Lysocardiolipin acyltransferase regulates NSCLC cell proliferation and migration by modulating mitochondrial dynamics

Lysocardiolipin acyltransferase (LYCAT), a cardiolipin (CL)-remodeling enzyme, is crucial for maintaining normal mitochondrial function and vascular development. Despite the well-characterized role for LYCAT in the regulation of mitochondrial dynamics, its involvement in lung cancer, if any, remains incompletely understood. In this study, in silico analysis of TCGA lung cancer data sets revealed a significant increase in LYCAT expression, which was later corroborated in human lung cancer tissues and immortalized lung cancer cell lines via indirect immunofluorescence and immunoblotting, respectively. Stable knockdown of LYCAT in NSCLC cell lines not only reduced CL and increased monolyso-CL levels but also reduced in vivo tumor growth, as determined by xenograft studies in athymic nude mice. Furthermore, blocking LYCAT activity using a LYCAT mimetic peptide attenuated cell migration, suggesting a novel role for LYCAT activity in promoting NSCLC. Mechanistically, the pro-proliferative effects of LYCAT were mediated by an increase in mitochondrial fusion and a G1/S cell cycle transition, both of which are linked to increased cell proliferation. Taken together, these results demonstrate a novel role for LYCAT in promoting NSCLC and suggest that targeting LYCAT expression or activity in NSCLC may provide new avenues for the therapeutic treatment of lung cancer.

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Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines

Toxicology in Vitro ◽

10.1016/j.tiv.2011.04.014 ◽

2011 ◽

Vol 25 (7) ◽

pp. 1274-1280 ◽

Cited By ~ 52

Author(s):

Chun-Yin Huang ◽

Chia-Yu Lin ◽

Chia-Wen Tsai ◽

Mei-Chin Yin

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Lines ◽

Ursolic Acid ◽

Cancer Cell ◽

Human Lung ◽

Human Lung Cancer ◽

Lung Cancer Cell ◽

Invasion And Migration ◽

And Migration

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ID: 130: NOVEL ROLE FOR LYSOCARDIOLIPIN ACYLTRANSFERASE (LYCAT) IN NON-SMALL CELL LUNG CANCER

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.125 ◽

2016 ◽

Vol 64 (4) ◽

pp. 971.1-971 ◽

Cited By ~ 1

Author(s):

MM Van Scoyk ◽

S Avasarala ◽

RA Winn ◽

R Bikkavilli ◽

V Natarajan ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Epithelial Cell ◽

Cell Lines ◽

Mitochondrial Dynamics ◽

Small Cell ◽

Nsclc Cell ◽

Small Cell Lung ◽

Epithelial Cell Lines

Lung cancer is the leading cause of deaths in United States and non-small cell lung cancer (NSCLC) accounts for ∼85% of all lung cancers with a 5-year survival rate of approximately ∼16%. Therefore there is an immediate need to develop new strategies for early detection and more effective treatments options. Mitochondrial dysfunction including but not limited to defects in mitochondrial genomics and dynamics has long been implicated to play a role in human health and disease particularly in cancer initiation, progression and treatment options since it plays a pivotal role in cell death and survival. Lysocardiolipin acyltransferase (LYCAT), a Cardiolipin remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, plays a crucial role in maintaining normal mitochondrial function and vascular development. LYCAT was shown to be up-regulated in cancers; however, the role of LYCAT in lung cancer is yet unclear. Probing the protein expression of LYCAT in lung cancer specimens, non-transformed bronchial epithelial cell lines and 5 lung cancer cell lines revealed increased LYCAT expression and activity in all the lung cancer samples and cell lines tested in comparison to the control lung tissues and non-transformed epithelial cell lines. To determine the role of LYCAT in lung cancer, NSCLC cell lines H2122 and H23 were transfected with either scrambled or LYCAT shRNA and differences in serum-induced cell proliferation, migration, clonogenecity and mitochondrial dynamics were determined. Our results demonstrated that down-regulation of LYCAT by shRNA significantly attenuated cell migration, proliferation, and invasion in NSCLC cell lines compared to control cell lines. Furthermore knockdown of LYCAT expression in NSCLC cell lines inhibited mitochondrial fragmentation and enhanced mitochondrial fusion. Taken together, these data demonstrate a strong association between increased LYCAT expression and cell proliferation, motility, invasion and mitochondrial dynamics in NSCLC cells. Thus, development of targeted therapies to reduce LYCAT expression in NSCLC should be beneficial. This work in part was supported by funds from the College of Medicine, UIC and NIH HL98050 to VN.

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Knockdown CYP2S1 inhibits lung cancer cells proliferation and migration

Cancer Biomarkers ◽

10.3233/cbm-210189 ◽

2021 ◽

pp. 1-9

Author(s):

Huan Guo ◽

Baozhen Zeng ◽

Liqiong Wang ◽

Chunlei Ge ◽

Xianglin Zuo ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Lung Cancer Cells ◽

Invasion And Migration ◽

And Migration

BACKGROUND: The incidence of lung cancer in Yunnan area ranks firstly in the world and underlying molecular mechanisms of lung cancer in Yunnan region are still unclear. We screened a novel potential oncogene CYP2S1 used mRNA microassay and bioinformation database. The function of CYP2S1 in lung cancer has not been reported. OBJECTIVE: To investigate the functions of CYP2S1 in lung cancer. METHODS: Immunohistochemistry and Real-time PCR were used to verify the expression of CYP2S1. Colony formation and Transwell assays were used to determine cell proliferation, invasion and migration. Xenograft assays were used to detected cell growth in vivo. RESULTS: CYP2S1 is significantly up-regulated in lung cancer tissues and cells. Knockdown CYP2S1 in lung cancer cells resulted in decrease cell proliferation, invasion and migration in vitro. Animal experiments showed downregulation of CYP2S1 inhibited lung cancer cell growth in vivo. GSEA analysis suggested that CYP2S1 played functions by regulating E2F targets and G2M checkpoint pathway which involved in cell cycle. Kaplan-Meier analysis indicated that patients with high CYP2S1 had markedly shorter event overall survival (OS) time. CONCLUSIONS: Our data demonstrate that CYP2S1 exerts tumor suppressor function in lung cancer. The high expression of CYP2S1 is an unfavorable prognostic marker for patient survival.

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Nicotine promotes the development of non-small cell lung cancer through activating LINC00460 and PI3K/Akt signaling

Bioscience Reports ◽

10.1042/bsr20182443 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 1

Author(s):

Hongying Zhao ◽

Yu Wang ◽

Xiubao Ren

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Lines ◽

Akt Signaling ◽

Small Cell ◽

Nsclc Cell ◽

Expression Level ◽

In Vitro Experiments ◽

Small Cell Lung

Abstract Objective: Nicotine, the main ingredient in tobacco, is identified to facilitate tumorigenesis and accelerate metastasis in tumor. Studies in recent years have reported that long intergenic non-protein coding RNA 460 (LINC00460) is strongly associated with lung cancer poor prognosis and nicotine dependence. Nonetheless, it is unclear whether nicotine promotes the development of lung cancer through activation of LINC00460. Methods: We determined that LINC00460 expression in lung cancer tissues and the prognosis in patients with non-small cell lung carcinoma (NSCLC) using Gene Expression Profiling Interactive Analysis (GEPIA) website and The Cancer Genome Atlas (TCGA) database. Through in vitro experiments, we studied the effects of nicotine on LINC00460 in NSCLC cells lines using Cell Counting Kit-8 (CCK-8), transwell test, flow cytometry, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot assays. Results: We identified the significant up-regulated expression level of LINC00460 in NSCLC tissues and cell lines, especially, the negative correlation of LINC00460 expression level with overall survival (OS). In in vitro experiments, LINC00460 was overexpressed in NSCLC cell lines under nicotine stimulation. Nicotine could relieve the effect of LINC00460 knockdown on NSCLC cell proliferation, migration and apoptosis. The same influence was observed on PI3K/Akt signaling pathway. Conclusions: In summary, this is the first time to examine the potential roles of LINC00460 in lung cancer cell proliferation, migration and apoptosis induced by nicotine. This may help to develop novel therapeutic strategies for the prevention and treatment of metastatic tumors from cigarette smoke-caused lung cancer by blocking the nicotine-activated LINC00460 pathway.

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Circular RNA circPVT1 Promotes Proliferation and Invasion Through Sponging miR-125b and Activating E2F2 Signaling in Non-Small Cell Lung Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000495876 ◽

2018 ◽

Vol 51 (5) ◽

pp. 2324-2340 ◽

Cited By ~ 39

Author(s):

Xiuyuan Li ◽

Zenglei Zhang ◽

Hua Jiang ◽

Qiang Li ◽

Ruliang Wang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Promoter Region ◽

Small Cell ◽

Nsclc Cell ◽

Small Cell Lung ◽

Proliferation And Invasion

Background/Aims: Circular RNAs (circRNAs) are key regulators in the development and progression of human cancers, however its role in non-small cell lung cancer (NSCLC) tumorigenesis is not well understood. The aim of this study is to identify the expression level of circPVT1 in NSCLC and further investigated its functional relevance with NSCLC progression both in vitro and in vivo. Methods: Quantative real-time PCR was used for the measurement of circPVT1 in NSCLC specimens and cell lines. Fluorescence in situ hybridization analysis (FISH) assay was used for the identification of sublocation of circPVT1 in NSCLC cells. Bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to verify the binding of c-Fos at circPVT1 promoter region, and the direct interaction between circPVT1 and miR-125b. Gain- or loss-function assays were performed to evaluate the effects of circPVT1 on cell proliferation and invasion. Western blot and immunohistochemistry assays were performed to detect the protein levels involved in E2F2 pathway. Results: We found that circPVT1 was upregulated in NSCLC specimens and cells. The transcription factor c-Fos binded to the promoter region of circPVT1, resulting in the overexpression of circPVT1 in NSCLC. Knockdown of circPVT1 suppressed NSCLC cell proliferation, migration and invasion, and increased apoptosis. In addition, circPVT1 mediated NSCLC progression via the regulation of E2F2 signaling pathway. More importantly, circPVT1 was predominantly abundant in the cytoplasm of NSCLC cells, and circPVT1 could serve as a competing endogenous RNA to regulate E2F2 expression and tumorigenesis in a miR-125b-dependent manner, which is further verified by using an in vivo xenograft model. Conclusion: circPVT1 promotes NSCLC cell growth and invasion, and may serve as a promising therapeutic target for NSCLC patients. Therefore, silence of circPVT1 could be a future direction to develop a novel treatment strategy.

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Knockdown of LncRNA LINC00958 Inhibits the Proliferation and Migration of NSCLC Cells by MiR-204-3p/KIF2A Axis

Cell Transplantation ◽

10.1177/09636897211025500 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110255

Author(s):

Qing Wang ◽

Kai Li ◽

Xiaoliang Li

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Tumor Model ◽

Luciferase Reporter ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence suggests that long non-coding RNAs (lncRNAs) function in the tumorigenesis of NSCLC. LINC00958, a newly identified lncRNA, has been reported to be closely linked to tumorigenesis in several cancers. However, its specific role in NSCLC remains unclear. In this study, we determined the expression of LINC00958 in NSCLC by RT-qPCR analysis and evaluated cell proliferation and migration by CCK-8 and transwell assays, respectively. We established a xenograft tumor model to examine the effect of LINC00958 on tumor growth in vivo. Luciferase reporter assays were performed to determine the interaction between LINC00958 and miR-204-3p and the interaction between miR-204-3p and KIF2A. We found that LINC00958 was up-regulated in NSCLC tissues and cell lines. Down-regulation of LINC00958 inhibited cell proliferation and migration in vitro and suppressed tumor growth in vivo. Besides, miR-204-3p was identified as a target of LINC00958 and miR-204-3p inhibitor could reverse the inhibitory effect of LINC00958 knockdown on proliferation and migration of NSCLC cells. We also validated that KIF2A, a direct target of miR-204-3p, was responsible for the biological role of LINC00958. KIF2A antagonized the effect of miR-204-3p on NSCLC cell proliferation and migration and was regulated by LINC00958/miR-204-3p. Taken together, these data indicate that the LINC00958/miR-204-3p/KIF2A axis is critical for NSCLC progression, which might provide a potential therapeutic target of NSCLC.

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Protein tyrosine kinase 2: a novel therapeutic target to overcome acquired EGFR-TKI resistance in non-small cell lung cancer

Respiratory Research ◽

10.1186/s12931-019-1244-2 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Xuexia Tong ◽

Ryosuke Tanino ◽

Rong Sun ◽

Yukari Tsubata ◽

Tamio Okimoto ◽

...

Keyword(s):

Lung Cancer ◽

Cell Lines ◽

Protein Tyrosine Kinase ◽

Nsclc Cell ◽

Tyrosine Kinase 2 ◽

Tki Resistance ◽

Egfr Mutant ◽

Egfr Tki ◽

Protein Tyrosine Kinase 2

Abstract Background Protein tyrosine kinase 2 (PTK2) expression has been reported in various types of human epithelial cancers including lung cancer; however, the role of PTK2 in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has not been elucidated. We previously reported that pemetrexed-resistant NSCLC cell line PC-9/PEM also acquired EGFR-TKI resistance with constitutive Akt activation, but we could not find a therapeutic target. Methods Cell viability in EGFR-mutant NSCLC cell lines was measured by the WST-8 assay. Phosphorylation antibody array assay for receptor tyrosine kinases was performed in PC-9 and PC-9/PEM cell lines. We evaluated the efficacy of EGFR and PTK2 co-inhibition in EGFR-TKI-resistant NSCLC in vitro. Oral defactinib and osimertinib were administered in mice bearing subcutaneous xenografts to evaluate the efficacy of the treatment combination in vivo. Both the PTK2 phosphorylation and the treatment combination efficacy were evaluated in erlotinib-resistant EGFR-mutant NSCLC cell lines. Results PTK2 was hyperphosphorylated in PC-9/PEM. Defactinib (PTK2 inhibitor) and PD173074 (FGFR inhibitor) inhibited PTK2 phosphorylation. Combination of PTK2 inhibitor and EGFR-TKI inhibited Akt and induced apoptosis in PC-9/PEM. The combination treatment showed improved in vivo therapeutic efficacy compared to the single-agent treatments. Furthermore, erlotinib-resistant NSCLC cell lines showed PTK2 hyperphosphorylation. PTK2 inhibition in the PTK2 hyperphosphorylated erlotinib-resistant cell lines also recovered EGFR-TKI sensitivity. Conclusion PTK2 hyperphosphorylation occurs in various EGFR-TKI-resistant NSCLCs. Combination of PTK2 inhibitor and EGFR-TKI (defactinib and osimertinib) recovered EGFR-TKI sensitivity in the EGFR-TKI-resistant NSCLC. Our study result suggests that this combination therapy may be a viable option to overcome EGFR-TKI resistance in NSCLC.

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Long noncoding RNA HOXA-AS2 promotes non-small cell lung cancer progression by regulating miR-520a-3p

Bioscience Reports ◽

10.1042/bsr20190283 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 3

Author(s):

Yunpeng Liu ◽

Xingyu Lin ◽

Shiyao Zhou ◽

Peng Zhang ◽

Guoguang Shao ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Small Cell Lung

Abstract Background: The HOXA cluster antisense RNA 2 (HOXA-AS2) has recently been discovered to be involved in carcinogenesis in multiple cancers. However, the role and underlying mechanism of HOXA-AS2 in non-small cell lung cancer (NSCLC) yet need to be unraveled. Methods: HOXA-AS2 expression in NSCLC tissues and cell lines was detected using quantitative real-time PCR (qRT-PCR). Furthermore, the effects of HOXA-AS2 on NSCLC cell proliferation, apoptosis, migration, and invasion were assessed by MTS, flow cytometry, wound healing and transwell invasion assays, respectively. Starbase2.0 predicted and luciferase reporter and RNA immunoprecipitation (RIP) assays were used to validate the association of HOXA-AS2 and miR-520a-3p in NSCLC cells. Results: Our results revealed that HOXA-AS2 in NSCLC tissues were up-regulated and cell lines, and were associated with poor prognosis and overall survival. Further functional assays demonstrated that HOXA-AS2 knockdown significantly inhibited NSCLC cell proliferation, induced cell apoptosis and suppressed migration and invasion. Starbase2.0 predicted that HOXA-AS2 sponge miR-520a-3p at 3′-UTR, which was confirmed using luciferase reporter and RIP assays. miR-520a-3p expression was inversely correlated with HOXA-AS2 expression in NSCLC tissues. In addition, miR-520a-3p inhibitor attenuated the inhibitory effect of HOXD-AS2-depletion on cell proliferation, migration and invasion of NSCLC cells. Moreover, HOXA-AS2 could regulate HOXD8 and MAP3K2 expression, two known targets of miR-520a-3p in NSCLC. Conclusion: These findings implied that HOXA-AS2 promoted NSCLC progression by regulating miR-520a-3p, suggesting that HOXA-AS2 could serve as a therapeutic target for NSCLC.

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