Adipocyte-derived exosomes promote lung cancer metastasis byincreasing MMP9 activity via transferring MMP3 to lung cancer cells

AbstractActin filament associated protein 1 antisense RNA 1 (named AFAP1-AS1) is a long non-coding RNA and overexpressed in many cancers. This study aimed to identify the role and mechanism of AFAP1-AS1 in lung cancer. The AFAP1-AS1 expression was firstly assessed in 187 paraffin-embedded lung cancer and 36 normal lung epithelial tissues by in situ hybridization. The migration and invasion abilities of AFAP1-AS1 were investigated in lung cancer cells. To uncover the molecular mechanism about AFAP1-AS1 function in lung cancer, we screened proteins that interact with AFAP1-AS1 by RNA pull down and the mass spectrometry analyses. AFAP1-AS1 was highly expressed in lung cancer clinical tissues and its expression was positively correlated with lung cancer patients’ poor prognosis. In vivo experiments confirmed that AFAP1-AS1 could promote lung cancer metastasis. AFAP1-AS1 promoted lung cancer cells migration and invasion through interacting with Smad nuclear interacting protein 1 (named SNIP1), which inhibited ubiquitination and degradation of c-Myc protein. Upregulation of c-Myc molecule in turn promoted the expression of ZEB1, ZEB2, and SNAIL gene, which ultimately enhanced epithelial to mesenchymal transition (EMT) and lung cancer metastasis. Understanding the molecular mechanism by which AFAP1-AS1 promotes lung cancer’s migration and invasion may provide novel therapeutic targets for lung cancer patients’ early diagnosis and therapy.

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Suppression of lung cancer metastasis-related protein 1 promotes apoptosis in lung cancer cells

International Journal of Molecular Medicine ◽

10.3892/ijmm.2012.1160 ◽

2012 ◽

Vol 30 (6) ◽

pp. 1481-1486 ◽

Cited By ~ 5

Author(s):

YANG XU ◽

CHUNSUN LI ◽

QING TIAN ◽

YANQIN LI ◽

ZHEN YANG ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Lung Cancer Cells ◽

Related Protein ◽

Lung Cancer Metastasis

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Gigantol Inhibits Epithelial to Mesenchymal Process in Human Lung Cancer Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/4561674 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 14

Author(s):

Thitita Unahabhokha ◽

Pithi Chanvorachote ◽

Boonchoo Sritularak ◽

Jutarat Kitsongsermthon ◽

Varisa Pongrakhananon

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Therapeutic Potential ◽

Public Health Problem ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Mesenchymal Transition ◽

Lung Cancer Metastasis

Lung cancer remains a leading public health problem as evidenced by its increasing death rate. The main cause of death in lung cancer patients is cancer metastasis. The metastatic behavior of lung cancer cells becomes enhanced when cancer cells undergo epithelial to mesenchymal transition (EMT). Gigantol, a bibenzyl compound extracted from the Thai orchid,Dendrobium draconis, has been shown to have promising therapeutic potential against cancer cells, which leads to the hypothesis that gigantol may be able to inhibit the fundamental EMT process in cancer cells. This study has demonstrated for the first time that gigantol possesses the ability to suppress EMT in non-small cell lung cancer H460 cells. Western blot analysis has revealed that gigantol attenuates the activity of ATP-dependent tyrosine kinase (AKT), thereby inhibiting the expression of the major EMT transcription factor, Slug, by both decreasing its transcription and increasing its degradation. The inhibitory effects of gigantol on EMT result in a decrease in the level of migration in H460 lung cancer cells. The results of this study emphasize the potential of gigantol for further development against lung cancer metastasis.

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Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells

Oncotarget ◽

10.18632/oncotarget.18737 ◽

2017 ◽

Vol 8 (47) ◽

pp. 81880-81891 ◽

Cited By ~ 21

Author(s):

Jiaoli Wang ◽

Yilei Wu ◽

Jufeng Guo ◽

Xuefeng Fei ◽

Lei Yu ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Metastasis ◽

Lung Cancer Cells ◽

Lung Cancer Metastasis

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Lung Cancer Cells-Controlled Dkk-1 Production in Brain Metastatic Cascade Drive Microglia to Acquire a Pro-tumorigenic Phenotype

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.591405 ◽

2020 ◽

Vol 8 ◽

Author(s):

Dong-Xue Gan ◽

Yi-Bei Wang ◽

Ming-Yang He ◽

Zi-Yang Chen ◽

Xiao-Xue Qin ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Animal Studies ◽

Cancer Metastasis ◽

Direct Interaction ◽

Lung Cancer Cells ◽

Brain Endothelium ◽

Metastatic Niche ◽

Lung Cancer Metastasis

ObjectivesOrganotropism is primarily determined by tumor-derived exosomes. To date, the role of lung cancer cells-derived exosomes underlying the pre-metastatic niche formation is unclear.Materials and MethodsThe animal models of retro-orbital and intra-ventricular injection were constructed to administrate lung cancer cells-derived exosomes. Cytokine array was used to screen the cytokines released from brain endothelium after internalization of lung cancer cells-derived exosomes. The cellular co-culture system was established to mimic microglia-vascular niche contained lung cancer cells-derived exosomes. The levels of Dkk-1 and the activities of microglia were analyzed by qRT-PCR, western blot and immunofluorescence. In vivo selections of highly brain metastatic cells were performed to analyze the direct interaction of lung cancer cells with microglia.ResultsAnimal studies demonstrated that there was a suppressive signal transferred from brain endothelium to microglia after internalization of lung cancer cells-derived exosomes into brain endothelium, which caused an absolutely less M1 phenotypic microglia and a relatively more M2 phenotypic microglia. Further results indicated that lung cancer cells-derived exosomes induced a release of endogenous Dkk-1 from brain endothelium, which rendered microglia to acquire a pro-tumorigenic feature in pre-metastatic niche. Subsequently, the declines of Dkk-1 in metastatic lung cancer cells removed the suppression on microglia and enhanced microglial activation in metastatic niche.ConclusionOur findings shed a new light on the synergistic reaction of the different cells in “neurovascular units” toward the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.

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Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition

Molecules ◽

10.3390/molecules26030638 ◽

2021 ◽

Vol 26 (3) ◽

pp. 638

Author(s):

Kittipong Sanookpan ◽

Nongyao Nonpanya ◽

Boonchoo Sritularak ◽

Pithi Chanvorachote

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Colony Formation ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

A549 Cells ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Mesenchymal Transition

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

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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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Cancer-educated mesenchymal stem cells promote the survival of cancer cells at primary and distant metastatic sites via the expansion of bone marrow-derived-PMN-MDSCs

Cell Death and Disease ◽

10.1038/s41419-019-2149-1 ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 2

Author(s):

Buqing Sai ◽

Yafei Dai ◽

Songqing Fan ◽

Fan Wang ◽

Lujuan Wang ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cancer Cells ◽

Cancer Metastasis ◽

Primary Tumour ◽

Lung Cancer Cells ◽

Gm Csf ◽

Metastatic Sites

AbstractBone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types. BMSCs are chemotactically guided towards the cancer cells and contribute to the formation of a cancer microenvironment. The homing of BMSCs was affected by various factors. Disseminated tumour cells (DTCs) in distant organs, especially in the bone marrow, are the source of cancer metastasis and cancer relapse. DTC survival is also determined by the microenvironment. Here we aim to elucidate how cancer-educated BMSCs promote the survival of cancer cells at primary tumour sites and distant sites. We highlight the dynamic change by identifying different gene expression signatures in intratumoral BMSCs and in BMSCs that move back in the bone marrow. Intratumoral BMSCs acquire high mobility and displayed immunosuppressive effects. Intratumoral BMSCs that ultimately home to the bone marrow exhibit a strong immunosuppressive function. Cancer-educated BMSCs promote the survival of lung cancer cells via expansion of MDSCs in bone marrow, primary tumour sites and metastatic sites. These Ly6G+ MDSCs suppress proliferation of T cells. CXCL5, nitric oxide and GM-CSF produced by cancer-educated BMSCs contribute to the formation of malignant microenvironments. Treatment with CXCL5 antibody, the iNOS inhibitor 1400w and GM-CSF antibody reduced MDSC expansion in the bone marrow, primary tumour sites and metastatic sites, and promoted the efficiency of PD-L1 antibody. Our study reveals that cancer-educated BMSCs are the component of the niche for primary lung cancer cells and DTCs, and that they can be the target for immunotherapy.

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Inhibitory Effects of Furanocoumarins From the Roots of Angelica dahurica on Ionizing Radiation-Induced Migration of A549 Human Non-Small Cell Lung Cancer Cells

Natural Product Communications ◽

10.1177/1934578x20915036 ◽

2020 ◽

Vol 15 (4) ◽

pp. 1934578X2091503

Author(s):

Sang Hoon Lee ◽

Ah-Reum Han ◽

Unwoo Kang ◽

Jin-Baek Kim ◽

Eun Kyoung Seo ◽

...

Keyword(s):

Lung Cancer ◽

Ionizing Radiation ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Cancer Metastasis ◽

Small Cell ◽

Lung Cancer Cells ◽

Angelica Dahurica ◽

Small Cell Lung

Radiation therapy is a very effective tool for the treatment of advanced human lung cancers. However, as one of its malignancy-promoting behaviors, ionizing radiation (IR) increases cell migration and radiation resistance in several lung cancer cells, including non-small cell lung cancer (NSCLC) cells. As part of our ongoing search for potent radiotherapy enhancers from medicinal herbs, a chloroform-soluble fraction of the roots of Angelica dahurica was subjected to phytochemical investigation, leading to the isolation of 8 furanocoumarins. Of these, psoralen (1), xanthotoxin (2), and bergapten (3) inhibited IR-induced migration at a non-cytotoxic concentration (50 μM) in human NSCLC A549 cells. This study is the first to report on the inhibitory activities of these constituents of A. dahurica against IR-induced cancer metastasis.

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