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.

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.

Isoorientin Decreases Cell Migration via Decreasing Functional Activity and Molecular Expression of Proton-Linked Monocarboxylate Transporters in Human Lung Cancer Cells

2020 ◽  
Vol 48 (01) ◽  
pp. 201-222
Author(s):  
Hsu-Kai Huang ◽  
Shin-Yi Lee ◽  
Shu-Fen Huang ◽  
Yu-San Lin ◽  
Shih-Chi Chao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Lung Adenocarcinoma ◽  
Cell Viability ◽  
Cancer Cells ◽  
Functional Activity ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Human Lung Cancer Cells

Aggressive tumor cells mainly rely on glycolysis, and further release vast amounts of lactate and protons by monocarboxylate transporter (MCT), which causes a higher intracellular pH (pHi) and acidic extracellular pH. Isoorientin, a principle flavonoid compound extracted from several plant species, shows various pharmacological activities. However, effects of isoorientin on anticancer and MCT await to explore in human lung cancer cells. Human lung cancer tissues were obtained from cancer patients undergoing surgery, while the human lung adenocarcinoma cells (A549) were bought commercially. Change of pHi was detected by microspectrofluorometry method with a pH-sensitive fluorescent dye, BCECF. MTT and wound-healing assay were used to detect the cell viability and migration, respectively. Western blot techniques and immunocytochemistry staining were used to detect the protein expression. Our results indicated that the expression of MCTs1/4 and CD147 were upregulated significantly in human lung tissues. In experiments of A549 cells, under HEPES-buffer, the resting pHi was 7.47, and isoorientin (1–300[Formula: see text][Formula: see text]M) inhibited functional activity of MCT concentration-dependently (up to [Formula: see text]%). Pretreatment with isoorientin (3–100[Formula: see text][Formula: see text]M) for 24[Formula: see text]h, MCT activity and cell migration were significantly inhibited ([Formula: see text]% and [Formula: see text]%, respectively), while the cell viability was not affected. Moreover, the expression of MCTs1/4, CD147, and matrix metalloproteinase (MMP) 2/9 were significantly down regulated. In summary, MCTs1/4 and CD147 are significantly upregulated in human lung adenocarcinoma tissues, and isoorientin inhibits cells-migration by inhibiting activity/expression of MCTs1/4 and MMPs2/9 in human lung cancer cells. These novel findings suggest that isoorientin could be a promising pharmacological agent for lung cancer.

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.

Abnormalp53Expression in Human Lung Cancer is Associated with Histologic Subtypes and Patient Smoking History

1994 ◽  
Vol 102 (5) ◽  
pp. 660-664 ◽  
Author(s):  
Dosaka-Akita Hirotoshi ◽  
Masanobu Shindoh ◽  
Michihiro Fujino ◽  
Ichiro Kinoshita ◽  
Kenji Akie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Smoking History ◽  
Histologic Subtypes

TRANSFORMING GROWTH FACTOR-b1 AND ITS RECEPTORS IN HUMAN LUNG CANCER AND MOUSE LUNG CARCINOGENESIS

2000 ◽  
Vol 26 (8) ◽  
pp. 685-707 ◽  
Author(s):  
Yang Kang ◽  
Margaret A. Prentice ◽  
Jennifer M. Mariano ◽  
Shekar Davarya ◽  
R. Ilona Linnoila ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Mouse Lung ◽  
Lung Carcinogenesis

scholarly journals Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma

2019 ◽  
Author(s):  
Sarah Neidler ◽  
Björn Kruspig ◽  
Kay Hewit ◽  
Tiziana Monteverde ◽  
Katarina Gyuraszova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Mouse Model ◽  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Human Lung ◽  
Tumour Progression ◽  
Human Lung Cancer ◽  
Invasive Adenocarcinoma ◽  
Molecular Events

Inducible genetically defined mouse models of cancer uniquely facilitate the investigation of early events in cancer progression, however there are valid concerns about the ability of such models to faithfully recapitulate human disease.  We developed an inducible mouse model of progressive lung adenocarcinoma (LuAd) that combines sporadic activation of oncogenic KRasG12D with modest overexpression of c-MYC (KM model). Histological examination revealed a highly reproducible transition from adenoma to locally invasive adenocarcinoma within 6 weeks of oncogene activation.  Laser-capture microdissection coupled with RNA-SEQ was employed to determine transcriptional changes associated with tumour progression.  Upregulated genes were triaged for relevance to human LuAd using datasets from Oncomine and cBioportal.  Selected genes were validated by RNAi screening in human lung cancer cell lines and examined for association with lung cancer patient overall survival using KMplot.com.  Depletion of progression-associated genes resulted in pronounced viability and/or cell migration defects in human lung cancer cells.  Progression-associated genes moreover exhibited strong associations with overall survival, specifically in human lung adenocarcinoma, but not in squamous cell carcinoma. The KM mouse model faithfully recapitulates key molecular events in human lung cancer and is a useful tool for mechanistic interrogation of LuAd progression.

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