c-Myc shuttled by tumour-derived extracellular vesicles promotes lung bronchial cell proliferation through miR-19b and miR-92a

Abstract Lung cancer causes approximately one fifth of all cancer deaths. Tumour cells actively communicate with the surrounding microenvironment to support malignant progression. Extracellular vesicles (EVs) play a pivotal role in intercellular communication and modulate recipient cells by delivering their contents, including proteins and nucleic acids such as microRNAs (miRNAs). We isolated EVs from the conditioned medium (CM) of human lung cancer cell lines and plasma of lung cancer patients and cancer-free smokers using an ultracentrifugation method. A significant increase in bronchial HBEC-KRASV12high cell proliferation, confirmed by cell cycle analysis, was observed after treatment with cancer-derived EVs. Lung cancer-derived EVs induced transcription of the pri-miR-92a gene, resulting in the overexpression of mature miR-19b and miR-92a in recipient bronchial cells. Modulation of these two miRNAs using miRNA mimics or inhibitors confirmed their ability to promote proliferation. In silico analysis and experimental validation showed that miR-19b and miR-92a impaired the TGF-beta (TGFB) pathway and identified TGFBRI and TGFBRII as target genes involved in EV-mediated bronchial cell proliferation. Interestingly, the oncoprotein c-Myc, a well-known miR-17-92 cluster activator, was detected only in the EVs derived from lung cancer patients and cell lines and was able to modulate the proliferation of HBEC-KRASV12high recipient cells. These data support the role of c-Myc shuttling in lung cancer-derived EVs in inducing the upregulation of onco-miR-19b and miR-92a expression with concomitant impairment of the TGFB signalling pathway in recipient cells.

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Circulating or tissue microRNAs and extracellular vesicles as potential lung cancer biomarkers: a systematic review

The International Journal of Biological Markers ◽

10.5301/ijbm.5000307 ◽

2017 ◽

Vol 33 (1) ◽

pp. 3-9 ◽

Cited By ~ 7

Author(s):

Yan Song ◽

Xiuli Yu ◽

Zongmei Zang ◽

Guijuan Zhao

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Cancer Patients ◽

Extracellular Vesicles ◽

Target Genes ◽

Enrichment Analysis ◽

Cancer Biomarkers ◽

Biological Processes ◽

Lung Cancer Patients ◽

Prediction Of Prognosis

For both lung cancer patients and clinical physicians, tumor biomarkers for more efficient early diagnosis and prediction of prognosis are always wanted. Biomarkers in circulating serum, including microRNAs (miRNAs) and extracellular vesicles, hold the greatest possibilities to partially substitute for tissue biopsy. In this systematic review, studies on circulating or tissue miRNAs and extracellular vesicles as potential biomarkers for lung cancer patients were reviewed and are discussed. Furthermore, the target genes of the miRNAs indicated were identified through the miRTarBase, while the relevant biological processes and pathways of miRNAs in lung cancer were analyzed through MiRNA Enrichment Analysis and Annotation (MiEAA). In conclusion, circulating or tissue miRNAs and extracellular vesicles provide us with a window to explore strategies for diagnosing and assessing prognosis and treatment in lung cancer patients.

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Circulating extracellular vesicles from individuals at high-risk of lung cancer induce pro-tumorigenic conversion of stromal cells through transfer of miR-126 and miR-320

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02040-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Francesca Pontis ◽

Luca Roz ◽

Mavis Mensah ◽

Miriam Segale ◽

Massimo Moro ◽

...

Keyword(s):

Lung Cancer ◽

Endothelial Cells ◽

High Risk ◽

Cancer Patients ◽

Extracellular Vesicles ◽

In Vivo Models ◽

Lung Cancer Patients

Abstract Background Extracellular vesicles (EVs) containing specific subsets of functional biomolecules are released by all cell types and analysis of circulating EVs can provide diagnostic and prognostic information. To date, little is known regarding the role of EVs both as biomarkers and potential key players in human lung cancer. Methods Plasma EVs were isolated from 40 cancer-free heavy-smokers classified according to a validated 24-microRNA signature classifier (MSC) at high (MSCpos-EVs) or low (MSCneg-EVs) risk to develop lung cancer. EVs origin and functional properties were investigated using in vitro 3D cultures and in vivo models. The prognostic value of miRNAs inside EVs was assessed in training and in validation cohorts of 54 and 48 lung cancer patients, respectively. Results Different membrane composition, biological cargo and pro-tumorigenic activity were observed in MSCpos vs MSCneg-EVs. Mechanistically, in vitro and in vivo results showed that miR-126 and miR-320 from MSCpos-EVs increased pro-angiogenic phenotype of endothelial cells and M2 polarization of macrophage, respectively. MSCpos-EVs prompted 3D proliferation of non-tumorigenic epithelial cells through c-Myc transfer. Moreover, hypoxia was shown to stimulate the secretion of EVs containing c-Myc from fibroblasts, miR-126-EVs from endothelial cells and miR-320-EVs from granulocytes. Lung cancer patients with higher levels of mir-320 into EVs displayed a significantly shorter overall survival in training [HR2.96] and validation sets [HR2.68]. Conclusion Overall our data provide a new perspective on the pro-tumorigenic role of circulating EVs in high risk smokers and highlight the significance of miR-320-EVs as a new prognostic biomarker in lung cancer patients.

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The LncRNA EPEL Promotes Lung Cancer Cell Proliferation Through E2F Target Activation

Cellular Physiology and Biochemistry ◽

10.1159/000487460 ◽

2018 ◽

Vol 45 (3) ◽

pp. 1270-1283 ◽

Cited By ~ 16

Author(s):

Seong-Min Park ◽

Eun-Young Choi ◽

Dong-Hyuck Bae ◽

Hyun Ahm Sohn ◽

Seon-Young Kim ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cancer Patients ◽

Cancer Cell ◽

Target Genes ◽

Cyclin B1 ◽

Cancer Cell Proliferation ◽

Lung Cancer Cell ◽

Lung Cancer Patients

Background/Aims: Recent studies have revealed that many long non-coding RNAs (lncRNAs) play oncogenic or tumor-suppressive roles in various cancers. Lung cancer is the leading cause of cancer-related death worldwide, and many lung cancer patients frequently relapse after surgery, even those in the early stages. However, the oncogenic or tumor-suppressive roles and clinical implications of lncRNAs in lung cancer have not been fully elucidated. Methods: The association between an E2F-mediated cell proliferation enhancing lncRNA (EPEL) expression and lung cancer patient survival was accessed using public microarray data with clinical information. Cancer-related phenotypes were analyzed by the siRNA knockdown of EPEL in two lung cancer cell lines. Gene set analysis of gene expression data were performed to identify pathways regulated by EPEL. RNA immunoprecipitation, RT-qPCR, and ChIP assays were performed to explore the functions of selected target genes regulated by EPEL. Results: EPEL, known as LOC90768 and MGC45800, was associated with the relapse and survival of lung cancer patients and promoted lung cancer cell proliferation through the activation of E2F target genes. EPEL knockdown specifically down-regulated the expression of cell cycle-related E2F target genes, including Cyclin B1 (CCNB1), in lung cancer cells but not that of apoptosis- or metabolism-related E2F target genes. EPEL interacted with E2F1 and regulated the expression of the E2F target genes by changing the binding efficiency of E2F1 to the E2F target promoters. Moreover, the expression levels of EPEL and CCNB1 both alone and in combination were robust prognostic markers for lung cancer. Conclusions: Considering its specific effects on cell cycle-related E2F target genes and its significant association with the prognosis of lung cancer patients, we suggest that the transcriptional regulation of EPEL through E2F target genes is potentially a target for the development of novel therapeutic strategies for lung cancer patients.

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The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

Scientific Reports ◽

10.1038/s41598-019-54065-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Matheus Molina Silva ◽

Clarissa Ribeiro Reily Rocha ◽

Gabriela Sarti Kinker ◽

Alessandra Luiza Pelegrini ◽

Carlos Frederico Martins Menck

Keyword(s):

Lung Cancer ◽

Dna Repair ◽

Cancer Patients ◽

Cell Lines ◽

Target Genes ◽

Cisplatin Resistance ◽

Related Factor ◽

Repair Capacity ◽

Lung Cancer Patients ◽

Dismal Prognosis

AbstractLung cancer patients face a dismal prognosis mainly due to the low efficacy of current available treatments. Cisplatin is the first-line chemotherapy treatment for those patients, however, resistance to this drug is a common and yet not fully understood phenomenon. Aiming to shed new light into this puzzle, we used established normal and malignant lung cell lines displaying different sensitivity towards cisplatin treatment. We observed a negative correlation between cell viability and DNA damage induction upon cisplatin treatment. Interestingly, drug sensitivity in those cell lines was not due to either difference on DNA repair capacity, or in the amount of membrane ion channel commonly used for cisplatin uptake. Also, we noted that glutathione intracellular levels, and expression and activity of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene expression in non-small cell lung cancer patients of the TCGA data bank revealed that there is a significant lower overall survival rate in the subset of patients bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, increased expression of NRF2 target genes. Thus, the results indicate that NRF2 and glutathione levels figure as important cisplatin resistance biomarkers in lung cancer.

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Role of LDH, 17-ß-hydroxysteroid dehydrogenase and Myloperoxidase Enzymes in early diagnosis for Lung Cancer patients

International Journal of Pharmaceutical Research ◽

10.31838/ijpr/2020.sp1.272 ◽

2020 ◽

Vol 12 (sp1) ◽

Keyword(s):

Lung Cancer ◽

Early Diagnosis ◽

Cancer Patients ◽

Hydroxysteroid Dehydrogenase ◽

Lung Cancer Patients

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The positive effect of social support on psychological distress among Chinese lung cancer patients: The mediating role of self‐esteem

Nursing Open ◽

10.1002/nop2.793 ◽

2021 ◽

Author(s):

Xu Tian ◽

Yanfei Jin ◽

Hui Chen ◽

Ling Tang ◽

Maria F. Jiménez‐Herrera

Keyword(s):

Lung Cancer ◽

Social Support ◽

Psychological Distress ◽

Cancer Patients ◽

Self Esteem ◽

Lung Cancer Patients ◽

Mediating Role ◽

Positive Effect

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Cisplatin-induced hydroxyl radicals mediate pro-survival autophagy in human lung cancer H460 cells

Biological Research ◽

10.1186/s40659-021-00346-2 ◽

2021 ◽

Vol 54 (1) ◽

Author(s):

Somruethai Sumkhemthong ◽

Eakachai Prompetchara ◽

Pithi Chanvorachote ◽

Chatchai Chaotham

Keyword(s):

Lung Cancer ◽

Hydroxyl Radicals ◽

Human Lung ◽

Human Lung Cancer ◽

Radical Scavenger ◽

Apoptosis Resistance ◽

Lung Cancer Patients ◽

Human Lung Cancer Cells ◽

H460 Cells

Abstract Background Accumulated evidence demonstrates cisplatin, a recommended chemotherapy, modulating pro-survival autophagic response that contributes to treatment failure in lung cancer patients. However, distinct mechanisms involved in cisplatin-induced autophagy in human lung cancer cells are still unclear. Results Herein, role of autophagy in cisplatin resistance was indicated by a decreased cell viability and increased apoptosis in lung cancer H460 cells pre-incubated with wortmannin, an autophagy inhibitor, prior to treatment with 50 µM cisplatin for 24 h. The elevated level of hydroxyl radicals detected via flow-cytometry corresponded to autophagic response, as evidenced by the formation of autophagosomes and autolysosomes in cisplatin-treated cells. Interestingly, apoptosis resistance, autophagosome formation, and the alteration of the autophagic markers, LC3-II/LC3-I and p62, as well as autophagy-regulating proteins Atg7 and Atg3, induced by cisplatin was abrogated by pretreatment of H460 cells with deferoxamine, a specific hydroxyl radical scavenger. The modulations in autophagic response were also indicated in the cells treated with hydroxyl radicals generated via Fenton reaction, and likewise inhibited by pretreatment with deferoxamine. Conclusions In summary, the possible role of hydroxyl radicals as a key mediator in the autophagic response to cisplatin treatment, which was firstly revealed in this study would benefit for the further development of novel therapies for lung cancer.

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Evidence for a Negative Correlation between Human Reactive Enamine-Imine Intermediate Deaminase A (RIDA) Activity and Cell Proliferation Rate: Role of Lysine Succinylation of RIDA

International Journal of Molecular Sciences ◽

10.3390/ijms22083804 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3804

Author(s):

Luisa Siculella ◽

Laura Giannotti ◽

Benedetta Di Chiara Stanca ◽

Matteo Calcagnile ◽

Alessio Rochira ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Lines ◽

Negative Correlation ◽

Cancer Biology ◽

Human Tumor ◽

In Silico Analysis ◽

Proliferation Rate ◽

Reactive Intermediate ◽

Cell Proliferation Rate

Reactive intermediate deaminase (Rid) proteins are enzymes conserved in all domains of life. UK114, a mammalian member of RidA subfamily, has been firstly identified as a component of liver perchloric acid-soluble proteins (L-PSP). Although still poorly defined, several functions have been attributed to the mammalian protein UK114/RIDA, including the reactive intermediate deamination activity. The expression of UK114/RIDA has been observed in some tumors, arousing interest in this protein as an evaluable tumor marker. However, other studies reported a negative correlation between UK114/RIDA expression, tumor differentiation degree and cell proliferation. This work addressed the question of UK114/RIDA expression in human non-tumor HEK293 cell lines and in some human tumor cell lines. Here we reported that human RIDA (hRIDA) was expressed in all the analyzed cell line and subjected to lysine (K-)succinylation. In HEK293, hRIDA K-succinylation was negatively correlated to the cell proliferation rate and was under the control of SIRT5. Moreover, K-succinylation clearly altered hRIDA quantification by immunoblotting, explaining, at least in part, some discrepancies about RIDA expression reported in previous studies. We found that hRIDA was able to deaminate reactive enamine-imine intermediates and that K-succinylation drastically reduced deaminase activity. As predicted by in silico analysis, the observed reduction of deaminase activity has been related to the drastic alterations of hRIDA structure inferred by K-succinylation. The role of hRIDA and the importance of its K-succinylation in cell metabolism, especially in cancer biology, have been discussed.

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