNA SNHG3 directly bound to miR‑1343‑3p and that it could downregulate the expression levels of miR‑1343‑3p to promote the progression of NSCLC. Rescue experiments indicated that lncRNA SNHG3 increased nuclear factor IX (NFIX) expression by sequestering miR‑1343‑3p in NSCLC. These results suggested that the SNHG3/miR‑1343‑3p/NFIX axis may serve as a novel prognostic biomarker and therapeutic target for NSCLC.

MicroRNA (miRNA or miR)‑10b is an oncogenic miRNA associated with metastasis that is present in various types of tumor, including lung cancer. However, whether miR‑10b is involved in different malignant characteristics, such as drug resistance or stemness, remains unclear. Therefore, the present study investigated whether miR‑10b is an upstream regulator of p53. Ectopic expression of miR‑10b‑agomir decreased the expression of p53 and its downstream effectors, such as Bax and p53 upregulated modulator of apoptosis. Two non‑canonical sites, including 1,580‑1,587 and 2,029‑2,035, located in p53 3'‑untranslated region (UTR) were affected by the presence of miR‑10b. In functional assays, upregulation of the p53 signaling pathway following cisplatin treatment was associated with decreased levels of miR‑10b and upregulation of the luciferase activity of wild‑type, but not 1,584, 2,032‑dual‑mutant, p53 3'‑UTR. The ectopic expression of miR‑10b‑agomir attenuated the stability of p53 3'‑UTR and the expression of p53 and its downstream effectors induced by cisplatin. By contrast, the knockdown of miR‑10b induced the stability of p53 3'‑UTR and increased levels of p53 and the sensitivity of A549 cells to cisplatin treatment. Similar results were also observed for Beas 2B cells. In the clinical investigation, p53 exhibited two distinct associations (cocurrent and countercurrent) with miR‑10b in patients with lung cancer. Patients with lung cancer with low p53 and high miR‑10b levels exhibited the poorest prognosis, while those with high p53 and low miR‑10b exhibited the most favorable prognosis. These findings indicate a novel pathway in which cisplatin induces the levels of p53 by increasing mRNA stability via miR‑10b, indicating a novel oncogenic role of miR‑10b in promoting the malignant characteristics of non‑small cell lung carcinoma.

Ceramide is a biologically active sphingomyelin that inhibits cell growth and proliferation. In previous studies, it was demonstrated that the use of lipopolysaccharides induces acid sphingomyelinases to produce ceramide, promoting lung cancer cell apoptosis; however, the specific mechanisms of this action remain unclear. Thioredoxin‑interacting protein (Txnip) plays an important role in the signal transmission of redox reactions inside and outside the cell. Thus, it was hypothesized that ceramide induces apoptosis in lung adenocarcinoma cells (A549 and PC9) by modulating the Txnip/Trx1 complex. In the present study, the Cell Counting kit‑8 method was used to detect cell activity and the drug concentration. Hoechst 33258 staining and flow cytometry were used to detect cell apoptosis, and the positional association between Txnip and Trx1 upregulated by ceramide was observed by immunofluorescence confocal microscopy. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to detect the changes in related gene, mRNA and protein expression levels. The results revealed that ceramide treatment resulted in the upregulation of Txnip and in the reduction of Trx1 activities. However, the Txnip inhibitor, verapamil, reversed these changes. The analysis of mRNA expression further verified the changes observed in the protein expression of Txnip, Trx1 and apoptosis‑related proteins. On the whole, the present study demonstrates that ceramide induces the apoptosis of lung cancer cells by regulating the Txnip/Trx1 complex.

Lung cancer is one of the most malignant type of tumors worldwide. Non‑small cell lung cancer (NSCLC), which is the most common type of lung cancer, is defined as a distinct disease that exhibits both genetic and cellular heterogeneity. Although in the past two decades significant advances in the treatment of NSCLC have besen performed, the 5‑year survival rate of patients with NSCLC remains <20%. Thus, there is an urgent requirement to gain an in‑depth understanding of the molecular mechanisms that promote NSCLC development and to identify novel therapeutic targets. In the present study, the gene expression profiles of patients with NSCLC from The Cancer Genome Atlas database were analyzed to determine potential therapeutic targets, and transmembrane protein 100 (TMEM100) was identified as a candidate tumor suppressor. TMEM100 expression level was discovered to be decreased in both NSCLC tissues and cell lines, and it was observed to be negatively associated with the TNM stage and positively associated with prognosis. Moreover, TMEM100 inhibited tumor growth and promoted cell apoptosis in A549 and H460 cells. Mechanistically, TMEM100 was demonstrated to induce autophagy in A549 cells via inhibiting the PI3K/AKT signaling pathway, whereas inhibiting autophagy using bafilomycin A1 significantly enhanced TMEM100‑induced apoptosis to compensate for the cell death. In conclusion, these findings suggested that TMEM100 may serve as a tumor suppressor in NSCLC and promote autophagy via inhibiting the PI3K/AKT signaling pathway.

Circular RNAs (circRNAs) are a class of novel endogenous transcripts with limited protein‑coding abilities. CircRNAs have been demonstrated to function as critical regulators of tumor development and distant metastasis through binding to microRNAs (miRNAs) and interacting with RNA‑binding proteins, thereby regulating transcription and translation. Emerging evidence has illustrated that certain circRNAs can serve as biomarkers for diagnosis and prognosis of cancer, and/or serve as potential therapeutic targets. Expression of functional circRNAs is commonly dysregulated in cancer and this is correlated with advanced Tumor‑Node‑Metastasis stage, lymph node status, distant metastasis, poor differentiation and shorter overall survival of cancer patients. Recently, an increasing number of studies have shown that circRNAs are closely associated with NSCLC. Functional experiments have revealed that circRNAs are intricately associated with the pathological progression of NSCLC. The present review provides an overview of the regulatory effect of circRNAs in the development and progression of NSCLC, taking into consideration various physiological and pathological processes, such as proliferation, apoptosis, invasion and migration, and their potential value as biomarkers and therapeutic targets.

The development of multidrug resistance is the major obstacle to successful lung cancer chemotherapy. Cancer cells gain resistance through increased levels of P‑glycoprotein (P‑gp), which is encoded by the multidrug resistance‑associated protein 1 ( MDR1 ) gene. Leucine‑rich PPR motif‑containing protein (LRPPRC), a member of the PPR family, has been verified to regulate the transcription of MDR1 . This regulation is influenced by the methylation status of the GC ‑100 box in the MDR1 promoter. The present study aimed to investigate the effect of LRPPRC on cisplatin (DDP) resistance in lung cancer cells and explore the underlying mechanism. DDP‑resistant non‑small cell lung cancer cell lines (A549/DDP, H1299/DDP) were generated. The expression levels of LRPPRC and P‑gp/ MDR1 , investigated by qPCR and western blot analysis, were increased in the A549/DDP and H1299/DDP cells compared with that in the parental cells. LRPPRC silencing with shRNA increased DDP sensitivity in vitro and in vivo . LRPPRC silencing inhibited the level of LRPPRC binding with the MDR1 promoter, investigated by chromatin immunoprecipitation‑qPCR, and the corresponding MDR1 expression. Demethylation treatment rescued the decrease in the level of LRPPRC binding with MDR1 and the corresponding expression of MDR1 and the increase in DDP sensitivity due to LRPPRC silencing. Our study suggests that LRPPRC contributes to DDP resistance in lung cancer cells by regulating MDR1 transcription. Thus, LRPPRC may serve as a potential molecular target for chemo‑resistance reversal in lung cancer.

Obstructive sleep apnea (OSA) is a sleep‑related disorder characterized by chronic intermittent hypoxia (CIH). Previous studies have found that intermittent hypoxia promotes drug resistance, cell proliferation, migration and invasion in non‑small cell lung cancer (NSCLC). Endothelial cell‑specific molecule‑1 (ESM1) is a molecule shown to be overexpressed in several types of tumors. The purpose of this study was to investigate the correlation between CIH and ESM1 and their potential roles in the progression of NSCLC. Tumorspheres, cell viability and colony formation assays were used to evaluate cell proliferation. The expression levels of cancer stem cell (CSC) markers CD44, CD133, OCT4 and SOX2 were measured with western blotting and/or RT‑qPCR. Transwell assays were applied to assess cell migration and invasion. Changes in the expression levels of epithelial‑mesenchymal transition (EMT)‑associated proteins were also detected by western blotting. The results indicated that CIH enhanced lung cancer stem cell (LCSC) NSCLC progression by promoting stemness, drug resistance, cell proliferation, migration and invasion via the ESM1/HIF‑1α pathway. Unexpectedly, inhibition of ESM1 reversed the CIH‑involved negative effects on LCSCs and in a mouse model. ESM1 therefore appears to be crucial mediator of CIH‑mediated lung cancer progression.

As a potential oncogene, nucleolar and spindle‑associated protein 1 (NUSAP1) is involved in the regulation of tumor cell proliferation, metastasis and drug resistance. However, the role of NUSAP1 in non‑small cell lung cancer (NSCLC) remains unclear. The present study aimed to investigate the biological function and underlying molecular mechanisms of NUSAP1 in NSCLC. NUSAP1 expression was measured in NSCLC tissues and cell lines via immunohistochemistry and western blotting, respectively. NSCLC cell lines stably inhibiting NUSAP1 were established to investigate its effects on cell proliferation, colony formation and invasion, and on in vivo tumorigenicity. Additionally, the upstream and downstream mechanisms of NUSAP1 in regulating NSCLC progression were investigated. The results indicated that NUSAP1 expression was upregulated in NSCLC tissues and cell lines. High NUSAP1 expression was associated with tumor size, TNM stage, lymph node metastasis and poor patient survival, whereas knockdown of NUSAP1 inhibited NSCLC cell proliferation, colony formation and invasion. Furthermore, downregulation of NUSAP1 decreased the growth of NSCLC xenografts in vivo. In addition, myocyte enhancer factor 2D (MEF2D) directly targeted the NUSAP1 promoter, thereby enhancing the mRNA and protein expression levels of NUSAP1. Moreover, the results demonstrated that MEF2D expression was upregulated in NSCLC tissues and was positively correlated with NUSAP1 expression. MEF2D‑knockdown decreased NSCLC cell proliferation, colony formation and invasion. NUSAP1 upregulation reversed the effects of MEF2D‑knockdown on NSCLC progression. Furthermore, it was observed that MEF2D‑knockdown inhibited the accumulation and nuclear translocation of β‑catenin, thereby repressing the activation of the Wnt/β‑catenin signaling pathway in NSCLC cells, whereas NUSAP1 upregulation rescued the effects of MEF2D‑knockdown on the activation of the Wnt/β‑catenin signaling pathway. In conclusion, the findings of the present study indicated that the MEF2D/NUSAP1 signaling pathway promoted NSCLC progression by inducing the activation of Wnt/β‑catenin signaling, and this novel mechanism may represent a potential treatment target for patients with NSCLC.

Non‑small cell lung cancer (NSCLC) remains an intractable disease, which is primarily due to tumor metastasis and the acquisition of resistance to chemotherapy. Therefore, there is an urgent need for novel therapeutics to overcome these obstacles. It was recently demonstrated that upregulated expression of monoamine oxidase A (MAOA) contributes to the progression of NSCLC. G10, a tumor‑targeting representative conjugate of heptamethine carbocyanine dye and an inhibitor of MAOA, was shown to exert potent cytotoxic effects, comparable to those of doxorubicin, against prostate cancer cell lines, as well as moderate MAOA inhibitory activity. The research described herein aimed to extend our previous study on the antitumor function of G10 in NSCLC in vitro and in vivo, and to elucidate the mechanisms through which G10 exerts its antineoplastic effects. G10 markedly inhibited the proliferation of paclitaxel‑resistant NSCLC cells (H460/PTX) and reduced tumor cell migration and invasion. Gene expression profiling of paclitaxel‑resistant NSCLC cells following treatment with G10 demonstrated that the expression of genes associated with the extracellular matrix was significantly affected, particularly the metastasis‑related genes matrix metallopeptidase (MMP)2, MMP14 and COL6A, which exhibited notably reduced expression. Additionally, the results also demonstrated that MAOA‑related pathways, including AKT and hypoxia‑inducible factor‑1α, were also inhibited by G10 treatment and, subsequently, the downstream molecules of these pathways, such as p21, MMP2 and vascular endothelial growth factor, were also downregulated, highlighting a possible mechanism through which G10 suppresses tumor cell migration, invasion and proliferation. Importantly, in mouse NSCLC xenografts, combined treatment with G10 and paclitaxel resulted in pronounced inhibition of tumor growth. Taken together, the results of the present study highlight the potential of G10 as a novel therapeutic targeting MAOA in paclitaxel‑resistant NSCLC.

Deoxyribonucleic acid (DNA) epigenetic modification has been linked to specific sequences of CpG islands and plays roles in the progression of lung cancer. In this study, it was found that peroxiredoxin‑5 (PRDX5) was highly expressed in non‑small cell lung cancer (NSCLC) tissues; however, its specific regulatory mechanisms and functions in NSCLC remain unknown. The present study therefore explored the regulatory mechanism of PRDX5 under conditions of oxidative stress (OS) in NSCLC. The results revealed that 79 of 121 NSCLC patients exhibited demethylation in the PRDX5 promoter region, which was related to the tumor, node and metastasis (TNM) stage (P=0.027). PRDX5 messenger ribonucleic acid (mRNA) expression positively correlated with the demethylation status of the promoter region. The results of bisulfite sequencing polymerase chain reaction (BSP) revealed lower demethylation frequencies in H1299 cells treated with 0 µM H2O2, but maximum demethylation following treatment with 100 µM H2O2. Using chromatin immunoprecipitation (ChIP) and luciferase detection assays, the effective binding of STAT3 to the transcriptional binding sites of the PRDX5 promoter region was confirmed (2 sites confirmed: Site 1, ‑444 to ‑434 bp; and site 4, ‑1,417 to ‑1,407 bp). STAT3 knockdown significantly decreased the protein expression of PRDX5, while the overexpression of STAT3 significantly increased the protein levels of PRDX5. When PRDX5 was overexpressed in lung cancer cells under conditions of OS, the levels of the epithelial‑mesenchymal transition (EMT) biomarkers, E‑cadherin and vimentin, were significantly decreased and increased, respectively. By contrast, PRDX5 knockdown resulted in significantly increased E‑cadherin and decreased vimentin protein expression levels. Ultimately, when PRDX5‑small interfering RNA (siRNA) or pcDNA3.1‑PRDX5 expression vector were constructed and transfected into H1299 cells pre‑treated with 100 µM H2O2, the nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) signaling pathway was inhibited or activated. All these results suggested that the reactive oxygen species (ROS)‑mediated hypomethylation of PRDX5 enhanced STAT3 binding affinity with the promoter region, and resulted in the promotion of cell migration and invasion, as well as in the activation of the Nrf2 signaling pathway in NSCLC. The demethylation status of the PRDX5 promoter may thus be used as an epigenetic biomarker in NSCLC. STAT3/PRDX5 signaling may also prove to be a potential strategy for the treatment of this type of cancer.

Increasing evidence has demonstrated the important roles of long non‑coding (lnc) RNA in non‑small cell lung cancer (NSCLC). lncRNA gastric cancer‑associated transcript 1 (GACAT1) has been reported to play an oncogenic role in different types of cancer; however, the function of GACAT1 in NSCLC remains unclear. The present study found that GACAT1 was overexpressed in NSCLC tissues and was associated with poor outcomes in patients with NSCLC. Functional experiments revealed that GACAT1 downregulation inhibited proliferation, induced apoptosis and cell cycle arrest of 2 NSCLC cell lines. GACAT1 was found to target microRNA(miR)‑422a mechanically and negatively regulated miR‑422a expression. Reduced expression of miR‑422a in NSCLC tissues was inversely correlated with that of GACAT1. Furthermore, YY1 transcription factor (YY1) was identified as a downstream miR‑422a target. Reduced expression of GACAT1 inactivated YY1 by sponging miR‑422a in NSCLC cells. YY1 reintroduction reversed the reduced proliferation of NSCLC cells via GACAT1 knockdown. Taken together, these results revealed the novel role of the GACAT1/miR‑422a pathway in the progression of NSCLC cell lines, providing a possible therapeutic strategy for NSCLC treatment.

Sphingosine kinase1 (SphK1) is an oncogenic enzyme that regulates tumor cell apoptosis, proliferation and survival. SphK1 has been reported to promote the development of non‑small cell lung cancer (NSCLC), although the underlying mechanism remains to be determined. The aim of the present study was to examine the expression and function of SphK1 in NSCLC and to explore the underlying molecular mechanism. The results of the present study demonstrated that SphK1 expression was upregulated in NSCLC tissues and cell lines. Overexpression of SphK1 increased the proliferation and migration of NSCLC cells. Additionally, overexpression of SphK1 induced expression of antiapoptotic and migration‑associated genes, such as Bcl‑2, matrix metallopeptidase 2 and cyclin D1. Of note, signal transducer and activator of transcription 3 (STAT3) was also activated in the SphK1‑overexpressing cells. By treatment with a STAT3 inhibitor, it was demonstrated that the SphK1‑induced changes in expression of target genes, as well as the increase in proliferation and migration of NSCLC cells were mediated by STAT3. In conclusion, the effects of SphK1 overexpression on the development of NSCLC were demonstrated to be mediated by the activation of STAT3. These results suggested that inhibition of the SphK1‑STAT3 axis may be a potential strategy for the treatment of NSCLC.

Resistance to platinum‑based drugs, such as cisplatin (CDDP), has been one of the major factors adversely affecting the clinical prognosis of patients with advanced non‑small cell lung cancer (NSCLC). While it has been demonstrated that dysregulation of microRNAs (miRNAs) may contribute to cisplatin resistance in NSCLC, the underlying mechanisms remain largely unclear. In the present study, the effect of exosomal miR‑1273a on cisplatin sensitivity of NSCLC was investigated. Microarray analysis was conducted to analyze the miRNA expression profiles in exosomes isolated from A549 cells treated with or without CDDP, and miR‑1273a was found to be the most prominently downregulated miRNA in CDDP‑treated exosomes. Overexpression of miR‑1273a significantly increased the cytotoxicity of CDDP and induced apoptosis in A549 cells. Syndecan binding protein (SDCBP) was predicted to be a direct target of miR‑1273a by bioinformatics and was found to be downregulated by miR‑1273a in A549 cells. Furthermore, decreased plasma exosomal miR‑1273a and increased plasma SDCBP levels were found to be associated with worse therapeutic outcomes of patients with advanced NSCLC receiving platinum‑based chemotherapy. These findings suggest that miR‑1273a is closely associated with the development of cisplatin resistance and may serve as a potential prognostic biomarker and therapeutic target for NSCLC.

The aim of the present study was to identify natural compounds that bear significant anti‑tumor activity. Thus, the effects of 63 small molecules that were isolated from traditional Chinese medicinal herbs on A549 human non‑small cell lung cancer (NSCLC) and MCF‑7 breast cancer cells were examined. It was found that ursolic acid (UA), a natural pentacyclic triterpenoid, exerted significant inhibitory effect on these cells. Further experiments revealed that UA inhibited the proliferation of various lung cancer cells, including the NSCLC cells, H460, H1975, A549, H1299 and H520, the human small cell lung cancer (SCLC) cells, H82 and H446, and murine Lewis lung carcinoma (LLC) cells. UA induced the apoptosis and autophagy of NSCLC cells. The inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, but not the activation of the extracellular signal‑regulated kinase 1/2 (ERK1/2) signaling pathway contributed to the UA‑induced autophagy of NSCLC cells. Moreover, the inhibition of autophagy by chloroquine (CQ) or siRNA for autophagy‑related gene 5 (ATG5) enhanced the UA‑induced inhibition of cell proliferation and promotion of apoptosis, indicating that UA‑induced autophagy is a pro‑survival mechanism in NSCLC cells. On the whole, these findings suggest that combination treatment with autophagy inhibitors may be a novel strategy with which enhance the antitumor activity of UA in lung cancer.

Lung cancer has the highest incidence and mortality rates among the malignant tumor types worldwide. Platinum‑based chemotherapy is the main treatment for advanced non‑small‑cell lung cancer (NSCLC), and epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) have greatly improved the survival of patients with EGFR‑sensitive mutations. However, there is no standard therapy for treating patients who are EGFR‑TKI resistant. Combining EGFR‑TKIs and platinum‑based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR‑TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR‑TKI) and cisplatin (a main platinum‑based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co‑immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefitinib could selectively inhibit EGFR from entering the nucleus, decrease DNA‑PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA‑dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.

Drug resistance is a major obstacle in the therapy of malignant tumors, including non‑small cell lung cancer (NSCLC). Long non‑coding RNAs (lncRNAs) have been demonstrated to be involved in chemoresistance. The present study aimed to investigate the role of lung cancer‑associated transcript 1 (LUCAT1) in cisplatin (DDP) resistance in NSCLC. By using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), it was found that the expression of LUCAT1 was elevated and that of microRNA‑514a‑3p (miR‑514a‑3p) was decreased in DDP‑resistant NSCLC tissues and cells. Functionally, LUCAT1 upregulation enhanced cisplatin resistance by promoting the viability, autophagy and metastasis, and inhibiting the apoptosis of NSCLC cells, as demonstrated by Cell Counting kit‑8 (CCK‑8) assay, western blot analysis, Transwell assay and flow cytometric analysis. LUCAT1 was identified as a sponge of miR‑514a‑3p and uncoordinated‑51‑like kinase 1 (ULK1) was proven to be a target gene of miR‑514a‑3p by bioinformatics analysis, dual‑luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The enhancing effect of miR‑514a‑3p on cisplatin sensitivity was reversed by the elevation of LUCAT1. ULK1 knockdown suppressed cisplatin resistance, while this effect was attenuated by miR‑514a‑3p inhibition. Moreover, LUCAT1 positively regulated ULK1 expression by targeting miR‑514a‑3p. In addition, LUCAT1 knockdown suppressed tumor growth in vivo. On the whole, the findings of the present study demonstrate that LUCAT1 contributes to the resistance of NSCLC cells to cisplatin by regulating the miR‑514a‑3p/ULK1 axis, elucidating a novel regulatory network in cisplatin resistance in NSCLC.

The increased tyrosine kinase activity of non‑small cell lung cancer (NSCLC)‑associated epidermal growth factor receptor (EGFR) mutants results in deregulated pathways that contribute to malignant cell survival, tumor progression and metastasis. Previous studies investigating lung cancer‑associated EGFR have focused on the prognostic implications of receptor kinase mutations in patients with NSCLC; however, the role of EGFR mutations in tumor cell invasion and migration remains undetermined. The present study was designed to investigate the role of NSCLC‑associated mutant EGFR‑driven signaling pathways in cell proliferation and invasion. Non‑endogenous EGFR‑expressing 293 cells stably expressing EGFR mutants that are sensitive or resistant to Food and Drug Administration (FDA)‑approved EGFR‑targeted tyrosine kinase inhibitors (TKIs) were used in the present study. The experiments demonstrated an increased phosphorylation of phospholipase (PLC)γ1, c‑Cbl, signal transducer and activator of transcription (Stat), extracellular regulated kinase (Erk)1/2, Akt, Shc and Gab1 proteins in cells expressing a mutant form, rather than the wild‑type receptor. As PLCγ1 is a known regulator of metastatic development, mutant receptor‑mediated PLCγ1 activation was further evaluated. To examine the effects of EGFR and PLCγ1 phosphorylation, the metastatic potential of cells expressing mutants was investigated using wound healing, Transwell cell migration and invasion assays. The inhibition of receptor phosphorylation with the 1st, 2nd and 3rd generation TKIs, gefitinib, afatinib, osimertinib, respectively, reduced PLCγ1 phosphorylation, and reduced the invasive and migratory potential of 293 cells, confirming PLCγ1 as one of the probable downstream effectors of mutant EGFR signaling. However, the PLC inhibitor, U73122, inhibited cell migration and invasion without affecting EGFR signaling and PLCγ1 phosphorylation. Notably, U73122 reduced Akt and Erk1/2 phosphorylation within 25 min of its application; however, 100% cell viability was recorded even after 48 h. Upon further investigation, proliferative signaling pathways remained active at 48 h, in accordance with cell viability. Therefore, the present study concludes that mutant receptor‑mediated PLCγ1 activation may play a significant role in the migration and invasion of NSCLC tumors; however, its regulatory role in tumor cell proliferation warrants further investigation and validation in lung tumor cell lines harboring EGFR mutations.

Numerous studies have identified that microRNAs (miRs) play a crucial role in the tumorigenesis of non‑small cell lung cancer (NSCLC). However, to the best of our knowledge, the physiological function of miR‑103 in NSCLC is not fully understood. Experiments in the present study revealed that miR‑103 expression was increased in NSCLC cell lines. In addition, a series of methods, including MTT, colony formation, 5‑ethynyl‑2'‑deoxyuridine, Transwell, wound healing, flow cytometric, reverse transcription‑quantitative PCR and western blot assays, were performed, which revealed that overexpression of miR‑103 enhanced cell growth, migration, invasion and epithelial‑mesenchymal transition (EMT), and suppressed apoptosis of A549 and H1299 cells. Additionally, a dual‑luciferase reporter assay indicated that miR‑103 directly targets the 3'‑untranslated region of Kruppel‑like factor 7 (KLF7), and KLF7 expression was negatively regulated by miR‑103 expression. Furthermore, the present findings demonstrated that miR‑103 promoted EMT via regulating the Wnt/β‑catenin signaling pathway in NSCLC. Collectively, the current results demonstrated that miR‑103 serves a tumorigenesis role in NSCLC development by targeting KLF7, at least partly via the Wnt/β‑catenin signaling pathway. Consequently, these findings indicated that miR‑103/KLF7/Wnt/β‑catenin may provide a novel insight into underlying biomarkers for improving the diagnosis and treatment of NSCLC.

Although significant progress has been made in the treatment of lung cancer, it remains the leading cause of cancer‑associated mortality. Liriopesides B (LPB) is a natural product isolated from the tuber of Liriope platyphylla, whose effective substances have exhibited antitumor activity in several types of cancer. However, the functions of LPB in non‑small cell lung cancer (NSCLC) require further investigation. Therefore, the present study aimed to investigate whether LPB influences the pathogenic effects of NSCLC. In the present study, it was demonstrated that LPB reduced proliferation, and induced apoptosis and cell cycle arrest in non‑small cell lung cancer cells. CCK‑8 and colony formation assays demonstrated that LPB decreased cell viability and proliferation of H460 and H1975 cells in a dose‑dependent manner. Flow cytometry revealed that LPB significantly induced apoptosis of NSCLC cells, along with changes in the expression of apoptosis‑associated proteins, including an increase in Bax, caspase‑3, and caspase‑8 expression, and a decrease in Bcl‑2 and Bcl‑xl expression. LPB inhibited the progression of the cell cycle from the G1 to the S phase. Furthermore, autophagy was increased in cells treated with LPB. Finally, the expression of programmed death‑ligand 1 was significantly decreased by LPB. In conclusion, the results of the present study highlight a potential novel strategy for the clinical treatment of NSCLC.

Cancer‑associated fibroblasts (CAFs) exhibit tumor‑stimulating properties and are associated with poor survival in several types of cancer, making them potential therapeutic targets. The present study aimed to determine whether CAFs were associated with cell migration and invasion in lung squamous cell carcinoma (LUSC), as well as their association with microRNA‑369 (miR‑369) in these processes. Firstly, the changes of the malignant biological behavior were observed by treating the LUSC cells with the CAFs‑derived extracellular vesicles (CAFs‑EVs). Subsequently, the differentially expressed miRNAs in the cells treated with CAFs‑EVs were analyzed by microarray analysis. Following inhibition of miR‑369 expression in CAFs‑EVs, LUSC cells were co‑cultured, and the malignant biological behavior of the cells was re‑examined. Then, through bioinformatics analysis and verification, the mRNA targets of miR‑369 and the corresponding downstream signaling pathway were screened out. Finally, the effects of CAFs‑EVs on the growth and metastasis of LUSC were demonstrated by in vivo tumor formation and metastasis experiments. It was identified that miR‑369 was expressed at a relatively high level in the CAFs‑EVs. Neurofibromin‑1 (NF1) was hypothesized as a direct target of miR‑369 in LUSC. Also, the overexpression of miR‑369 activated the mitogen‑activated protein kinase signaling pathway by interacting with NF1, consequently potentiating LUSC cell growth. The present study provided novel insights into the action of miR‑369 in CAFs‑EVs in controlling LUSC cell migration, invasion and tumorigenesis, and identified miR‑369 in CAFs‑EVs as an important prognostic marker and therapeutic target.

Non‑small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and is the leading cause of cancer‑associated mortality worldwide. Propofol is an anesthetic drug frequently used during tumor resection. It is also known to exert inhibitory effects on cancer. Although the role of propofol in NSCLC has been reported, its underlying mechanisms remain unknown. The present study aimed therefore to investigate the mechanisms of propofol action on NSCLC. Starbase V3.0 project was used to analyze the expression levels of microRNA‑21‑5p (miR‑21‑5p) and mitogen‑activated protein kinase 10 (MAPK10) in NSCLC and adjacent normal tissues from patients with NSCLC and the association between miR‑21‑5p and MAPK10 expression level in NSCLC tissues. The correlation between MAPK10 expression and disease‑free survival (DFS) in patients with NSCLC was analyzed using GEPIA software version 1.0. miR‑21‑5p and MAPK10 expression in tumor and adjacent normal tissues from patients with NSCLC was evaluated by reverse transcription‑quantitative (RT‑q) PCR and western blotting. Cell viability and apoptosis were assessed by using Cell Counting Kit‑8 assay and flow cytometry, respectively. The interaction between miR‑21‑5p and MAPK10 was predicted by TargetScan/miRanda and verified by dual luciferase assay. The regulatory effect of propofol on miR‑21‑5p and MAPK10 expression in NSCLC cell lines was examined by RT‑qPCR and western blotting. Starbase V3.0 project and the results of the present study indicated that tumor tissues presented a significantly lower MAPK10 level and a higher miR‑21‑5p level compared with the normal samples, and that miR‑21‑5p expression was negatively correlated with MAPK10 expression in the tumor tissues of patients with NSCLC. Furthermore, miR‑21‑5p targeted the 3'‑untranslated region of MAPK10. In addition, compared with BEAS‑2B cells, a higher miR‑21‑5p and a lower MAPK10 expression was observed in the NSCLC cell lines A549 and H1299, which was reversed by propofol. The overexpression of miR‑21‑5p abrogated the effects of propofol on A549 and H1299 cell viability and apoptosis by targeting MAPK10. Taken together, these findings demonstrated that propofol inhibited the viability and promoted the apoptosis of NSCLC cells by downregulating the miR‑21‑5p/MAPK10 axis.

Gefitinib is currently the preferred treatment for non‑small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)‑activating mutation. However, some patients gradually develop acquired resistance after receiving treatment. In addition to secondary T790M mutation, the remaining mechanisms contributing to non‑T790M mutations need to be explored. In the present study, NSCLC‑derived HCC827 and PC‑9 cells and the corresponding gefitinib‑resistant cell lines (HCC827GR and PC9GR) were utilized. Next‑generation DNA sequencing was performed on the HCC827GR and PC9GR cells. Under AXL receptor tyrosine kinase (AXL) knockdown or miR‑625‑3p overexpressing conditions, a cell growth inhibition assay was performed to evaluate gefitinib sensitivity. Wound healing and Transwell assays were used to examine the migratory and invasive abilities of the cells. Moreover, we also carried out western blot analysis to detect the altered downstream signaling pathway. Our study revealed markedly decreased miR‑625‑3p expression in the HCC827GR cell line, while its overexpression partly reversed gefitinib resistance. Integrated analysis based on Targetscan website showed that AXL can be potentially targeted by miR‑625‑3p and we further verified the hypothesis via dual‑luciferase reporter assays. Mechanistic analysis revealed that TGF‑β1‑induced EMT may contribute to the miR‑625‑3p/AXL axis‑mediated gefitinib resistance. Our data demonstrated that miR‑625‑3p contributes to the acquired resistance of gefitinib, which may provide novel insight to combat resistance to EGFR‑TKIs.

Non‑small cell lung cancer (NSCLC) accounts for over 80% of all diagnosed lung cancer cases. Lung cancer is the leading cause of cancer‑related deaths worldwide. Most NSCLC cells overexpress vascular endothelial growth factor‑A (VEGF‑A) which plays a pivotal role in tumour angiogenesis. Anti‑angiogenic therapies including VEGF‑A neutralisation have significantly improved the response rates, progression‑free survival and overall survival of patients with NSCLC. However, the median survival of these patients is shorter than 18 months, suggesting that NSCLC cells secrete VEGF‑independent angiogenic factors, which remain unknown. We aimed to explore these factors in human NSCLC cell lines, A549, Lu99 and EBC‑1 using serum‑free culture, to which only EBC‑1 cells could adapt. By mass spectrometry, we identified 1,007 proteins in the culture supernatant derived from EBC‑1 cells. Among the identified proteins, interleukin‑8 (IL‑8), macrophage migration inhibitory factor (MIF), galectin‑1, midkine (MK), IL‑18, galectin‑3, VEGF‑A, hepatoma‑derived growth factor (HDGF), osteopontin (OPN), connective tissue growth factor (CTGF) and granulin (GRN) are known to be involved in angiogenesis. Tube formation, neutralisation and RNA interference assays revealed that VEGF‑A and HDGF function as angiogenic factors in EBC‑1 cells. To confirm whether VEGF‑A and HDGF also regulate angiogenesis in the other NSCLC cell lines, we established a novel culture method. NSCLC cells were embedded in collagen gel and cultured three‑dimensionally. Tube formation, neutralisation and RNA interference assays using the three‑dimensional (3D) culture supernatant showed that VEGF‑A and HDGF were not angiogenic factors in Lu99 cells. By gene microarray in EBC‑1 and Lu99 cells, we identified 61 mRNAs expressed only in Lu99 cells. Among these mRNAs, brain‑derived neurotrophic factor (BDNF), fibroblast growth factor‑2 (FGF‑2) and FGF‑5 are known to be involved in angiogenesis. Tube formation and neutralisation assays clarified that FGF‑2 functions as an angiogenic factor in Lu99 cells. These results indicate that HDGF enhances VEGF‑dependent angiogenesis and that FGF‑2 is a VEGF‑independent angiogenic factor in human NSCLC cells.

A long non‑coding RNA (lncRNA) called prostate cancer‑associated non‑coding RNA 1 (PRNCR1) serves crucial roles in the aggressive phenotypes of colorectal cancer and non‑small cell lung cancer. However, there is little research on the expression profile, clinical value and detailed functions of PRNCR1 in tongue squamous cell carcinoma (TSCC). The aim of the present study was to determine PRNCR1 expression in TSCC and to examine the involvement of PRNCR1 in TSCC progression. The molecular mechanisms behind the oncogenic effects of PRNCR1 in TSCC cells were also investigated. PRNCR1 was revealed to be upregulated in TSCC tumors and cell lines. The high PRNCR1 expression showed a significant correlation with tumor size, clinical stage, lymph node metastasis, and shorter overall survival times among patients with TSCC. A PRNCR1‑knockdown reduced TSCC cell proliferation, migration and invasion, and increased apoptosis in vitro. Additionally, the PRNCR1‑knockdown slowed down in vivo tumor growth of TSCC cells. With regards to the mechanism, PRNCR1 acted as a competing endogenous RNA on microRNA‑944 (miR‑944) in TSCC cells, and the effects of the PRNCR1‑knockdown were reversed by an miR‑944‑knockdown. HOXB5 was validated as a direct target gene of miR‑944 in TSCC cells, and HOXB5 expression was found to be positively regulated by PRNCR1. Furthermore, resumption of HOXB5 expression reversed the tumor‑suppressive actions of miR‑944 in TSCC cells. In conclusion, PRNCR1 acts as an oncogenic lncRNA in TSCC through the upregulation of HOXB5 by sponging miR‑944, thereby indicating a potential therapeutic target in TSCC.

Cluster of differentiation 44 (CD44) as a transmembrane glycoprotein is found to be expressed in non‑small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild‑type NSCLC cells to cisplatin and how it affects wild‑type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild‑type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G0/G1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44‑silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild‑type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild‑type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild‑type NSCLC.

The Nemo‑like kinase (NLK), a conserved serine/threonine kinase, plays a critical role in the regulation of a variety of transcription factors, with important roles in determining cell fate. Although recent studies have demonstrated decreased expression patterns of NLK in various types of human cancer, the functional mechanism of NLK in cancer development has not been elucidated. Here, in the present study overexpression of NLK was found to inhibit the growth and migration of the non‑small cell lung cancer A549 cell line. NLK was subsequently found to interact with 14‑3‑3ζ (also known as YWHAZ), which is responsible for E‑cadherin silencing during epithelial‑mesenchymal transition (EMT). Furthermore, NLK overexpression was able to restore the expression of E‑cadherin inhibited by 14‑3‑3ζ. Notably, NLK interacts with 14‑3‑3ζ and prevents its dimerization, which is essential for 14‑3‑3ζ stability and function. By fusing two copies of the 14‑3‑3ζ gene, via a Gly‑rich linker, a non‑dissociable dimer of 14‑3‑3ζ was formed. It was found that NLK was unable to restore the expression of E‑cadherin inhibited by the overexpression of the fused dimer of 14‑3‑3ζ. In addition, the increased ability of migration induced by the overexpression of fused 14‑3‑3ζ dimer could not be altered by NLK overexpression. The results from the present study indicate that NLK is a negative regulator of 14‑3‑3ζ and plays a tumor suppressive role in the inhibition of cancer cell migration.

Costunolide being a sesquiterpene lactone, is known to have anticancer properties. The present study investigated the anticancer effects of costunolide against the H1299 human non‑small‑cell lung cancer (NSCLC) cell line. Inhibition of cell viability by costunolide was assessed via a MTT assay. Furthermore, the apoptotic rate was detected using Annexin V/propidium iodide labeling. A colony forming cell assay was performed to investigate the antiproliferative effects of costunolide. Wound healing and Transwell assays were performed to determine the inhibitory effects of costunolide on migration and invasion, respectively. Western blot analysis was undertaken to determine protein expression, and reverse transcription‑quantitative PCR was performed to assess mRNA expression levels. The results demonstrated that costunolide inhibited the viability of H1299 cells, with a half maximal inhibitory concentration value of 23.93±1.67 µM and induced cellular apoptosis in a dose‑dependent manner. Furthermore, the colony formation, migrative and invasive abilities of the H1299 cells were inhibited in a dose‑ or time‑dependent manner. The protein expression levels of E‑cadherin increased and those of N‑cadherin decreased following treatment with costunolide, which suggested that costunolide inhibited epithelial‑to‑mesenchymal transition. The mRNA levels of B‑Raf, E‑cadherin, N‑cadherin, integrins α2 and β1, as well as matrix metalloproteinases 2 were also found to be regulated costunolide. These findings indicate the potential of costunolide in the treatment of NSCLC.

Hispidulin is a medicinal natural compound isolated from S. involucrata, which exhibits potent anticancer properties. However, there are few reports on its effects on lung cancer cells. Therefore, the current study investigated the effects of hispidulin on cell viability and apoptosis in human non‑small‑cell lung cancer (NSCLC) cell lines NCI‑H460 and A549 in vitro and in vivo. Methyl thiazolyl tetrazolium, colony formation assay, Hoechst 33342 staining, flow cytometry and western blotting were performed on Human NCI‑H460 and A549 cells. A mouse xenograft model was also established using NCI‑H460 cells. The results showed that the growth of NCI‑H460 and A549 cells was inhibited, while apoptosis was promoted by hispidulin via increased generation of reactive oxygen species (ROS) in a dose‑dependent manner. Furthermore, hispidulin triggered apoptosis in NSCLC cells through upregulating the expression of cleaved caspase‑3 and cleaved poly [ADP‑ribose] polymerase. All these effects were reversed upon pretreatment with glutathione, a selective ROS inhibitor. In addition, endoplasmic reticulum stress (ER stress) in NCI‑H460 cells was activated by hispidulin. Pretreatment with tauroursodeoxycholic acid, a specific ER stress inhibitor, effectively reduced the cell apoptosis induced by hispidulin. In conclusion, hispidulin induces ROS‑mediated apoptosis via activating the ER stress pathway. The current study provides theoretical basis for the antitumor effect of hispidulin in NSCLC.

The epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitor (TKI), gefitinib, is an effective therapeutic drug used in the treatment of non‑small cell lung cancers (NSCLCs) harboring EGFR mutations. However, acquired resistance significantly limits the efficacy of EGFR‑TKIs and consequently, the current chemotherapeutic strategies for NSCLCs. It is, therefore, necessary to overcome this resistance. In the present study, the anticancer potential of natural extracts of Coptis chinensis (ECC) against gefitinib‑resistant (GR) NSCLC cells were investigated in vitro and in vivo. ECC inhibited the viability, migration and invasion, and effectively induced the apoptosis of GR cells. These effects were associated with the suppression of EGFR/AKT signaling and the expression of anti‑apoptotic proteins, Mcl‑1 and Bcl‑2, which were overexpressed in GR NSCLC cells. Combination treatment with ECC and gefitinib enhanced the sensitivity of GR cells to gefitinib in vitro, but not in vivo. However, ECC increased the survival of individual zebrafish without affecting the anticancer effect to cancer cells in vivo, which indicated a specific cytotoxic effect of ECC on cancer cells, but not on normal cells; this is an important property for the development of novel anticancer drugs. On the whole, the findings of the present study indicate the potential of ECC for use in the treatment of NSCLC, particularly in combination with EGFR‑TKI therapy, in EGFR‑TKI‑resistant cancers.

Numerous studies have reported that oestrogens may contribute to the development of non‑small cell lung cancer (NSCLC). Although different steroidogenic enzymes have been detected in the lung, the precise mechanism leading to an exaggerated accumulation of active oestrogens in NSCLC remains unexplained. 17‑β‑Hydroxysteroid dehydrogenase type 2 (HSD17B2) is an enzyme involved in oestrogen and androgen inactivation by converting 17‑β‑oestradiol into oestrone, and testosterone into 4‑androstenedione. Therefore, the enzyme serves an important role in regulation of the intracellular availability of active sex steroids. This study aimed to determine the expression levels of HSD17B2 in lung cancer (LC) and adjacent histopathologically unchanged tissues obtained from 161 patients with NSCLC, and to analyse the association of HSD17B2 with clinicopathological features. For that purpose, reverse transcription‑quantitative PCR, western blotting and immunohistochemistry were conducted. The results revealed that the mRNA and protein expression levels of HSD17B2 were significantly decreased in LC tissues compared with matched controls (P<10‑6). Conversely, strong cytoplasmic staining of HSD17B2 was detected in the unchanged respiratory epithelium and in glandular cells. Notably, a strong association was detected between reduced HSD17B2 expression and advanced tumour stage, grade and size. Furthermore, it was revealed that HSD17B2 may have potential prognostic significance in NSCLC. A log‑rank test revealed the benefit of high HSD17B2 protein expression for the overall survival (OS) of patients (P=0.0017), and multivariate analysis confirmed this finding (hazard ratio=0.21; 95% confidence interval=0.07‑0.63; P=0.0043). Stratified analysis in the Kaplan‑Meier Plotter database indicated that patients with higher HSD17B2 expression presented better OS and post‑progression survival. This beneficial effect was particularly evident in patients with adenocarcinoma and during the early stages of NSCLC. Decreased expression of HSD17B2 appears to be a frequent feature in NSCLC. Retrospective analysis suggests that the HSD17B2 mRNA and protein status might be independent prognostic factors in NSCLC and should be further investigated.

The ankyrin repeat and KH domain‑containing 1 (ANKHD1) protein was recently reported to be a potential member of the Hippo signaling pathway. However, its role in human non‑small‑cell lung cancer (NSCLC) has not been extensively investigated. The aim of the present study was to examine the expression of ANKHD1 in primary human tissues and cells and determine whether it is correlated with the clinical characteristics of tumor growth. The biological functions of ANKHD1 were evaluated in vitro and in vivo. Yes‑associated protein (YAP) expression and phosphorylation induced by ANKHD1 were evaluated by western blotting and immunoprecipitation. Marked upregulation of ANKHD1 protein expression was observed in NSCLC cells and tissues, which was associated with advanced pathological tumor‑node‑metastasis stage, lymph node metastasis and poor prognosis in patients with NSCLC. ANKHD1 overexpression also promoted the proliferation and invasion of NSCLC cells. ANKHD1 upregulation inactivated Hippo signaling via increasing YAP protein levels, as well as inhibiting YAP protein phosphorylation, whereas depletion of YAP abolished the effects of ANKHD1 on cell proliferation and invasion. Therefore, ANKHD1 may play an important role in NSCLC through regulating the YAP‑dependent Hippo signaling pathway.

The underlying molecular mechanisms of cisplatin resistance in non‑small cell lung cancer (NSCLC) are unclear. In this study, a novel differential methylation region located in the upstream regulatory region of the forkhead box F1 (FOXF1) gene was identified. The abnormal hypomethylation of FOXF1 increased the expression of FOXF1, and the high expression of FOXF1 promoted cell proliferation and inhibited cell apoptosis induced by cisplatin, which resulted in cisplatin resistance in NSCLC cells. In addition, FOXF1 promoted the expression of stem cell markers and self‑renewal capability, indicating that FOXF1 regulated cisplatin resistance by promoting cancer stem cell properties in NSCLC cells. Moreover, a strong association was observed between FOXF1 upregulation and the presence of platinum‑based chemotherapy resistance in patients with NSCLC. On the whole, the findings of this study indicate the regulatory mechanisms of cisplatin resistance by FOXF1 in NSCLC, and suggest that FOXF1 may be used as a prognostic biomarker of platinum‑based chemotherapy resistance in NSCLC.

Non‑small cell lung cancer (NSCLC) is the most common type of lung cancer, and numerous oncogenes are associated with this disease. Oxysterol‑binding protein‑related protein 8 (ORP8) is essential for cell growth, migration and the modulation of mitochondrial respiration and morphology. However, the underlying role of ORP8 in NSCLC remains unclear. In the present study, it was reported that the expression of ORP8 was low in NSCLC cells and tissues. The ORP8 expression levels were analyzed by immunohistochemistry (IHC), quantitative real‑time PCR (qPCR) and western blot analysis. ORP8 overexpression inhibited cell growth and induced apoptosis in NSCLC cells with MTS, anchorage‑independent growth and Hoechst 33342 staining assay. Further experiments demonstrated that ORP8 overexpression induced the apoptosis of NSCLC cells via the release of cytochrome c from mitochondria into the cytoplasm with western blot analysis and confocal microscopy results. In addition, qPCR analysis showed that miR‑421 was upregulated in NSCLC cell lines, with the bioinformatics analysis, western blot analysis and Dual‑Luciferase reporter assay, it was determined that miR‑421 could target ORP8. The inhibition of cell proliferation via ORP8 overexpression was rescued by a miR‑421 mimic, which aided in maintaining the proliferative potential of the cells. Overall, the present study revealed that ORP8 may be a candidate target in the prevention and treatment of NSCLC.

Long non‑coding RNAs (lncRNAs) have critical functions in non‑small cell lung cancer (NSCLC) growth. In the present study, we showed that lncRNA‑CCAT1 was upregulated in NSCLC tissues. High expression of lncRNA‑CCAT1 was related to tumor growth and reduced survival rate. We used short hairpin RNAs (shRNAs) to inhibit the expression of lncRNA‑CCAT1 in NSCLC cells. In vitro and in vivo results demonstrated that lncRNA‑CCAT1 knockdown suppressed tumor proliferation and induced apoptosis. Furthermore, microRNA‑218 (miR‑218) was confirmed as an effective target of lncRNA‑CCAT1 in NSCLC. B lymphoma Mo‑MLV insertion region 1 homolog (BMI‑1), which served as a downstream target of miR‑218, was also inhibited by lncRNA‑CCAT1 knockdown. In conclusion, the present study indicated that upregulation of lncRNA‑CCAT1 in NSCLC is associated with tumor malignant potential. lncRNA‑CCAT1 enhances tumor growth in NSCLC by directly inhibiting miR‑218 and indirectly increasing BMI‑1 expression.

Pulmonary sarcomatoid carcinomas (PSCs) are a rare subtype of non‑small‑cell lung cancer and are typically biphasic neoplasms. No effective treatment for PSCs is currently available in clinical practice. The expression of the epithelial‑mesenchymal transition (EMT) transcription factors, Twist1, Slug and Snail, as well as the EMT phenotype and vasculogenic mimicry (VM) were analysed in 41 PSC and 79 pulmonary squamous carcinoma (PSCC) samples. Compared with the PSCCs, the PSCs exhibited an EMT phenotype and VM, and they also exhibited an increased expression of the Twist1, Slug, Snail and VM markers. Twist1 expression was associated with metastasis and TNM stage. Twist1‑positive patients exhibited a poorer prognosis for overall survival (OS) than those with Twist1‑negative PSCs. Transforming growth factor β1 (TGFβ1) was used to induce an EMT transition in a PSCC cell line. SK‑MES‑1 cells treated with TGFβ1 exhibited an increased expression of Twist1. The EMT phenotype, VM and increased migratory and invasive abilities were induced following TGFβ1 treatment. Importantly, in cells treated with TGFβ1, the EMT phenotype was reversed, VM marker expression was decreased, and the migratory and invasive ability of the PSCC cell line was decreased following Twist1 knockdown. Collectively, this study provides a new perspective of Twist1 in the aggressiveness of PSCs. The identification of Twist1 as an independent marker of poor prognoses may lead to the development of novel strategies for improving the treatment of patients with PSC.