Accumulating studies have suggested that microRNAs (miRs) play a significant role in lung cancer development and progression, especially in non-small cell lung cancer (NSCLC). The present study aimed to investigate the associations between miR-454-3p and NSCLC progression. qPCR assay was applied to examine the expression of miR-454-3p and transforming growth factor-β2 (TGFB2) in tissues and cell lines. CCK-8 and EdU assays were used to detect cell proliferation. Wound-healing and Transwell assays were conducted to assess cell migration and invasion. Western blotting assay was performed to explore the protein levels of epithelial-mesenchymal transition (EMT) markers. The interaction between miR-454-3p and TGFB2 was investigated with a luciferase reporter assay. miR-454-3p was downregulated in NSCLC tissues and NSCLC cell lines. miR-454-3p overexpression led to the suppression of proliferation, migration, and invasion in A549 and NCI-H1650 cells. In addition, the overexpression of miR-454-3p in A549 and NCI-H1650 cells significantly inhibited EMT. TGFB2 was revealed to be a direct target of miR-454-3p by using TargetScan database and luciferase reporter assay. TGFB2 was observed to be upregulated in NSCLC tissues and cell lines. Further mechanistic studies revealed that the inhibitory effects of miR-454-3p on NSCLC were reversed upon overexpression of TGFB2. These findings provided strong evidence that miR-454-3p suppressed NSCLC cell proliferation and metastasis by targeting TGFB2. The study suggests that targeting miR-454-3p could be a promising strategy for treating NSCLC.
Cisplatin resistance is a major therapeutic challenge in non-small cell lung cancer (NSCLC). Herein, the regulatory role of long non-coding RNA (lncRNA) ITGB2-AS1 in regulating NSCLC cisplatin resistance was investigated. NSCLC cisplatin resistance cells were constructed using A549 and H1975 cells. Cell viability and proliferation were detected by MTT assay and colony formation assay, respectively. Cell apoptosis and cell cycle were examined by flow cytometry. GSH, MDA, ROS, and Fe 2+ levels were measured by the corresponding kits. The expressions of ferroptosis-negative regulation genes (GPX4 and SLC7A11) were determined by qRT-PCR and western blot. Molecular interactions were analyzed by RNA pull-down, RIP, ChIP, and dual-luciferase reporter assays. The effects of ITGB2-AS1 silencing on NSCLC cisplatin resistance in vivo were elevated by the tumor xenograft experiment. ITGB2-AS1 expression was increased in NSCLC patients and cisplatin-resistant NSCLC cells, which was positively correlated with ferroptosis-negative regulation genes. ITGB2-AS1 knockdown suppressed resistant cell proliferation and promoted cell apoptosis and ferroptosis. ITGB2-AS1 increased NAMPT expression by binding to FOSL2, thereby repressing p53 expression. The ITGB2-AS1 knockdown also inhibited NSCLC cisplatin resistance in vivo. ITGB2-AS1 promoted NSCLC cisplatin resistance by inhibiting p53-mediated ferroptosis via activating the FOSL2/NAMPT axis.
Cancer stem cells (CSCs) can induce recurrence and chemotherapy resistance of lung adenocarcinoma (LUAD). Reliable markers identified based on CSC characteristic of LUAD may improve patients’ chemotherapy response and prognosis. OCLR was used to calculate mRNA expression-based stemness index (mRNAsi) of LUAD patients’ data in TCGA. Association analysis of mRNAsi was performed with clinical features, somatic mutation, and tumor immunity. A prognostic prediction model was established with LASSO Cox regression. Kaplan-Meier Plotter (KM-plotter) and time-dependent ROC were applied to assess signature performance. For LUAD, univariate and multivariate Cox analysis was performed to identify independent prognostic factors. LUAD tissues showed a noticeably higher mRNAsi in than nontumor tissues, and it showed significant differences in T, N, M, AJCC stages, and smoking history. The most frequently mutated gene was TP53, with a higher mRNAsi relating to more frequent mutation of TP53. The mRNAsi was significantly negatively correlated with immune score, stromal score, and ESTIMATE score in LUAD. The blue module was associated with mRNAsi. The 5-gene signature was confirmed as an independent indicator of LUAD prognosis that could promote personalized treatment of LUAD and accurately predict overall survival (OS) of LUAD patients.
Background: The therapeutic strategies and prognosis of local advanced and metastatic lung cancer have been extensively investigated. However, the prognosis of early-stage lung cancer patients undergoing radical surgery has not been fully studied due to the difficulties in follow-up and assessment.Methods: We recruited 447 stage I-III lung adenocarcinoma (LUAD) patients who underwent radical surgery and investigated the influence of main driver gene mutations and clinicopathological factors on patient overall survival (OS). Cancer tissue samples were collected retrospectively and mutational status and tumor mutational burden (TMB) were determined by whole-exome sequencing (WES).Results: Distinct stage-dependent mutational frequency was revealed in main driver genes including EGFR, TP53, KRAS, STK11, ATM and NF1. Patients with TP53 mutations exhibited a trend of better survival than those with wild type TP53 (P=0.066), and STK11 mutations exhibited worse survival in stage III patients (P=0.031). EGFR mutations eliminated the across-stage difference in survival, which was still present in other wild type and mutant driver genes. Furthermore, patients with wild type TP53 appeared to have significantly worse survival than patients with other wild type driver genes in stage I (P<0.001). TMB cannot stratify the survival of LUAD patients in stage I-III. Age, gender, smoking status, smoking years, prior cancer history and cancer location had no stratification effect on patient survival, while T grading (P<0.001) and N grading (P<0.001) had significant stratification on survival.Conclusions: TP53, EGFR and STK11 mutational status influenced the prognosis of stage I-III LUAD. T and N grading also stratified the patient survival. T grading was an independent risk factor.
Background: Tumor cells expressing programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) correlate with a better prognosis of immunotherapy in non-small cell lung cancer (NSCLC) patients. Expression of PD-1 and PD-L1 on immune cells is also concerned by more and more researchers.Methods: This study included 174 patients with NSCLC, and collected from the month of December in 2012 to April 2019. Formalin-fixed paraffin-embedded (FFPE) samples from NSCLC patients were performed by multiplex immunohistochemistry (IHC) staining using CD8, CD57, CD68, CD163, PD-1 and PD-L1. Marker localization included each type of immune cell subset with PD-1 or PD-L1 was quantified and analyzed.Results: The present study revealed distribution characteristics of PD-1 and PD-L1 on CD8+ T cells, CD57+ NK cells, CD68+ macrophages and CD163+ M2 macrophages in NSCLC patients using multiplex IHC, which indicated that expression of PD-1 was higher on CD8+ T cells and expression of PD-L1 was higher on CD8+ T cells and CD68+ macrophages. Immune clustering analysis showed that the low immune feature group displayed more survival rate than the high group. The reason was due to higher ratios of CD8/PD-L1 in the low group compared with the high group in the NSCLC cohort. Further, the Kaplan-Meier analysis of survival rate according infiltration of different immune cells also indicated that low CD57+ NK cells and low CD68+ macrophages were associated with a higher survival rate. The similar results were observed in the Kaplan-Meier analysis of expression of PD-1 and PD-L1 on immune cells.Conclusions: Taken together, we displayed the expression characteristics of PD-1 and PD-L1 on tumor-infiltrating immune cells and revealed that high expression of PD-1 and PD-L1 on immune cells was associated with poor survival rate. The present study provided further evidence to better guide clinical treatment in NSCLC.
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