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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.

Circular RNAs (circRNAs) have good stability and long half-life in blood and other body fluid, and possess regulatory effects on various biological processes as miRNA/RNA-binding protein sponges, or by competing endogenous RNA, indicating their great potential as biomarkers or targets of cancer therapy. In this study, we mainly explored the role and mechanism of circular RNA SMARCA5 (circsSMARCA5) in non-small cell lung cancer (NSCLC). Quantitative RT-PCR was applied to measure the expression levels of genes, and then, the relationships among circsSMARCA5, microRNA-670-5p (miR-670-5p), and RBM24 were further analyzed. Animal and cell experiments were performed to explore the functions of circsSMARCA5 in NSCLC cells. The results showed that circsSMARCA5 was expressed at low level in NSCLC tissues and cells, while miR-670-5p had high level in NSCLC tissues. Dual luciferase reporter assay verified that miR-670-5p was the target of circsSMARCA5, and RBM24 has the binding site of miR-670-5p. Further analysis showed that circsSMARCA5 could negatively regulate miR-670-5p and had positive relationship with RBM24. Moreover, circsSMARCA5 obviously inhibited tumor growth in vivo, reduced cell proliferation and increased cell apoptosis in vitro, while miR-670-5p mimic or RBM24 knockdown could reverse these effects. Thus, circsSMARCA5 may serve as an NSCLC suppressor by regulating the miR-670-5p/RBM24 axis, and it may have the potential to be a biomarker or therapeutic target for NSCLC., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study aimed to investigate the correlation of C-X-C chemokine receptor 2 (CXCR2) with clinicopathological characteristics and survival in non-small cell lung cancer (NSCLC) patients and further explore its effect on proliferation, apoptosis, invasion, stemness, chemosensitivity as well as JAK2/STAT3 pathway in NSCLC cells. The expression of CXCR2 in tumor tissues and adjacent tissues from 340 NSCLC patients received surgery was detected by immunohistochemistry. CXCR2 overexpression and knockdown were constructed through plasmid transfection and the effect of CXCR2 dysregulation on cell proliferation, apoptosis, invasion, stemness, chemosensitivity as well as its regulatory effect on JAK2/STAT signaling pathway was assessed in NCI-H1437 cells and NCI-H1299 cells. CXCR2 expression was higher in tumor tissues than that in paired adjacent tissues, and it was correlated with poor pathological differentiation, greater tumor size, lymph node metastasis, higher TNM stage and poor survival in NSCLC patients. In vitro , CXCR2 expression was increased in human NSCLC cell lines compared with human normal lung bronchus epithelial cells. CXCR2 promoted cell proliferation and invasion, while suppressed cell apoptosis in NCI-H1437/NCI-H1299 cells. Additionally, CXCR2 increased CD133 + cell rate and cell sphere-forming ability, while reduced chemosensitivity to cisplatin and gemcitabine in NCI-H1437/NCI-H1299 cells. Besides, CXCR2 activated the JAK2/STAT3 signaling pathway in NCI-H1437/NCI-H1299 cells. In conclusion, the clinical implication and the molecular function of CXCR2 discovered in our study reveal the potential of CXCR2 as a future target for disease monitoring and treatment of NSCLC.

MicroRNAs (miRNAs) play critical roles in the development and progression of various cancers, including non-small-cell lung cancer (NSCLC). Studies have suggested that miR-330-5p is involved in the progression of several cancers. However, the role of miR-330-5p in NSCLC remains unclear. We investigated the effect on and mechanism of miR-330-5p in the progression of NSCLC. We found that miR-330-5p was significantly downregulated in NSCLC tissues and cell lines as detected by real-time quantitative polymerase chain reaction (RT-qPCR). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), bromodeoxyuridine (BrdU), colony formation and cell cycle assays showed that overexpression of miR-330-5p markedly inhibited cell growth. Annexin V-FITC/PI and caspase-3 activity assays showed that overexpression of miR-330-5p significantly promoted cell apoptosis of NSCLC cells. Bioinformatics analysis and dual-luciferase reporter assays confirmed NIN/RPN12 binding protein 1 (NOB1) as a target gene of miR-330-5p. RT-qPCR and Western blot analysis showed that overexpression of miR-330-5p inhibited the expression of NOB1 as well as cyclin D1 and cyclin-dependent kinase 4 in NSCLC cells. Moreover, overexpression of NOB1 markedly reversed the miR‑330-5p-mediated inhibitory effect on NSCLC cell growth. Correlation analysis showed that miR‑330-5p expression was inversely correlated with NOB1 mRNA expression in NSCLC tissues. Taken together, our results indicate that miR-330-5p inhibits NSCLC cell growth through downregulation of NOB1 expression. Our study suggests that miR-330-5p may serve as a potential therapeutic target for the treatment of NSCLC.

Non-small cell lung cancer (NSCLC) is the most common type of lung tumor with poor prognosis, in which the Notch signaling pathway plays an important role. Notch activation complex kinase (NACK) has been reported both as a co-activator and a target gene of the Notch pathway. However, the molecular mechanism of NACK in NSCLC still remains unknown. In this study, the expression of NACK was analyzed in 35 paired NSCLC tumor samples and 2 NSCLC cell lines. MTT assay, cell migration assay, cell invasion assay, flow cytometry assay, and xenograft model were employed to detect the effect of NACK knockdown on the cell proliferation, metastasis, invasion and apoptosis of NSCLC. The relationship between NACK and Notch1 signaling pathway in NSCLC cells was assessed by western blot and luciferase reporter assay. We found that the expression of NACK in the NSCLC tissues and lung cancer cells were significantly increased. High level of NACK expression is remarkable associated with tumor differentiation, lymphatic metastasis, clinical stage and poor survival prognosis. The interference of NACK significantly inhibited cell proliferation, invasion and metastasis through inducing apoptosis in NSCLC cells. The transcriptional activity of related Notch1 target genes were significantly suppressed resulting from NACK knockdown. This study demonstrates that interference of NACK inhibits NSCLC progression through Notch1 signaling pathway and targeting NACK may be an effective approach for NSCLC therapy.

The ribosomal protein (RP)-p53 pathway has been shown to play a key role in apoptosis and senescence of cancer cells. miR-1908 is a newly found miRNA that was reported to have prognostic potential in melanoma. However, its role and mechanism in the progression of non-small cell lung cancer (NSCLC) are largely unknown. In this study, we found that expression of miR-1908 was significantly downregulated in human NSCLC cell lines, including SK-MES-1, A549, and NCI-H460. Then the role of miR-1908 in NSCLC cell proliferation was explored. The miR-1908 mimic was transfected into NSCLC cell lines, and their proliferation was detected. MTT and Cell Titer-Blue H analyses showed that the cell proliferation was notably reduced by the miR-1908 mimic transfection. Moreover, we found the RP-p53 pathway was activated by miR-1908 mimic. Moreover, the miR-1908 inhibitor transfection had a completely opposite effect on the NSCLC cell proliferation than that of miR-1908 mimic. To explore the underlying mechanism of that, TargetScan bioinformatics server and 3'-UTR luciferase reporter assay were applied to identify the targets of miR-1908. Our results showed that AKT1 substrate 1 (AKT1S1), a newly proven suppressor of the RP-p53 pathway, was a target of miR-1908, suggesting a probable mechanism for miR-191 suppressing NSCLC cell proliferation. Our findings provide a novel molecular target for the regulation of NSCLC cell proliferation.

The incidence of non‑small cell lung cancer (NSCLC) has significantly increased in China, while the prognosis of affected patients is poor. The pathogenesis of NSCLC is thought to be regulated by microRNAs (miRs). The present study used a miR array in order to determine the expression of miR‑361‑5p, which was significantly lower in NSCLC tissues compared with that in adjacent tissues, indicating a crucial role of miR‑361‑5p during the progression of NSCLC. Furthermore, the effects of transfection-induced upregulation of miR‑361‑5p on the NSCLC cell line H23 were assessed. Overexpression of miR‑361‑5p inhibited the proliferation and colony formation ability of H23 cells. In addition, apoptosis of H23 cells was induced by upregulation of miR‑361‑5p. Furthermore, signal transducer and activator of transcription 6 (STAT6) was confirmed as a direct target of miR‑361‑5p by a dual‑luciferase reporter assay. Moreover, inhibition of STAT6 by small interfering RNA or miR‑361‑5p also decreased the expression of B-cell lymphoma extra large (Bcl-xL). In vivo, miR‑361‑5p significantly reduced tumor growth in a nude mouse xenograft model, and suppressed STAT6 and Bcl-xL expression. In conclusion, the present study indicated that miR‑361‑5p may represent a novel molecular tool for therapeutic and diagnostic strategies in NSCLC.