Background: Long noncoding RNAs (lncRNAs) are known to regulate tumorigenesis and cancer progression, but their contributions to non-small-cell lung cancer (NSCLC) metastasis remain poorly understood. Our previous and other studies have revealed the involvement of upregulated LINC01234 in regulating gastric cancer and colon cancer cells proliferation, and we aimed to investigate whether LINC01234 overexpression also contribute to cancer cells metastasis in this study. Methods:We collect the NSCLC tissues and adjacent non-tumor tissues and analyzed expression levels of LINC01234 by quantitative reverse-transcription PCR. LINC01234 were knocked down by using siRNAs or shRNAs, and overexpressed by transfection with overexpression vector; RNA levels of miRNA were downregulated or upregulated with inhibitors or mimics. Transwell assays were used to evaluate cell migration and invasive ability; in vivo metastasis experiments were performed to investigate the effect of LINC01234 on NSCLC cells metastasis. Luciferase reporter, RIP, and ChIP assays were used to determine the regulation of LINC01234 on its targets.Results: LINC01234 expression is increased in NSCLC tissues, and its upregulation is associated with metastasis and shorter survival in NSCLC. Downregulation of LINC01234 impairs cell migration and invasion in vitro, and inhibits cells metastasis in vivo by acting as a competing endogenous RNA for the miR-340-5p and miR-27b-3p. LINC01234 also interacts with the RNA-binding proteins LSD1 and EZH2, leading to histone modification and transcriptional repression of the anti-proliferative genes BTG2. Conclusions: Taken together, our findings identify two oncogenic regulatory axes in NSCLC centering on LINC01234: one involving miR-340-5p/miR-27b-3p in the cytoplasm and the second involving EZH2, LSD1, and BTG2 in the nucleus. Our study indicates that these genes may be targeted to reduce or prevent NSCLC metastasis.

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Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has greatly affected clinical outcomes in non-small cell lung cancer (NSCLC) patients. The long noncoding RNAs (lncRNAs) are known to regulate tumorigenesis and cancer progression, but their contributions to NSCLC gefitinib resistance remain poorly understood. In this study, by analyzing the differentially expressed lncRNAs in gefitinib-resistant cells and gefitinib-sensitive cells in the National Institute of Health GEO dataset, we found that lncRNA CASC9 expression was upregulated, and this was also verified in resistant tissues. Gain and loss of function studies showed that CASC9 inhibition restored gefitinib sensitivity both in vitro and in vivo, whereas CASC9 overexpression promoted gefitinib resistance. Mechanistically, CASC9 repressed the tumor suppressor DUSP1 by recruiting histone methyltransferase EZH2, thereby increasing the resistance to gefitinib. Furthermore, ectopic expression of DUSP1 increased gefitinib sensitivity by inactivating the ERK pathway. Our results highlight the essential role of CASC9 in gefitinib resistance, suggesting that the CASC9/EZH2/DUSP1 axis might be a novel target for overcoming EGFR-TKI resistance in NSCLC.

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Lung cancer is the most common cancer all around the world, with high morbidity and mortality. Long noncoding RNA (lncRNA) has been reported to have a critical role in non-small-cell lung cancer (NSCLC) proliferation and migration. In the present study, we analyzed The Cancer Genome Atlas (TCGA) data, and we found that lncRNA Small Nucleolar RNA Host Gene 17 (SNHG17) was upregulated in NSCLC driven by the amplification of copy number, indicating the special role of SNHG17 in NSCLC. The full exact length of SNHG17 was determined by rapid amplification of cDNA ends (RACE). We modulated SNHG17 expression by RNAi and a series of functional assays were performed. Flow cytometry was used to explore the involvement of SNHG17 in NSCLC cell apoptosis. Results showed that the knockdown of SNHG17 inhibited the proliferation and migration and promoted the apoptosis of NSCLC cells. We acquired the global gene expression profile regulated by SNHG17 in A549 through RNA sequencing (RNA-seq) assays. We found 637 genes were upregulated while 581 genes were downregulated. We selected three genes (FOXA1, XAF1, and BIK) that were closely related to proliferation and apoptosis, and we confirmed their altered expression in A549 and PC-9 cells treated with small interfering RNA si-SNHG17. Our findings indicated gene amplification-driven lncRNA SNHG17 promotes cell proliferation and migration in NSCLC, suggesting its potential value as a biomarker in NSCLC.

The number of documented long noncoding RNAs (lncRNAs) has dramatically increased, and their biological functions and underlying mechanisms in pathological processes, especially cancer, remain to be elucidated. Actin filament‐associated protein 1 antisense RNA 1 (AFAP1‐AS1) is a 6810‐nt lncRNA located on chromosome 4p16.1 that was first reported to be upregulated in esophageal adenocarcinoma tissues and cell lines. Here we reported that AFAP1‐AS1, recruiting and binding to lysine‐specific demethylase 1 (LSD1), was generally overexpressed in human non‐small‐cell lung cancer (NSCLC) tissues using quantitative real‐time PCR. Higher AFAP1‐AS1 expression was significantly correlated with larger tumor size (P = .008), lymph node metastasis (P = .025), higher TNM stage (P = .024), and worse overall survival in NSCLC patients. In vitro experiments revealed that AFAP1‐AS1 downregulation inhibited cell migration and induced apoptosis; AFAP1‐AS1 knockdown also hindered tumorigenesis in vivo. Moreover, mechanistic investigations including RNA immunoprecipitation and ChIP assays validated that AFAP1‐AS1 repressed HMG box‐containing protein 1 (HBP1) expression by recruiting LSD1 to the HBP1 promoter regions in PC‐9 and H1975 cells. Furthermore, HBP1 functions as a tumor suppressor, and its ectopic expression hindered cell proliferation. Rescue assays determined that the oncogenic effect of AFAP1‐AS1 is partially dependent on the epigenetic silencing of HBP1. In conclusion, our results indicate that AFAP1‐AS1 is carcinogenic and that the AFAP1‐AS1/LSD1/HBP1 axis could constitute a new therapeutic direction for NSCLC.

Long non-coding RNA (lncRNA) SPRY4 intronic transcript 1 (SPRY4-IT1) is reported to play important roles in the occurrence and development of many tumors. However, the possible role of SPRY4-IT1 in cisplatin (DDP) resistance of non-small-cell lung cancer (NSCLC) remains unclear. The aim of this study is to investigate the functions and molecular mechanisms underlying SPRY4-IT1 of cisplatin resistance in NSCLC. Methods: Expression of SPRY4-IT1 was analyzed in A549 and cisplatin-resistant A549/DDP cell lines by quantitative real-time polymerase chain reaction (RT-qPCR). Overexpression techniques were applied to investigate the biological functions of SPRY4-IT1 in cisplatinresistant A549/DDP cells. The effects of SPRY4-IT1 on proliferation and apoptosis were evaluated using cell counting kit-8 (CCK8) assays, colony formation assay and flowcytometric analysis. The expressions of epithelial-mesenchymal transition (EMT)-associated proteins, including E-cadherin and Vimentin, were detected by Western blot. Microarray analysis was performed to identify the putative targets of SPRY4-IT1, which were further verified by Western blotting and RT-qPCR. A549/DDP cells transfected with pCDNA-SPRY4-IT1 were injected into nude mice in order to verify the effect of SPRY4-IT1 on cisplatin resistance in vivo. Results: The present study demonstrated that SPRY4-IT1 expression was decreased in A549/DDP cells compared with parental A549 cells. Upregulation of SPRY4-IT1 suppressed cell proliferation and caused apoptosis of A549/DDP cells both in vitro and in vivo. MPZL-1 was negatively regulated by SPRY4-IT1. Furthermore, upregulation of SPRY4-IT1 and downregulation of MPZL-1 could suppress epithelial-mesenchymal transition (EMT), which was characterized by increased E-cadherin expression and decreased Vimentin expression. Conclusion: Upregulation of SPRY4-IT1 reversed the cisplatin-resistant phenotype of NSCLC partially by downregulating MPZL-1 via inhibiting EMT process.