Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells

The robust proliferation of cancer cells requires vastly elevated levels of protein synthesis, which relies on a steady supply of aminoacylated tRNAs. Delivery of tRNAs to the cytoplasm is a highly regulated process, but the machinery for tRNA nuclear export is not fully elucidated. In this study, using a live cell imaging strategy that visualizes nascent transcripts from a specific tRNA gene in yeast, we identified the nuclear basket proteins Mlp1 and Mlp2, two homologs of the human TPR protein, as regulators of tRNA export. TPR expression is significantly increased in lung cancer tissues and correlated with poor prognosis. Consistently, knockdown of TPR inhibits tRNA nuclear export, protein synthesis and cell growth in lung cancer cell lines. We further show that NXF1, a well-known mRNA nuclear export factor, associates with tRNAs and mediates their transport through nuclear pores. Collectively, our findings uncover a conserved mechanism that regulates nuclear export of tRNAs, which is a limiting step in protein synthesis in eukaryotes.

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Long noncoding RNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 to predict poor prognosis in lung cancer patients

10.21203/rs.2.16166/v2 ◽

2020 ◽

Author(s):

Haihua Tian ◽

Jinchang Pan ◽

Shuai Fang ◽

Chengwei Zhou ◽

Hui Tian ◽

...

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Western Blot ◽

Cancer Cells ◽

Cancer Patients ◽

Colony Formation ◽

Poor Prognosis ◽

Lung Cancer Cell ◽

Lung Cancer Patients ◽

Cancer Tissues

Abstract Background: Long noncoding RNAs (lncRNAs) play oncogenic or tumor-suppressive roles in various cancers. However, the epigenetic modification of lncRNA and its cognate sense gene in lung cancer remain largely unknown.Methods: qRT-PCR and Western blot were conducted to detect the expressions of DDP10-AS1 and DPP10 expression in lung cancer cell lines and tissues. The impact of DDP10-AS1 on DPP10 expression, cell growth, invasion, apoptosis and in vivo tumor growth were investigated in lung cancer cells by Western blot, rescue experiments, colony formation, flow cytometry and xenograft animal experiment. Results: A novel antisense lncRNA, DPP10-AS1, is found to be highly expressed in cancer tissues and the upregulation of DPP10-AS1 predicts poor prognosis in lung cancer patients. Notably, DPP10-AS1 promotes lung cancer cell growth, colony formation, cell cycle progression and represses apoptosis in lung cancer cells by upregulating DPP10 expression. Additionally, DPP10-AS1 facilitates lung tumor growth via upregulation of DPP10 protein in xenograft mouse model. Importantly, DPP10-AS1 positively regulates DPP10 gene expression and they are coordinately upregulated in lung cancer tissues. Mechanically, DPP10-AS1 associates with DPP10 mRNA but does not enhance DPP10 mRNA stability. Hypomethylation of DPP10-AS1 and DPP10 contributes to their coordinate upregulation in lung cancer.Conclusions: These findings indicate that the upregulated antisense lncRNA DPP10-AS1 promotes lung cancer malignant processes and facilitates tumorigenesis by epigenetically regulating its cognate sense gene DPP10, and DPP10-AS1 may act as a candidate prognostic biomarker and a potential therapeutic target in lung cancer.

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Long noncoding RNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 to predict poor prognosis in lung cancer patients

10.21203/rs.2.16166/v1 ◽

2019 ◽

Author(s):

Haihua Tian ◽

Jinchang Pan ◽

Shuai Fang ◽

Chengwei Zhou ◽

Hui Tian ◽

...

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Western Blot ◽

Cancer Cells ◽

Cancer Patients ◽

Colony Formation ◽

Poor Prognosis ◽

Lung Cancer Cell ◽

Lung Cancer Patients ◽

Cancer Tissues

Abstract Background Long noncoding RNAs (lncRNAs) play oncogenic or tumor-suppressive roles in various cancers. However, the epigenetic modification of lncRNA and its cognate sense gene in lung cancer remain largely unknown.Methods : qRT-PCR and Western blot were conducted to detect the expressions of DDP10-AS1 and DPP10 expression in lung cancer cell lines and tissues. The impact of DDP10-AS1 on DPP10 expression, cell growth, invasion, apoptosis and in vivo tumor growth were investigated in lung cancer cells by Western blot, rescue experiments, colony formation, flow cytometry and xenograft animal experiment.Results A novel antisense lncRNA, DPP10-AS1, is found to be highly expressed in cancer tissues and the upregulation of DPP10-AS1 predicts poor prognosis in lung cancer patients. Notably, DPP10-AS1 promotes lung cancer cell growth, colony formation, cell cycle progression and represses apoptosis in lung cancer cells by upregulating DPP10 expression. Additionally, DPP10-AS1 facilitates lung tumor growth via upregulation of DPP10 protein in xenograft mouse model. Importantly, DPP10-AS1 positively regulates DPP10 gene expression and they are coordinately upregulated in lung cancer tissues. Mechanically, DPP10-AS1 associates with DPP10 mRNA but does not enhance DPP10 mRNA stability. Hypomethylation of DPP10-AS1 and DPP10 contributes to their coordinate upregulation in lung cancer.Conclusions These findings indicate that the upregulated antisense lncRNA DPP10-AS1 promotes lung cancer malignant processes and facilitates tumorigenesis by epigenetically regulating its cognate sense gene DPP10, and DPP10-AS1 may act as a candidate prognostic biomarker and a potential therapeutic target in lung cancer.

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Inhibitory effect of microRNA-608 on lung cancer cell proliferation, migration, and invasion by targeting BRD4 through the JAK2/STAT3 pathway

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2019.4216 ◽

2019 ◽

Cited By ~ 3

Author(s):

Weigang Xu ◽

Dapeng Sun ◽

Yanqin Wang ◽

Xinlin Zheng ◽

Yan Li ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Migration And Invasion ◽

Cancer Cell Proliferation ◽

Lung Cancer Cell ◽

Stat3 Pathway ◽

Normal Tissues ◽

Cancer Tissues

Lung cancer is the leading cause of cancer-related mortality around the world. This malignancy has a 5-year survival rate of 21%, because most of the patients are diagnosed in the middle or late stage of the disease when local metastasis and tumor invasion have already progressed. Therefore, the investigation of the pathogenesis of lung cancer is an issue of crucial importance. MicroRNAs (miRNAs) seem to be involved in the evolution and development of lung cancer. MicroRNA-608 is likely to be downregulated in lung cancer tissues. Regarding this, the current study involved the determination of the fundamental mechanism of microRNA-608 in the development of lung cancer. Based on the results of quantitative reverse transcription polymerase chain reaction (RT-qPCR), the expression level of microRNA-608 was downregulated in 40 lung cancer tissues, compared to that in the adjacent normal tissues. The results of dual-luciferase reporter assay revealed that bromodomain-containing protein 4 (BRD4) was the direct target of microRNA-608. Accordingly, the lung cancer tissues had an elevated expression level of BRD4, in contrast to the adjacent normal tissues. The results of Cell Counting Kit 8 assay demonstrated that the high expression of microRNA-608 notably restrained lung cancer cell proliferation. The scratch wound and transwell assays showed that the upregulation of microRNA-608 suppressed the migration and invasion of lung cancer cells. Finally, the western blot assay showed that in the microRNA-608 mimics group, the expression levels of BRD4, p-JAK2, p-STATA3, CD44, and MMP9 were significantly decreased, compared with those in the negative control miRNA mimics group. Our results indicate that high expression of microRNA-608 inhibits the proliferation, migration, and invasion of lung cancer cells by targeting BRD4 via the JAK2/STAT3 pathway.

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Sevoflurane inhibits proliferation, invasion, but enhances apoptosis of lung cancer cells by Wnt/β-catenin signaling via regulating lncRNA PCAT6/ miR-326 axis

Open Life Sciences ◽

10.1515/biol-2020-0017 ◽

2020 ◽

Vol 15 (1) ◽

pp. 159-172

Author(s):

Guoning Su ◽

Zhibing Yan ◽

Min Deng

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Volatile Anesthetic ◽

Lung Cancer Cells ◽

Luciferase Reporter ◽

Dependent Manner ◽

Luciferase Reporter Gene ◽

Western Blot Assay ◽

Gene Assay ◽

Cancer Tissues

AbstractSevoflurane was frequently used as a volatile anesthetic in cancer surgery. However, the potential mechanism of sevoflurane on lung cancer remains largely unclear. In this study, lung cancer cell lines (H446 and H1975) were treated by various concentrations of sevoflurane. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assessment and colony formation assay were performed to detect the cell viability and proliferation, separately. Also, transwell assay or flow cytometry assay was applied as well to evaluate the invasive ability or apoptosis in lung cancer cells, respectively. Western blot assay was employed to detect the protein levels of β-catenin and Wnt5a. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the expression level of prostate cancer-associated transcript 6 (PCAT6) and miR-326 in lung cancer tissues and cells. The target interaction between miR-326 and PCAT6 or Wnt5a was predicted by bioinformatics analysis and verified by the dual-luciferase reporter gene assay. Sevoflurane inhibited the abilities on viability, proliferation, invasion, and activation of Wnt/β-catenin signaling, but promoted apoptosis of H446 and H1975 cells in a dose-dependent manner. The expression of PCAT6 was increased in lung cancer tissues and cells, except for that of miR-326. Besides, sevoflurane could lead to expressed limitation of PCAT6 or improvement of miR-326. This process presented a stepwise manner. Up-regulation of PCAT6 restored the suppression of sevoflurane on abilities of proliferation, invasion, rather than apoptosis, and re-activated the Wnt5a/β-catenin signaling in cells. Moreover, the putative binding sites between miR-326 and PCTA6 or Wnt5a were predicted by starBase v2.0 software online. PCAT6 suppressing effects on cells could be reversed by pre-treatment with miR-326 vector. The promotion of Wnt5a inverted effects led from miR-326 or sevoflurane. Our study indicated that sevoflurane inhibited the proliferation, and invasion, but enhanced the apoptosis in lung cancer cells by regulating the lncRNA PCAT6/miR-326/Wnt5a/β-catenin axis.

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Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

Antioxidants ◽

10.3390/antiox10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Kristell Le Gal ◽

Clotilde Wiel ◽

Mohamed X. Ibrahim ◽

Marcus Henricsson ◽

Volkan I. Sayin ◽

...

Keyword(s):

Lung Cancer ◽

Malignant Melanoma ◽

Cancer Cells ◽

Cancer Progression ◽

Nuclear Dna ◽

Human Melanoma ◽

Oxygen Species ◽

Lung Cancer Cell ◽

Primary Tumors ◽

Anti Cancer

Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.

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POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01476-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ronggang Luo ◽

Yi Zhuo ◽

Quan Du ◽

Rendong Xiao

Keyword(s):

Lung Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Progression ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Cancer Tissues

Abstract Background To detect and investigate the expression of POU domain class 2 transcription factor 2 (POU2F2) in human lung cancer tissues, its role in lung cancer progression, and the potential mechanisms. Methods Immunohistochemical (IHC) assays were conducted to assess the expression of POU2F2 in human lung cancer tissues. Immunoblot assays were performed to assess the expression levels of POU2F2 in human lung cancer tissues and cell lines. CCK-8, colony formation, and transwell-migration/invasion assays were conducted to detect the effects of POU2F2 and AGO1 on the proliferaion and motility of A549 and H1299 cells in vitro. CHIP and luciferase assays were performed for the mechanism study. A tumor xenotransplantation model was used to detect the effects of POU2F2 on tumor growth in vivo. Results We found POU2F2 was highly expressed in human lung cancer tissues and cell lines, and associated with the lung cancer patients’ prognosis and clinical features. POU2F2 promoted the proliferation, and motility of lung cancer cells via targeting AGO1 in vitro. Additionally, POU2F2 promoted tumor growth of lung cancer cells via AGO1 in vivo. Conclusion We found POU2F2 was highly expressed in lung cancer cells and confirmed the involvement of POU2F2 in lung cancer progression, and thought POU2F2 could act as a potential therapeutic target for lung cancer.

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Magnetic tri-bead microrobot assisted near-infrared triggered combined photothermal and chemotherapy of cancer cells

Scientific Reports ◽

10.1038/s41598-021-87010-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaoxia Song ◽

Zhi Chen ◽

Xue Zhang ◽

Junfeng Xiong ◽

Teng Jiang ◽

...

Keyword(s):

Lung Cancer ◽

Drug Delivery ◽

Cancer Cells ◽

Photothermal Therapy ◽

Near Infrared ◽

Stimuli Responsive ◽

Lung Cancer Cell ◽

Precise Movement ◽

Photothermal Property

AbstractMagnetic micro/nanorobots attracted much attention in biomedical fields because of their precise movement, manipulation, and targeting abilities. However, there is a lack of research on intelligent micro/nanorobots with stimuli-responsive drug delivery mechanisms for cancer therapy. To address this issue, we developed a type of strong covalently bound tri-bead drug delivery microrobots with NIR photothermal response azobenzene molecules attached to their carboxylic surface groups. The tri-bead microrobots are magnetic and showed good cytocompatibility even when their concentration is up to 200 µg/mL. In vitro photothermal experiments demonstrated fast NIR-responsive photothermal property; the microrobots were heated to 50 °C in 4 min, which triggered a significant increase in drug release. Motion control of the microrobots inside a microchannel demonstrated the feasibility of targeted therapy on tumor cells. Finally, experiments with lung cancer cells demonstrated the effectiveness of targeted chemo-photothermal therapy and were validated by cell viability assays. These results indicated that tri-bead microrobots have excellent potential for targeted chemo-photothermal therapy for lung cancer cell treatment.

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Quiescin Sulfhydryl Oxidase 1 (QSOX1) Secreted by Lung Cancer Cells Promotes Cancer Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms19103213 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3213 ◽

Cited By ~ 5

Author(s):

Hye-Jin Sung ◽

Jung-Mo Ahn ◽

Yeon-Hee Yoon ◽

Sang-Su Na ◽

Young-Jin Choi ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Sulfhydryl Oxidase ◽

Lung Cancers ◽

Normal Tissues ◽

Cancer Tissues ◽

Quiescin Sulfhydryl Oxidase

As lung cancer shows the highest mortality in cancer-related death, serum biomarkers are demanded for lung cancer diagnosis and its treatment. To discover lung cancer protein biomarkers, secreted proteins from primary cultured lung cancer and adjacent normal tissues from patients were subjected to LC/MS–MS proteomic analysis. Quiescin sulfhydryl oxidase (QSOX1) was selected as a biomarker candidate from the enriched proteins in the secretion of lung cancer cells. QSOX1 levels were higher in 82% (51 of 62 tissues) of lung cancer tissues compared to adjacent normal tissues. Importantly, QSOX1 serum levels were significantly higher in cancer patients (p < 0.05, Area Under curve (AUC) = 0.89) when measured by multiple reaction monitoring (MRM). Higher levels of QSOX1 were also uniquely detected in lung cancer tissues, among several other solid cancers, by immunohistochemistry. QSOX1-knock-downed Lewis lung cancer (LLC) cells were less viable from oxidative stress and reduced migration and invasion. In addition, LLC mouse models with QSOX1 knock-down also proved that QSOX1 functions in promoting cancer metastasis. In conclusion, QSOX1 might be a lung cancer tissue-derived biomarker and be involved in the promotion of lung cancers, and thus can be a therapeutic target for lung cancers.

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WRN modulates translation by influencing mRNA export from the nucleus through its interaction with the export receptor NXF1 in HeLa cancer cell

10.21203/rs.3.rs-33612/v2 ◽

2020 ◽

Author(s):

Juan Manuel Iglesias-Pedraz ◽

Diego Matia Fossatti Jara ◽

Valeria Del Carmen Valle-Riestra Felice ◽

Sergio Rafael Cruz Visalaya ◽

Jose Antonio Ayala Felix ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Synthesis ◽

Cancer Cells ◽

Nuclear Export ◽

Werner Syndrome ◽

Mrna Export ◽

Premature Aging ◽

Metabolic Shift ◽

Loss Of Function ◽

Global Protein Synthesis

Abstract Background The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.Results To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN directly interacts with mRNA and the mRNA export receptor Nuclear Export Factor 1 (NXF1).Conclusions Our findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

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Persistent effects of pair bonding in lung cancer cell growth in monogamous Peromyscus californicus

eLife ◽

10.7554/elife.64711 ◽

2021 ◽

Vol 10 ◽

Author(s):

Asieh Naderi ◽

Elham Soltanmaohammadi ◽

Vimala Kaza ◽

Shayne Barlow ◽

Ioulia Chatzistamou ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Nude Mice ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Lung Cancer Cell ◽

Peromyscus Californicus ◽

Pair Bonds ◽

The Impact

Epidemiological evidence suggests that social interactions and especially bonding between couples influence tumorigenesis, yet whether this is due to lifestyle changes, homogamy (likelihood of individuals to marry people of similar health), or directly associated with host-induced effects in tumors remains debatable. In the present study, we explored if tumorigenesis is associated with the bonding experience in monogamous rodents at which disruption of pair bonds is linked to anxiety and stress. Comparison of lung cancer cell spheroids that formed in the presence of sera from bonded and bond-disrupted deer mice showed that in monogamous Peromyscus polionotus and Peromyscus californicus, but not in polygamous Peromyscus maniculatus, the disruption of pair bonds altered the size and morphology of spheroids in a manner that is consistent with the acquisition of increased oncogenic potential. In vivo, consecutive transplantation of human lung cancer cells between P. californicus, differing in bonding experiences (n = 9 for bonded and n = 7 for bond-disrupted), and nude mice showed that bonding suppressed tumorigenicity in nude mice (p<0.05), suggesting that the protective effects of pair bonds persisted even after bonding ceased. Unsupervised hierarchical clustering indicated that the transcriptomes of lung cancer cells clustered according to the serum donors’ bonding history while differential gene expression analysis pointed to changes in cell adhesion and migration. The results highlight the pro-oncogenic effects of pair-bond disruption, point to the acquisition of expression signatures in cancer cells that are relevant to the bonding experiences of serum donors, and question the ability of conventional mouse models to capture the whole spectrum of the impact of the host in tumorigenesis.

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