scholarly journals Dissecting the multi-omics atlas of the exosomes released by human lung adenocarcinoma stem-like cells

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hai-Tao Luo ◽  
Yuan-Yuan Zheng ◽  
Jun Tang ◽  
Li-Juan Shao ◽  
Yi-Heng Mao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Regulatory Mechanisms ◽  
Cancer Development ◽  
Circular Rnas ◽  
Cell Populations ◽  
Poor Survival ◽  
Human Lung Adenocarcinoma ◽  
Tumor Exosomes

AbstractLung adenocarcinoma is heterogeneous and hierarchically organized, with a subpopulation of stem-like cells (CSCs) that reside at the apex of the hierarchy, in which exosomes act as important mediators by transporting specific molecules among different cell populations. Although there have been numerous studies on tumor exosomes, the constituents and functional properties of CSC-derived exosomes are still poorly characterized. Here we present a detail transcriptome and proteome atlas of the exosomes released by human lung adenocarcinoma stem-like cells (LSLCs). The transcriptome analysis indicates the specific patterns of exosomal constituents, including the fragmentation of transcripts and the low-level presence of circular RNAs, and identifies multiple exosomal-enriched mRNAs and lncRNAs. Integrative analysis of transcriptome and proteome data reveals the diverse functions of exosomal-enriched RNAs and proteins, many of which are associated with tumorigenesis. Importantly, several LSLC markers we identified are highly expressed in LSLC-derived exosomes and associate with poor survival, which may serve as promising liquid biopsy biomarkers for lung adenocarcinoma diagnosis. Our study provides a resource for the future elucidation of the functions of tumor-derived exosomes and their regulatory mechanisms in mediating lung cancer development.

The ADAM17 protease promotes tobacco smoke carcinogen-induced lung tumorigenesis

2019 ◽  
Vol 41 (4) ◽  
pp. 527-538 ◽  
Author(s):  
Mohamed I Saad ◽  
Louise McLeod ◽  
Liang Yu ◽  
Hiromichi Ebi ◽  
Saleela Ruwanpura ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Tobacco Smoke ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Smoking History ◽  
Lung Carcinogenesis ◽  
Wild Type Littermate ◽  
Human Lung Adenocarcinoma ◽  
Erk Mapk

Abstract Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumorigenic cytokines, growth factors and receptors, and therefore is an attractive target in cancer. However, the role of ADAM17 in promoting tobacco smoke carcinogen-induced lung carcinogenesis is unknown. The hypomorphic Adam17ex/ex mice—characterized by reduced global ADAM17 expression—were backcrossed onto the NNK-sensitive pseudo-A/J background. CRISPR-driven and inhibitor-based (GW280264X, and ADAM17 prodomain) ADAM17 targeting was employed in the human lung adenocarcinoma cell lines A549 and NCI-H23. Human lung cancer biopsies were also used for analyses. The Adam17ex/ex mice displayed marked protection against NNK-induced lung adenocarcinoma. Specifically, the number and size of lung lesions in NNK-treated pseudo-A/J Adam17ex/ex mice were significantly reduced compared with wild-type littermate controls. This was associated with lower proliferative index throughout the lung epithelium. ADAM17 targeting in A549 and NCI-H23 cells led to reduced proliferative and colony-forming capacities. Notably, among select ADAM17 substrates, ADAM17 deficiency abrogated shedding of the soluble IL-6 receptor (sIL-6R), which coincided with the blockade of sIL-6R-mediated trans-signaling via ERK MAPK cascade. Furthermore, NNK upregulated phosphorylation of p38 MAPK, whose pharmacological inhibition suppressed ADAM17 threonine phosphorylation. Importantly, ADAM17 threonine phosphorylation was significantly upregulated in human lung adenocarcinoma with smoking history compared with their cancer-free controls. Our study identifies the ADAM17/sIL-6R/ERK MAPK axis as a candidate therapeutic strategy against tobacco smoke-associated lung carcinogenesis.

Identification and characterization of SP cells in human lung adenocarcinoma SPC-A1 cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22230-e22230
Author(s):  
Y. Zhu ◽  
L. Chen
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Serum Free ◽  
Human Lung Adenocarcinoma ◽  
Colony Forming Efficiency ◽  
Forming Efficiency ◽  
Human Lung Adenocarcinoma Cell

e22230 Background: There has been an increasing interest in recent years in the role stem cells play in health and disease. With an extensive understanding of their biology, a major role for stem cells in the malignant process has been proposed and the existence of cancer stem cells(CSCs) has been confirmed in hematopoietic malignancies, brain cancer, and solid organ malignancies including breast, prostate, colon, and pancreatic cancer. Lung cancer is the leading cause of cancer mortality in most large cities of China. It is possible that lung cancer contains cancer stem cells responsible for its malignancy. The aim of this study is to identify, characterize and enrich the CSC population that drives and maintains lung adenocarcinoma growth and metastasis. Methods: Side population (SP) cell analysis and sorting were applied to established human lung adenocarcinoma cell line and an attempt to further enrich them by preliminary serum-free culture before fluorescence activated cell sorting(FACS) was done. Stem cell properties of SP cells were evaluated by their proliferative index, colony-forming efficiency, tumorigenic potential, bi-differentiation capacity and the expression of common stem cell surface markers. Results: Lung cancer cells could grow in a serum-free Medium (SFM) as non-adherent spheres similar to neurospheres or mammospheres. The proportion of SP cells in cell spheres was significantly higher than that in cells grown as monolayers. SP cells had a greater proliferative index, a higher colony-forming efficiency and a greater ability to form tumor in vivo. SP cells were both CCA positive and SP-C positive while non-SP cells were only SP-C positive. Flow cytometric analysis of cell phenotyping showed that SP cells expressed CD133 and CD44, the common cell surface markers of cancer stem cells, while non-SP cells only expressed CD44. Conclusions: SP cells existed in human lung adenocarcinoma cell lines and they could be further enriched by preliminary serum-free culture before FACS sorting. SP cells possessed the properties of cancer stem cells. No significant financial relationships to disclose.

scholarly journals A549 in-silico 1.0: A first computational model to simulate cell cycle dependent ion current modulation in the human lung adenocarcinoma

2021 ◽  
Vol 17 (6) ◽  
pp. e1009091
Author(s):  
Sonja Langthaler ◽  
Theresa Rienmüller ◽  
Susanne Scheruebel ◽  
Brigitte Pelzmann ◽  
Niroj Shrestha ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Membrane Potential ◽  
Lung Adenocarcinoma ◽  
Ion Channel ◽  
In Silico ◽  
Human Lung ◽  
Cell Model ◽  
Ion Current ◽  
Human Lung Adenocarcinoma

Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood. We here introduce the first approach of an in-silico whole-cell ion current model of a cancer cell, in particular of the A549 human lung adenocarcinoma, including the main functionally expressed ion channels in the plasma membrane as so far known. This hidden Markov-based model represents the electrophysiology behind proliferation of the A549 cell, describing its rhythmic oscillation of the membrane potential able to trigger the transition between cell cycle phases, and it predicts membrane potential changes over the cell cycle provoked by targeted ion channel modulation. This first A549 in-silico cell model opens up a deeper insight and understanding of possible ion channel interactions in tumor development and progression, and is a valuable tool for simulating altered ion channel function in lung cancer electrophysiology.

scholarly journals Transcriptional Response of Ovine Lung to Infection with Jaagsiekte Sheep Retrovirus

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Anna Eleonora Karagianni ◽  
Deepali Vasoya ◽  
Jeanie Finlayson ◽  
Henny M. Martineau ◽  
Ann R. Wood ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Animal Model ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Transcriptional Response ◽  
Human Lung Cancer ◽  
Ovine Pulmonary Adenocarcinoma ◽  
Jaagsiekte Sheep Retrovirus ◽  
Human Lung Adenocarcinoma ◽  
Naturally Occurring

ABSTRACT Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of ovine pulmonary adenocarcinoma (OPA), a neoplastic lung disease of sheep. OPA is an important economic and welfare issue for sheep farmers and a valuable naturally occurring animal model for human lung adenocarcinoma. Here, we used RNA sequencing to study the transcriptional response of ovine lung tissue to infection by JSRV. We identified 1,971 ovine genes differentially expressed in JSRV-infected lung compared to noninfected lung, including many genes with roles in carcinogenesis and immunomodulation. The differential expression of selected genes was confirmed using immunohistochemistry and reverse transcription-quantitative PCR. A key finding was the activation of anterior gradient 2, yes-associated protein 1, and amphiregulin in OPA tumor cells, indicating a role for this oncogenic pathway in OPA. In addition, there was differential expression of genes related to innate immunity, including genes encoding cytokines, chemokines, and complement system proteins. In contrast, there was little evidence for the upregulation of genes involved in T-cell immunity. Many genes related to macrophage function were also differentially expressed, reflecting the increased abundance of these cells in OPA-affected lung tissue. Comparison of the genes differentially regulated in OPA with the transcriptional changes occurring in human lung cancer revealed important similarities and differences between OPA and human lung adenocarcinoma. This study provides valuable new information on the pathogenesis of OPA and strengthens the use of this naturally occurring animal model for human lung adenocarcinoma. IMPORTANCE Ovine pulmonary adenocarcinoma is a chronic respiratory disease of sheep caused by jaagsiekte sheep retrovirus (JSRV). OPA is a significant economic problem for sheep farmers in many countries and is a valuable animal model for some forms of human lung cancer. Here, we examined the changes in host gene expression that occur in the lung in response to JSRV infection. We identified a large number of genes with altered expression in infected lung, including factors with roles in cancer and immune system function. We also compared the data from OPA to previously published data from human lung adenocarcinoma and found a large degree of overlap in the genes that were dysregulated. The results of this study provide exciting new avenues for future studies of OPA and may have comparative relevance for understanding human lung cancer.

scholarly journals Mutationally-activated PI3’-kinase-α promotes de-differentiation of lung tumors initiated by the BRAFV600E oncoprotein kinase

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
J Edward van Veen ◽  
Michael Scherzer ◽  
Julia Boshuizen ◽  
Mollee Chu ◽  
Annie Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Patient Survival ◽  
Genetically Engineered ◽  
Benign Tumors ◽  
Cell Of Origin ◽  
Genetically Engineered Mouse Models ◽  
Human Lung Adenocarcinoma ◽  
Insight Into

Human lung adenocarcinoma exhibits a propensity for de-differentiation, complicating diagnosis and treatment, and predicting poorer patient survival. In genetically engineered mouse models of lung cancer, expression of the BRAFV600E oncoprotein kinase initiates the growth of benign tumors retaining characteristics of their cell of origin, AT2 pneumocytes. Cooperating alterations that activate PI3’-lipid signaling promote progression of BRAFV600E-driven benign tumors to malignant adenocarcinoma. However, the mechanism(s) by which this cooperation occurs remains unclear. To address this, we generated mice carrying a conditional BrafCAT allele in which CRE-mediated recombination leads to co-expression of BRAFV600E and tdTomato. We demonstrate that co-expression of BRAFV600E and PIK3CAH1047R in AT2 pneumocytes leads to rapid cell de-differentiation, without decreased expression of the transcription factors NKX2-1, FOXA1, or FOXA2. Instead, we propose a novel role for PGC1α in maintaining AT2 pneumocyte identity. These findings provide insight into how these pathways may cooperate in the pathogenesis of human lung adenocarcinoma.

scholarly journals Siomycin A Induces Apoptosis in Human Lung Adenocarcinoma A549 Cells by Suppressing the Expression of FoxM1

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Xuedan Guo ◽  
Aiping Liu ◽  
Hongxia Hua ◽  
Huifen Lu ◽  
Dandan Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
A549 Cells ◽  
Migration And Invasion ◽  
Human Lung Adenocarcinoma ◽  
Forkhead Box M1 ◽  
Lung Adenocarcinoma A549 ◽  
Induced Apoptosis ◽  
Siomycin A

Forkhead box M1 (FoxM1), a transcription factor of the Forkhead family, is demonstrated to be critical for proliferation, apoptosis, migration and invasion of lung cancer. In this study, we extensively investigated the anticancer effect of siomycin A, which was identified as an inhibitor of FoxM1 transcriptional activity, on human lung adenocarcinoma A549 cells. Our study indicated that treatment with siomycin A resulted in the suppression of FoxM1 expression, which consequently contributed to its effect of cell growth inhibition and cell apoptosis induction in A549 cells. Then the molecular mechanism of siomycin A's apoptotic action on A549 cells was further investigated. The results revealed that siomycin A induced apoptosis by influencing the downstream events of FoxM1, including inhibiting the expression of Bcl-2 and Mcl-1, as well as leading to caspase-3 cleavage. Taken together, our findings may be useful for understanding the mechanism of action of siomycin A on lung cancer cells and provide new insights into the possible application of such a compound in lung cancer therapy in the future.

scholarly journals Andrographolide Induces Noxa-Dependent Apoptosis by Transactivating ATF4 in Human Lung Adenocarcinoma Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Junqian Zhang ◽  
Chunjie Li ◽  
Li Zhang ◽  
Yongqing Heng ◽  
Tong Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
High Dose ◽  
Dependent Manner ◽  
Human Lung Adenocarcinoma ◽  
Adenocarcinoma Cells ◽  
Human Lung Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
Induced Apoptosis

Lung adenocarcinoma is the most common pathological type of lung cancer with poor patient outcomes; therefore, developing novel therapeutic agents is critically needed. Andrographolide (AD), a major active component derived from the traditional Chinese medicine (TCM) Andrographis paniculate, is a potential antitumor drug, but the role of AD in lung adenocarcinoma remains poorly understood. In the present study, we demonstrated that AD inhibited the proliferation of broad-spectrum lung cancer cell lines in a dose-dependent manner. Meanwhile, we found that a high dose of AD induced Noxa-dependent apoptosis in human lung adenocarcinoma cells (A549 and H1299). Further studies revealed that Noxa was transcriptionally activated by activating transcription factor 4 (ATF4) in AD-induced apoptosis. Knockdown of ATF4 by small interfering RNA (siRNA) significantly diminished the transactivation of Noxa as well as the apoptotic population induced by AD. These results of the present study indicated that AD induced apoptosis of human lung adenocarcinoma cells by activating the ATF4/Noxa axis and supporting the development of AD as a promising candidate for the new era of chemotherapy.

scholarly journals Cytotoxic Constituents from the Sclerotia of Poria cocos against Human Lung Adenocarcinoma Cells by Inducing Mitochondrial Apoptosis

Cells ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 116 ◽  
Author(s):  
Seulah Lee ◽  
Seul Lee ◽  
Hyun-Soo Roh ◽  
Seong-Soo Song ◽  
Rhim Ryoo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cell Lines ◽  
Human Lung ◽  
Bioactive Constituents ◽  
Human Lung Adenocarcinoma ◽  
Adenocarcinoma Cells ◽  
Human Lung Adenocarcinoma Cells ◽  
P53 Status ◽  
Lung Adenocarcinoma Cells

Previous studies have revealed the antitumor potential of Poria cocos Wolf against a broad spectrum of cancers. However, the biological activity of P. cocos against lung cancer, which is known as the leading cause of cancer mortality worldwide, and its underlying chemical and molecular basis, remain to be investigated. We aimed to evaluate the in vitro cytotoxicity of P. cocos toward human lung adenocarcinoma cells with different p53 statuses, to identify the bioactive constituents of P. cocos, and explicate the molecular mechanisms underlying the cytotoxicity of these constituents in human lung adenocarcinoma cells. An EtOH extract of the sclerotia of P. cocos exhibited cytotoxicity toward four human lung cancer cell lines: A549, H1264, H1299, and Calu-6, regardless of their p53 status. Chemical investigation of the extract resulted in the isolation of two triterpenoids, dehydroeburicoic acid monoacetate (1) and acetyl eburicoic acid (4); a sterol, 9,11-dehydroergosterol peroxide (2); and a diterpenoid, dehydroabietic acid (3). All of the isolated compounds were cytotoxic to the lung adenocarcinoma cell lines, exhibiting IC50 values ranging from 63.6 μM to 171.0 μM at 48 h of treatment. The cytotoxicity of the extract and the isolated compounds were found to be mediated by apoptosis, and accompanied by elevated Bax expression and/or Bcl-2 phosphorylation along with caspase-3 activation. Our data demonstrate that the sclerotium of P. cocos and its four bioactive constituents (1–4) exert cytotoxicity against human lung adenocarcinoma cells, regardless of their p53 status, by inducing apoptosis associated with mitochondrial perturbation, and proposing the potential to employ P. cocos in the treatment of lung cancer.

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