scholarly journals KDM6B Elicits Cell Apoptosis by Promoting Nuclear Translocation of FOXO1 in Non-Small Cell Lung Cancer

2015 ◽  
Vol 37 (1) ◽  
pp. 201-213 ◽  
Author(s):  
Jun Ma ◽  
Ning Wang ◽  
Yurong Zhang ◽  
Cun Wang ◽  
Tianxiang Ge ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Small Cell ◽  
Nuclear Accumulation ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

Background/Aims: Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer and the cause of most cancer-related deaths. The molecular mechanisms that are involved in NSCLC development are currently not well understood. Accumulating evidence shows that histone demethylases play important roles in the regulation of pathological developmental processes in many diseases, including various types of cancers. Methods: Mitochondrial membrane potential assays, migration and invasion assays, caspase-3 and caspase-9 activity assays and western blot analysis were used in this research. Results: We found that overexpression of KDM6B, a demethylase that acts on histone H3 at lysine 27 (H3K27), inhibited cell growth by initiating mitochondria-dependent apoptosis and by attenuating the invasion-metastasis cascade in NSCLC cells. Moreover, our results showed that KDM6B directly interacted with FOXO1 and that overexpression of KDM6B promoted nuclear accumulation of FOXO1. The effects of KDM6B on cell apoptosis and metastasis were weakened by knockdown of FOXO1 expression. On the contrary, knocking down expression of KDM6B inhibited cell apoptosis and promoted cell growth by mitigating the nuclear translocation of FOXO1 in NSCLC cells. Conclusions: These findings suggest that KDM6B may act in a pro-apoptotic role in NSCLC by causing the nuclear translocation of FOXO1.

scholarly journals MicroRNA-138 Inhibits Cell Growth, Invasion, and EMT of Non-Small Cell Lung Cancer via SOX4/p53 Feedback Loop

2018 ◽  
Vol 26 (3) ◽  
pp. 385-400 ◽  
Author(s):  
Dandan Li ◽  
Changjun He ◽  
Junfeng Wang ◽  
Yanbo Wang ◽  
Jianlong Bu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung

Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop.

scholarly journals FUT4siRNA augments the chemosensitivity of non-small cell lung cancer to cisplatin through activation of FOXO1-induced apoptosis

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Wei Gao ◽  
Jinxiao Liang ◽  
Yiru Ye ◽  
Jinlan Lu ◽  
Tongtong Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Laser Scanning ◽  
Nuclear Translocation ◽  
Small Cell ◽  
Migration And Invasion ◽  
Cell Growth Inhibition ◽  
Small Cell Lung ◽  
Laser Scanning Confocal Microscope ◽  
Cisplatin Sensitivity ◽  
Induced Apoptosis

Abstract Background Increased fucosylation is associated with the chemoresistance phenotype. Meanwhile, fucosyltransferase IV (FUT4) amounts are frequently elevated in lung cancer and may be related to increased chemoresistance. Methods In the present work, FUT4’s role in cisplatin-induced apoptosis was assessed in A549 and H1975 cells, respectively. To clarify whether the FUT4 gene attenuates chemosensitivity in tumor cells, we constructed FUT4siRNA and evaluated its effects on cisplatin-induced apoptosis and cell growth inhibition. Cell viability, apoptosis, migration and invasion assay were conducted to investigate cisplatin sensitivity. The activation of EGFR/AKT/FOXO1 signaling were measured by western blot. The translocation of FOXO1 was assessed by IFC using Laser Scanning Confocal Microscope. Results We found that FUT4 knockdown dose-dependently increased cisplatin-associated cytotoxicity. Furthermore, FUT4 silencing induced apoptosis and inhibited proliferation in A549 and H1975 cells by suppressing Akt and FOXO1 phosphorylation induced by cisplatin administration, which resulted in nuclear translocation of FOXO1. Conclusion These results suggested FUT4 might control chemoresistance to cisplatin in lung cancer by suppressing FOXO1-induced apoptosis.

scholarly journals Long Non-Coding RNA THOR Depletion Inhibits Human Non-Small Cell Lung Cancer Cell Growth

2021 ◽  
Vol 11 ◽  
Author(s):  
Peng-Fei Jiao ◽  
Pei-jun Tang ◽  
Dan Chu ◽  
Ya-meng Li ◽  
Wei-hua Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Non Coding Rna ◽  
Primary Nsclc ◽  
Long Non Coding Rna

Long non-coding RNA (LncRNA) THOR (Lnc-THOR) is expressed in testis and multiple human malignancies. Lnc-THOR association with IGF2BP1 (IGF2 mRNA-binding protein 1) is essential for stabilization and transcription of IGF2BP1 targeted mRNAs. We tested its expression and potential functions in non-small cell lung cancer (NSCLC). In primary NSCLC cells and established cell lines, Lnc-THOR shRNA or CRISPR/Cas9-mediated knockout (KO) downregulated IGF2BP1 target mRNAs (IGF2, Gli1, Myc and SOX9), inhibiting cell viability, growth, proliferation, migration and invasion. Significant apoptosis activation was detected in Lnc-THOR-silenced/-KO NSCLC cells. Conversely, ectopic overexpression of Lnc-THOR upregulated IGF2BP1 mRNA targets and enhanced NSCLC cell proliferation, migration and invasion. RNA-immunoprecipitation and RNA pull-down assay results confirmed the direct binding between Lnc-THOR and IGF2BP1 protein in NSCLC cells. Lnc-THOR silencing and overexpression were ineffective in IGF2BP1-KO NSCLC cells. Forced IGF2BP1 overexpression failed to rescue Lnc-THOR-KO NSCLC cells. In vivo, intratumoral injection of Lnc-THOR shRNA adeno-associated virus potently inhibited A549 xenograft tumor growth in nude mice. At last we show that Lnc-THOR is overexpressed in multiple NSCLC tissues and established/primary NSCLC cells. Collectively, these results highlighted the ability of Lnc-THOR in promoting NSCLC cell growth by associating with IGF2BP1, suggesting that Lnc-THOR represents a promising therapeutic target of NSCLC.

scholarly journals Long Noncoding RNA DNAH17-AS1 Promotes Tumorigenesis and Metastasis of Non-Small Cell Lung Cancer via Regulating miR-877-5p/CCNA2 Pathway

2020 ◽  
Author(s):  
Li-juan Du ◽  
Long-jun Mao ◽  
Rui-jun Jing
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Molecular Mechanisms ◽  
Disease Free Survival ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Small Cell Lung

Abstract Background: A growing number of studies have revealed that long noncoding RNAs (lncRNAs) can function as important oncogenes or tumor suppressors. This study aimed to investigate the regulatory role of lncRNA DNAH17 antisense RNA 1 (DNAH17-AS1) on non-small cell lung cancer (NSCLC) and the underlying molecular mechanisms.Methods: RT-PCR was used to examine the expression of DNAH17-AS1, miR-877-5p and CCNA2 in NSCLC specimens and cell lines. The diagnostic and prognostic values of DNAH17-AS1 expression in NSCLC patients were statistically analyzed. We also evaluated the effects of DNAH17-AS1 on the proliferation, migration, invasion and apoptosis of H1299 and 95D cells. Bioinformatic analysis and luciferase reporter assays were carried to confirm the molecular binding.Results: The expression of DNAH17-AS1 and CCNA2 mRNA was distinctly upregulated in NSCLC specimens and cell lines, while miR-877-5p expression was significantly decreased. DNAH17-AS1 could be used to distinguish NSCLC specimens from adjacent non-tumor tissues. Clinical assays revealed that high DNAH17-AS1 was associated with TNM stage, distant metastasis and shorter overall survival and disease-free survival. Functional assays indicated that knockdown of DNAH17-AS1 suppressed the proliferation, migration and invasion of H1299 and 95D cells, and promoted apoptosis. Mechanically, DNAH17-AS1 served as competing endogenous RNA (ceRNA) for miR-877-5p to positively recover CCNA2.Conclusion: We identified a novel NSCLC-related lncRNA, DNAH17-AS1 which may exert an oncogenic function via serving as a sponge for miR-877-5p to upregulate CCNA2. Our study presents novel insights into NSCLC progression and provided a prospective therapeutic target for NSCLC.

scholarly journals MiR-224 Promotes Lymphatic Metastasis by Targeting ANGPTL1 in Non-Small-Cell Lung Carcinoma

2021 ◽  
Author(s):  
Haibo Han ◽  
Bo Pan ◽  
Fan Liang ◽  
Lina Wu ◽  
Xijuan Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lymphatic Metastasis ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Potential Marker

Abstract Background: MicroRNAs can regulates tumor metastasis either as an oncomiR or suppressor miRNA. Here, we investigate the role of miR-224 in lymphatic metastasis of non-small-cell lung cancer (NSCLC). Methods: The expression of miR-224 was demonstrated by a validation cohort of 156 lung cancer patients (77 cases with lymphatic metastasis) by q-PCR. In vitro and in vivo experiments were performed to study the malignant phenotype after upregulation and inhibition of miR-224 expression. Furthermore, the direct target genes of miR-224 were determined by a luciferase reporter assay. Results: miR-224 was identified as a high expression miRNA in the tumor tissues with lymphatic metastasis) with an area under the receiver operating characteristic curve (AUC) of 0.57. Forced expression of miR-224 in H1299 cells promoted not only the cell viability, plate clone formation, migration and invasion in vitro, but also tumor growth and lung metastasis in vivo. Consistently, inhibition of miR-224 suppressed the malignant characters both in vitro and in vivo. Molecular mechanism research suggested that miR-422a targeted the ANGPTL1 as a novel tumor suppressor.Conclusions: The present study demonstrates that miR-224 is a potential marker for the prediction of lymphatic metastasis of NSCLC. And application of miR-224 may help for prophylactic intervention of NSCLC in clinical practice.

scholarly journals Molecular Profiling in Non–Small Cell Lung Cancer: A Step Toward Personalized Medicine

2013 ◽  
Vol 137 (4) ◽  
pp. 481-491 ◽  
Author(s):  
Kirtee Raparia ◽  
Celina Villa ◽  
Malcolm M. DeCamp ◽  
Jyoti D. Patel ◽  
Minesh P. Mehta
Keyword(s):  
Lung Cancer ◽  
Lung Carcinoma ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Small Cell Lung Carcinoma ◽  
Locally Advanced ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

Context.—Lung carcinoma is the result of sequential accumulation of genetic and epigenetic changes. Lung adenocarcinoma is a heterogeneous disease with diverse somatic mutations, and several of them include the so-called driver mutations, which may serve as “druggable” therapeutic targets. Thus, development of personalized approaches for the treatment of non–small cell lung carcinoma (NSCLC) mandates that pathologists make a precise histologic classification inclusive of routine molecular analysis of such tumors. Objective.—To address the molecular mechanisms underlying NSCLC and how this knowledge reflects the multidisciplinary approach in the diagnosis and management of these patients. We will also summarize the current available and investigational personalized therapies for patients with resectable early-stage, unresectable locally advanced, and metastatic NSCLC. Data Sources.—Peer-reviewed published literature and personal experience. Conclusions.—There are multiple mechanisms involved in the pathogenesis of lung cancer, which operate in parallel and involve pathways of activation and inhibition of various cellular events. Further research is essential to characterize the histologic and mutational profiles of lung carcinomas, which will ultimately translate into improved and more personalized therapeutic management of patients with lung cancer.

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