scholarly journals Aspirin potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer by targeting GRP78 activity

2020 ◽  
Vol 12 ◽  
pp. 175883592094797
Author(s):  
Xiangyu Zhang ◽  
Jia Chen ◽  
Cheng Cheng ◽  
Ping Li ◽  
Fangfang Cai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Body Weight ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Mapk Signaling ◽  
Small Cell ◽  
Migration And Invasion ◽  
Small Cell Lung

Background: Aspirin has recently emerged as an anticancer drug, but its therapeutic effect on lung cancer has been rarely reported, and the mechanism of action is still unclear. Long-term use of celecoxib in large doses causes serious side effects, and it is necessary to explore better ways to achieve curative effects. In this study, we evaluated the synergistic anticancer effects of celecoxib and aspirin in non-small cell lung cancer (NSCLC) cells. Methods: In vitro, we evaluated the combined effects of celecoxib (40 μM) and aspirin (8 mM) on cell apoptosis, cell cycle distribution, cell proliferation, cell migration and signaling pathways. Furthermore, the effect of aspirin (100 mg/kg body weight) and celecoxib (50 mg/kg body weight) on the growth of xenograft tumors was explored in vivo. Results: Our data suggest that cancer sensitivity to combined therapy using low concentrations of celecoxib and aspirin was higher than that of celecoxib or aspirin alone. Further research showed that the anti-tumor effect of celecoxib combined with aspirin was mainly produced by activating caspase-9/caspase-3, arresting cell cycle and inhibiting the ERK-MAPK signaling pathway. In addition, celecoxib alone or in combination with aspirin inhibited the migration and invasion of NSCLC cells by inhibiting MMP-9 and MMP-2 activity levels. Moreover, we identified GRP78 as a target protein of aspirin in NSCLC cells. Aspirin induced an endoplasmic reticulum stress response by inhibiting GRP78 activity. Furthermore, combination therapy also exhibited a better inhibitory effect on tumor growth in vivo. Conclusions: Our study provides a rationale for further detailed preclinical and potential clinical studies of the combination of celecoxib and aspirin for NSCLC therapy.

scholarly journals Circ_ZFR contributes to the paclitaxel resistance and progression of non-small cell lung cancer by upregulating KPNA4 through sponging miR-195-5p

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Junmin Li ◽  
Rongmei Fan ◽  
Hui Xiao
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Small Cell Lung

Abstract Background A growing body of evidence has demonstrated the vital roles of circular RNAs (circRNAs) in cancer progression and drug resistance. We intended to explore the roles and mechanisms of circ_ZFR in the paclitaxel (PTX) resistance and progression of non-small cell lung cancer (NSCLC). Methods Two NSCLC cell lines A549 and H460 were used in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to measure the levels of circ_ZFR, ZFR, miR-195-5p and karyopherin subunit alpha 4 (KPNA4) mRNA. RNase R assay was used to analyze the characteristic of circ_ZFR. MTT assay was carried out to assess PTX resistance and cell proliferation. Flow cytometry analysis was utilized to analyze cell cycle and apoptosis. Transwell assay was used to examine cell migration and invasion. Western blot assay was conducted to measure the protein levels of Ki67, Twist1, E-cadherin and KPNA4. Dual-luciferase reporter assay was adopted to verify the combination between miR-195-5p and circ_ZFR or KPNA4. Murine xenograft model assay was used to investigate the effect of circ_ZFR on PTX resistance of NSCLC in vivo. Results Circ_ZFR level was enhanced in PTX-resistant NSCLC tissues and cells. Knockdown of circ_ZFR suppressed PTX resistance, cell cycle process, proliferation, migration and invasion and induced apoptosis in PTX-resistant NSCLC cells. For mechanism analysis, circ_ZFR knockdown markedly downregulated the expression of KPNA4 by sponging miR-195-5p, thereby promoting PTX sensitivity and suppressing cell progression in PTX-resistant NSCLC cells. In addition, circ_ZFR silencing enhanced PTX sensitivity of NSCLC in vivo. Conclusion Circ_ZFR knockdown played a positive role in overcoming PTX resistance of NSCLC via regulating miR-195-5p/KPNA4 axis, which might provide a possible circRNA-targeted therapy for NSCLC.

scholarly journals MiR-7-5p suppresses tumor metastasis of non-small cell lung cancer by targeting NOVA2

2019 ◽  
Vol 24 (1) ◽  
Author(s):  
Haiping Xiao
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Metastasis ◽  
Underlying Mechanism ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Small Cell Lung

Abstract Background Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Distant metastasis is thought to be one of the most important factors responsible for the failure of NSCLC therapy. MicroRNA-7-5p (miR-7-5p) has been demonstrated to be a tumor suppressor in breast cancer, hepatocarcinoma, prostate cancer and glioblastoma multiforme (GBM). However, its role in NSCLC is still not fully understood. This study evaluated the role of miR-7-5p in the progression of NSCLC and explored the underlying mechanism. Materials & methods The quantitative real-time PCR (qPCR), MTT, migration and invasion assays were used to evaluate the effects of miR-7-5p on the proliferation, migration and invasion of A549 and SPCA-1 cells. A tumor xenograft model was created to determine the effects of miR-7-5p on metastasis in vivo. The dual-luciferase reporter gene, neuro-oncological ventral antigen 2 (NOVA2) overexpression and western blotting assays were performed to explore the underlying mechanism. Results MiR-7-5p is downregulated in NSCLC tissues and lung cancer cell lines. It suppresses proliferation, migration, invasion and EMT marker expression in vitro and in vivo. Further study showed that miR-7-5p suppresses tumor metastasis of NSCLC by targeting NOVA2. Overexpression of NOVA2 attenuates the miR-7-5p-mediated inhibitory effect on lung cancer cells. Conclusion MiR-7-5p suppresses NSCLC metastasis. Targeting miR-7-5p may contribute to the success of NSCLC therapy.

scholarly journals Circular RNA circVAPA contributes to non-small-cell lung cancer progression via miR-342-3p-dependent regulation of ZEB2

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaoyang Liu ◽  
Yang Cheng ◽  
Yan Wang ◽  
Yinhong Zhang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Xenograft Tumor ◽  
Small Cell Lung

Abstract Background Accumulating evidence demonstrated that circular RNAs (circRNAs) play pivotal regulatory roles in the pathology of cancers. Disclosing the roles and molecular mechanisms of circRNAs in tumorigenesis and development is essential to identify novel diagnostic and therapeutic targets. In this study, we explored the role of circVAPA in non-small-cell lung cancer (NSCLC) progression and its associated mechanism. Methods The expression level of RNA was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation was assessed by MTT assay and colony-forming assay. Cell apoptosis was analyzed by flow cytometry. Cell migration and invasion were assessed by transwell assays. Dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays were used to test the intermolecular interactions. The role of circVAPA was assessed in vivo. And xenograft tumor tissues were analyzed by immunohistochemistry (IHC) staining. Results CircVAPA expression was upregulated in NSCLC tissues and cell lines, and a high level of circVAPA was associated with a poor prognosis of NSCLC patients. CircVAPA silencing suppressed the proliferation, migration, and invasion and induced the apoptosis of NSCLC cells. CircVAPA served as a molecular sponge for microRNA-342-3p (miR-342-3p). miR-342-3p interference largely reversed circVAPA knockdown-mediated anti-tumor effects in NSCLC cells. Zinc finger E-box-binding homeobox 2 (ZEB2) was a target of miR-342-3p, and miR-342-3p overexpression suppressed the malignant behaviors of NSCLC cells largely by downregulating ZEB2. CircVAPA silence repressed xenograft tumor growth in vivo, and IHC assay confirmed that circVAPA silence restrained the proliferation and metastasis but induced the apoptosis of NSCLC cells in vivo. Conclusion CircVAPA contributes to the progression of NSCLC by binding to miR-342-3p to upregulate ZEB2. CircVAPA/miR-342-3p/ZEB2 axis might be a novel potential target for NSCLC treatment.

scholarly journals Circ_PIP5K1A regulates cisplatin resistance and malignant progression in non-small cell lung cancer cells and xenograft murine model via depending on miR-493-5p/ROCK1 axis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Nan Feng ◽  
Zhi Guo ◽  
Xiaokang Wu ◽  
Ying Tian ◽  
Yue Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cell Motility ◽  
Cancer Progression ◽  
Cell Lung Cancer ◽  
Mtt Assay ◽  
Small Cell ◽  
Small Cell Lung

Abstract Background Chemoresistance limits the therapeutic effect of cisplatin (DDP) on non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) function as important regulators in chemoresistance. This study aimed to explore the regulation of circRNA Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Alpha (circ_PIP5K1A) in DDP resistance. Methods The expression analysis of circ_PIP5K1A, micoRNA-493-5p (miR-493-5p) and Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) was conducted through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell sensitivity was determined using 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell proliferation and cell viability were evaluated by colony formation assay and MTT assay, respectively. Cell cycle and apoptosis detection was performed via flow cytometry. Cell motility was examined by transwell migration or invasion assay. Dual-luciferase reporter assay was applied to confirm the target binding. ROCK1 protein level was assayed via Western blot. In vivo assay was carried out using xenograft model in mice. Results Circ_PIP5K1A level was abnormally increased in DDP-resistant NSCLC tissues and cells. Silencing circ_PIP5K1A reduced DDP resistance, proliferation, cell cycle progression and cell motility in DDP-resistant NSCLC cells. Circ_PIP5K1A directly interacted with miR-493-5p in NSCLC cells. The function of circ_PIP5K1A was dependent on the negative regulation of miR-493-5p. MiR-493-5p directly targeted ROCK1 and circ_PIP5K1A regulated the ROCK1 level via acting as a sponge of miR-493-5p. Overexpression of miR-493-5p inhibited chemoresistance and cancer progression by downregulating ROCK1 expression in DDP-resistant NSCLC cells. Circ_PIP5K1A regulated DDP sensitivity in vivo via the miR-493-5p/ROCK1 axis. Conclusion These findings suggested that circ_PIP5K1A upregulated the ROCK1 expression to promote DDP resistance and cancer progression in NSCLC by sponging miR-493-5p.

Hsa_circ_0003288 facilitates tumor progression by targeting miR-145 in non–small cell lung cancer cells

2021 ◽  
pp. 1-9
Author(s):  
Li-Na Pan ◽  
Yun-Fang Ma ◽  
Jia-An Hu ◽  
Zhi-Hong Xu
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Migration And Invasion ◽  
Small Cell Lung

Circular RNA (circRNA) has been shown to participate in various tumors, including lung cancer. In the present study, we explored the expression and functional relevance of hsa_circ_0003288 in human non-small cell lung cancer (NSCLC). We verified that hsa_circ_0003288 expression was upregulated in lung cancer tissues and cell lines. Overexpression of hsa_circ_0003288 dramatically promoted lung cancer cell proliferation, colony formation, inhibited apoptosis, and increased cell migration and invasion in vitro. Xenograft experiments showed that hsa_circ_0003288 overexpression accelerated tumor growth in vivo. Mechanistically, hsa_circ_0003288 negatively regulated miR-145 to exert the oncogenic role in lung cancer. Overexpression of miR-145 decreased cell proliferation, induced apoptosis, and suppressed migration and invasion in lung cancer. Additionally, miR-145 co-transfection abolished the oncogenic role of hsa_circ_0003288. Collectively, these findings identified a novel regulatory role of hsa_circ_0003288/miR-145 axis in the progression of NSCLC.

CALCR knockdown inhibits the development and progression of non-small-cell lung cancer

2021 ◽  
Author(s):  
Tao He ◽  
Feng Ling
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Expression Level ◽  
Cell Counting ◽  
Small Cell Lung

Abstract G protein-coupled receptors (GPCRs) have been reported to participant in the occurrence and development of a variety of human cancers. CALCR is one of the hundreds of GPCRs, but its expression level and functional importance have never been investigated in non-small-cell lung cancer (NSCLC). In the present study, the protein expression level of CALCR was detected by immunohistochemical staining and western blot analysis. The Celigo cell counting assay was used to assess cell proliferation. Both the wound healing assay and the transwell assay were performed to evaluate cell migration. Flow cytometric analysis was utilized to detect cell apoptosis and cell cycle. A mouse xenograft model was constructed to conduct the in vivo experiments. The results indicated that the CALCR expression was abundantly up-regulated in NSCLC and positively related to tumor infiltrate. Besides, CALCR knockdown could significantly suppress cell proliferation, migration, enhance apoptosis and arrest cell cycle. The in vivo study verified the inhibitory effects of CALCR knockdown on NSCLC tumorigenesis. The abovementioned results provided a reference for the treatment of NSCLC, that was, CALCR knockdown might be a considerable therapeutic strategy.

scholarly journals MiR-106b-5p Promotes Proliferation and Inhibits Apoptosis by Regulating BTG3 in Non-Small Cell Lung Cancer

2017 ◽  
Vol 44 (4) ◽  
pp. 1545-1558 ◽  
Author(s):  
Ke Wei ◽  
Chunfeng Pan ◽  
Guoliang Yao ◽  
Bin Liu ◽  
Teng Ma ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Luciferase Assay ◽  
Small Cell Lung

Background/Aims: MicroRNAs have been validated to play a crucial role in tumorigenesis of non-small cell lung cancer (NSCLC). Although miR-106b-5p has been reported to play a vital role in various malignancies the physiological function of miR-106b-5p in NSCLC still remain unknown. In this study, we investigated the role of miR-106b-5p in NSCLC. Methods: Quantitative real-time polymerase chain reaction was conducted to estimate the expression of miR-106b-5p and BTG3 in both NSCLC tissues and cell lines. The effects of miR-106b-5p on proliferation were determined in vitro using CCK-8 proliferation assays, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, colony formation assays and cell-cycle assays and the in vivo effects were evaluated by a mouse tumorigenicity model. Cell apoptosis and cell cycle was investigated by flow cytometric analysis in vitro. The molecular mechanism underlying the relevance between miR-106b-5p and BTG3 was confirmed by luciferase assay and western blot. Results: In current study, we found a relatively higher miR-106b-5p and lower BTG3 expression in NSCLC specimens and cell lines. BTG3 was verified as a direct target of miR-106b-5p by luciferase assay. In vitro, over-expression of miR-106b-5p promoted proliferation and inhibited apoptosis by down-regulating BTG3 expression. In vivo, miR-106b-5p promoted xenograft tumor formation. Conclusion: Our findings revealed for the first time that miR-106b-5p plays a tumorigenesis role in NSCLC progression by down-regulating BTG3 expression, which may lead to a novel insight to the potential biomarker and novel therapeutic strategies for NSCLC patients.

scholarly journals miR-147a suppresses the metastasis of non-small-cell lung cancer by targeting CCL5

2019 ◽  
Vol 48 (4) ◽  
pp. 030006051988309 ◽  
Author(s):  
Yan Lu ◽  
Xiao Rong Luan
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Xenograft Model ◽  
Small Cell ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Small Cell Lung ◽  
Mouse Xenograft Model

Objective MicroRNA (miR)-147a acts as an inhibitory miRNA in many cancers. However, its potential roles in non-small-cell lung cancer (NSCLC) remain unclear. Methods Levels of miR-147a and C-C motif chemokine ligand 5 (CCL5) were measured using a quantitative real-time PCR assay. Cell growth, migration, and invasion of NSCLC cells were assessed by colony formation, wound healing, and Transwell invasion assays, respectively. The role of miR-147a in the growth and metastatic ability of NSCLC in vivo was detected using a xenograft model and experimental lung metastasis model. Results miR-147a was downregulated in NSCLC cell lines as well as in tissues. Gain-of-function and loss-of-function analyses demonstrated that upregulation of miR-147a decreased the aggressiveness of NSCLC cells in vitro. In addition, CCL5 was identified as a target of miR-147a. We also demonstrated the effect of miR-147a in the progression of NSCLC cells via targeting CCL5. Finally, the in vivo mouse xenograft model showed that miR-147a inhibited progression of NSCLC cells. Conclusions Overall, expression of miR-147a was downregulated in NSCLC. Importantly, upregulation of miR-147a suppressed the growth and metastasis of NSCLC cells in vivo by targeting CCL5.

scholarly journals Human Antigen D (HuD) Promotes Tumorigenesis And Invasion of Small Cell Lung Cancer Via Targeting lncRNA LYPLAL1-DT /miR-204-5P/Profilin 2 Axis

2021 ◽  
Author(s):  
Shuxin Li ◽  
Jianyi Lv ◽  
Xing Zhang ◽  
Zhihui Li ◽  
Xueyun Huo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Rna Binding ◽  
Xenograft Model ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Small Cell Lung

Abstract Background: Small cell lung cancer (SCLC) is one of the most malignant tumors with poor prognosis. RNA-binding protein (RBP) human antigen D (HuD) has been indicated in the process of tumorigenesis and progression of lung tumors, as well as long noncoding RNAs (lncRNA). However, the role of HuD and lncRNA in SCLC remains unknown. Methods: Realtime PCR were used to examine the circulating levels of LYPLAL1-DT in the 46 SCLC patients and 18 normal controls. Assays of dual- luciferase reporter system, RNA pull-down were performed to determine that LYPLAL1-DT could sponge miR-204-5p to upregulate the expression of PFN2. Migration and invasion assay, CCK8 and colony formation assay were used to detect the malignant effect of HuD and LYPLAL1-DT. Tumor xenograft model was established and IHC assay was performed to determine how HuD and LAPLAL1-DT impact in vivo. Results: We revealed that HuD was highly expressed in SCLC tissues and cell lines. HuD boosts the proliferation, migration, invasion of SCLC cells by increasing the PFN2 mRNA stability, which promotes cytoskeleton formation. HuD also enhanced the stability of lncRNA LYPLAL1-DT, which expressed highly in the serum of patients with SCLC and acted as an oncogenic lncRNA in SCLC cells as confirmed in vitro and in vivo. Mechanistically, LYPLAL1-DT functioned as a competing endogenous RNA (ceRNA) for sponging miR-204-5p, leading to the upregulation of its target PFN2 to promote SCLC cell proliferation and invasion. In summary, our data reveal a regulatory pathway in which HuD stabilizes PFN2 mRNA and LYPLAL1-DT, which in turn increases PFN2 expression by binding to miR-204-5p, and ultimately promotes tumorigenesis and invasion in SCLC.Conclusions: Our findings reveal novel regulatory axes involving HuD/PFN2 and lncRNA LYPLAL1-DT/miR-204-5p/PFN2 in the development and progression of small cell lung cancer (SCLC), providing novel prognostic indicators and promising therapeutic targets.

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