Microbiome-TP53 Gene Interaction in Human Lung Cancer

AbstractBackgroundLung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) and cancer cases (n=143), we conducted 16S rRNA bacterial gene sequencing, with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort.ResultsOverall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma (SCC) specifically, a separate group of taxa were identified, in which Acidovorax was enriched in smokers (P =0.0013). Acidovorax temporans was identified by fluorescent in situ hybridization within tumor sections, and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD).ConclusionsThe results of this comprehensive study show both a microbiome-gene and microbiome-exposure interactions in SCC lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can damage epithelial function, have a unique bacterial consortia which is higher in relative abundance in smoking-associated SCC. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

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Interaction between the microbiome and TP53 in human lung cancer

Genome Biology ◽

10.1186/s13059-018-1501-6 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 44

Author(s):

K. Leigh Greathouse ◽

James R. White ◽

Ashely J. Vargas ◽

Valery V. Bliskovsky ◽

Jessica A. Beck ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Cigarette Smoke ◽

Squamous Cell ◽

Human Lung Cancer ◽

Normal Lung ◽

Lung Carcinogenesis ◽

Bacterial Gene ◽

Tp53 Mutations

Abstract Background Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort. Results Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas. Conclusions The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

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TIPE2 Induced the Proliferation, Survival, and Migration of Lung Cancer Cells Through Modulation of Akt/mTOR/NF-κB Signaling Cascade

Biomolecules ◽

10.3390/biom9120836 ◽

2019 ◽

Vol 9 (12) ◽

pp. 836 ◽

Cited By ~ 9

Author(s):

Devivasha Bordoloi ◽

Kishore Banik ◽

Ganesan Padmavathi ◽

Rajesh Vikkurthi ◽

Choudhary Harsha ◽

...

Keyword(s):

Lung Cancer ◽

Early Diagnosis ◽

Cancer Cells ◽

Therapeutic Interventions ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Normal Lung ◽

Lung Carcinogenesis ◽

And Migration

Lung cancer represents the most common cause of cancer deaths in the world, constituting around 11.6% of all new cancer cases and 18.4% of cancer-related deaths. The propensity for early spread, lack of suitable biomarkers for early diagnosis, as well as prognosis and ineffective existing therapies, contribute to the poor survival rate of lung cancer. Therefore, there is an urgent need to develop novel biomarkers for early diagnosis and prognosis which in turn can facilitate newer therapeutic avenues for the management of this aggressive neoplasm. TIPE2 (tumor necrosis factor-α-induced protein 8-like 2), a recently identified cytoplasmic protein, possesses enormous potential in this regard. Immunohistochemical analysis showed that TIPE2 was significantly upregulated in different stages and grades of lung cancer tissues compared to normal lung tissues, implying its involvement in the positive regulation of lung cancer. Further, knockout of TIPE2 resulted in significantly reduced proliferation, survival, and migration of human lung cancer cells through modulation of the Akt/mTOR/NF-κB signaling axis. In addition, knockout of TIPE2 also caused arrest in the S phase of the cell cycle of lung cancer cells. As tobacco is the most predominant risk factor for lung cancer, we therefore evaluated the effect of TIPE2 in tobacco-mediated lung carcinogenesis as well. Our results showed that TIPE2 was involved in nicotine-, nicotine-derived nitrosamine ketone (NNK)-, N-nitrosonornicotine (NNN)-, and benzo[a]pyrene (BaP)-mediated lung cancer through inhibited proliferation, survival, and migration via modulation of nuclear factor kappa B (NF-κB)- and NF-κB-regulated gene products, which are involved in the regulation of diverse processes in lung cancer cells. Taken together, TIPE2 possesses an important role in the development and progression of lung cancer, particularly in tobacco-promoted lung cancer, and hence, specific targeting of it holds an enormous prospect in newer therapeutic interventions in lung cancer. However, these findings need to be validated in the in vivo and clinical settings to fully establish the diagnostic and prognostic importance of TIPE2 against lung cancer.

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Comprehensive Analysis of the Expression and Prognosis for IRXs in Non-small Cell Lung Cancer

10.21203/rs.3.rs-78198/v1 ◽

2020 ◽

Author(s):

Qiongzi Wang ◽

Xueshan Qiu

Keyword(s):

Lung Cancer ◽

Human Lung ◽

Expression Patterns ◽

Human Lung Cancer ◽

Prognostic Indicators ◽

Normal Lung ◽

Kaplan Meier ◽

Go Enrichment ◽

Cancer Tissues ◽

Kaplan Meier Plotter

Abstract Iroquoishomeobox transcription factor family （IRXs）have been increasingly reported to play roles in suppressing or promoting a variety of cancers, however, little is known about their expression and prognostic value in terms of human lung cancer. In this study, Oncomine, GEPIA, Kaplan-Meier plotter, and cBioPortal databases were used to analyze the different expression patterns and prognostic values of six IRXs in NSCLC and examine their related functions and pathways using GO enrichment. Compared with normal lung cancer tissues, the expression of IRX1 and IRX2 in NSCLC tissues was significantly lower and was positively correlated with the 10-year survival rate of patients. Higher expression of IRX4 was related to terminal tumors, and suggested a poor prognosis. It was also found that IRXs may play a tumor-suppressive role in the localization of cytoplasm in NSCLC, while localization in the nucleus suggests a more malignant behavior. Together these results suggest that IRX1 and IRX2 may be prognostic indicators of LUAD, and that IRX4 could be a potential target for LUAD treatment.

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GPR115 Contributes to Lung Adenocarcinoma Metastasis Associated With LAMC2 and Predicts a Poor Prognosis

Frontiers in Oncology ◽

10.3389/fonc.2020.577530 ◽

2020 ◽

Vol 10 ◽

Author(s):

Yingjing Wang ◽

Muqi Shi ◽

Nan Yang ◽

Xiaoyu Zhou ◽

Liqin Xu

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Poor Prognosis ◽

Human Lung Cancer ◽

Normal Lung ◽

Migration And Invasion ◽

Epithelial Tissue ◽

Node Metastasis ◽

Tumor Node Metastasis Stage ◽

And Function

GPR115, a member of the adhesion G protein-coupled receptor family, is dysregulated in many cancers. However, the expression and function of GRP115 in non-small cell lung cancer (NSCLC) is not clear. Here, we examined the expression pattern, clinical significance, and function of GPR115 in NSCLC by analysis of clinical specimens and human cell lines and bioinformatics analysis. Immunohistochemical analysis of clinical samples showed that GPR115 was significantly upregulated in NSCLC tissues compares with normal lung epithelial tissue (P < 0.05). And GPR115 overexpression is an independent prognostic factor for 5-year overall survival of NSCLC patients [hazard ratio (HR)=1.625, P = 0.008]. Interestingly, higher expression of GPR115 was strongly correlation with differentiation level (P = 0.027), tumor size (P = 0.010), lymph node metastasis (P = 0.022), tumor-node-metastasis stage (P = 0.008), and poor prognosis of lung adenocarcinoma (LUAD, all P = 0.039), but not lung squamous cell carcinoma (LUSC, P > 0.05). Moreover, downregulation of GPR115 by RNA interference in human lung cancer lines inhibited cell proliferation, migration, and invasion. Preliminary bioinformatic analysis confirmed that GPR115 was closely associated with LAMC2 (Spearman correlation coefficient=0.67, P < 0.05), which was accumulated in ECM-receptor interaction and focal adhesion. Consistent with these findings, deceased of GPR115 was associated with E-cadherin, N-cadherin and Vimentin confirmed by western blot. In conclusion, these data suggest that GPR115 may play a role in the tumor growth and metastasis and may have utility as a diagnostic and prognostic marker for LUAD, but not LUSC.

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The ADAM17 protease promotes tobacco smoke carcinogen-induced lung tumorigenesis

Carcinogenesis ◽

10.1093/carcin/bgz123 ◽

2019 ◽

Vol 41 (4) ◽

pp. 527-538 ◽

Cited By ~ 6

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.

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The Marine Dinoflagellate Alexandrium minutum Activates a Mitophagic Pathway in Human Lung Cancer Cells

Marine Drugs ◽

10.3390/md16120502 ◽

2018 ◽

Vol 16 (12) ◽

pp. 502 ◽

Cited By ~ 6

Author(s):

Christian Galasso ◽

Genoveffa Nuzzo ◽

Christophe Brunet ◽

Adrianna Ianora ◽

Angela Sardo ◽

...

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Cancer Cells ◽

Human Lung ◽

Water Soluble ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Normal Lung ◽

Alexandrium Minutum ◽

Human Lung Cancer Cells

Marine dinoflagellates are a valuable source of bioactive molecules. Many species produce cytotoxic compounds and some of these compounds have also been investigated for their anticancer potential. Here, we report the first investigation of the toxic dinoflagellate Alexandrium minutum as source of water-soluble compounds with antiproliferative activity against human lung cancer cells. A multi-step enrichment of the phenol–water extract yielded a bioactive fraction with specific antiproliferative effect (IC50 = 0.4 µg·mL−1) against the human lung adenocarcinoma cells (A549 cell line). Preliminary characterization of this material suggested the presence of glycoprotein with molecular weight above 20 kDa. Interestingly, this fraction did not exhibit any cytotoxicity against human normal lung fibroblasts (WI38). Differential gene expression analysis in A549 cancer cells suggested that the active fraction induces specific cell death, triggered by mitochondrial autophagy (mitophagy). In agreement with the cell viability results, gene expression data also showed that no mitophagic event was activated in normal cells WI38.

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Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer

Journal of Experimental Medicine ◽

10.1084/jem.20190249 ◽

2019 ◽

Vol 216 (9) ◽

pp. 2128-2149 ◽

Cited By ~ 32

Author(s):

James Clarke ◽

Bharat Panwar ◽

Ariel Madrigal ◽

Divya Singh ◽

Ravindra Gujar ◽

...

Keyword(s):

Lung Cancer ◽

Single Cell ◽

Ex Vivo ◽

Cell Subset ◽

Chromatin Accessibility ◽

Transcriptomic Analysis ◽

Human Lung Cancer ◽

Normal Lung ◽

Molecular Characteristics ◽

Resident Memory T Cells

High numbers of tissue-resident memory T (TRM) cells are associated with better clinical outcomes in cancer patients. However, the molecular characteristics that drive their efficient immune response to tumors are poorly understood. Here, single-cell and bulk transcriptomic analysis of TRM and non-TRM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1–expressing TRM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1–expressing non-TRM cells. This feature was more prominent in the TRM cell subset coexpressing PD-1 and TIM-3, and it was validated by functional assays ex vivo and also reflected in their chromatin accessibility profile. This PD-1+TIM-3+ TRM cell subset was enriched in responders to PD-1 inhibitors and in tumors with a greater magnitude of CTL responses. These data highlight that not all CTLs expressing PD-1 are dysfunctional; on the contrary, TRM cells with PD-1 expression were enriched for features suggestive of superior functionality.

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Lycopene Protects against Smoking-Induced Lung Cancer by Inducing Base Excision Repair

Antioxidants ◽

10.3390/antiox9070643 ◽

2020 ◽

Vol 9 (7) ◽

pp. 643 ◽

Cited By ~ 1

Author(s):

Junrui Cheng ◽

Baxter Miller ◽

Emilio Balbuena ◽

Abdulkerim Eroglu

Keyword(s):

Oxidative Stress ◽

Lung Cancer ◽

Cigarette Smoke ◽

Connexin 43 ◽

Excision Repair ◽

Critical Role ◽

A549 Cells ◽

Human Lung Cancer ◽

Cigarette Smoke Exposure ◽

Mrna Levels

Background: Oxidative stress plays a critical role in lung cancer progression. Carotenoids are efficient antioxidants. The objective of this study was to explore the efficacy of all-trans retinoic acid (ATRA) and carotenoids in cigarette smoke-induced oxidative stress within A549 human lung cancer epithelial cells. Methods: A549 cells were pretreated with 1-nM, 10-nM, 100-nM, 1-μM and 10-μM ATRA, β-carotene (BC) and lycopene for 24 h, followed by exposure to cigarette smoke using a smoking chamber. Results: The OxyBlot analysis showed that smoking significantly increased oxidative stress, which was inhibited by lycopene at 1 nM and 10 nM (p < 0.05). In the cells exposed to smoke, lycopene increased 8-oxoguanine DNA glycosylase (OGG1) expression at 1 nM, 10 nM, 100 nM, and 1 μM (p < 0.05), but not at 10 μM. Lycopene at lower doses also improved Nei like DNA glycosylases (NEIL1, NEIL2, NEIL3), and connexin-43 (Cx43) protein levels (p < 0.05). Interestingly, lycopene at lower concentrations promoted OGG1 expression within the cells exposed to smoke to an even greater extent than the cells not exposed to smoke (p < 0.01). This may be attributed to the increased SR-B1 mRNA levels with cigarette smoke exposure (p < 0.05). Conclusions: Lycopene treatment at a lower dosage could inhibit smoke-induced oxidative stress and promote genome stability. These novel findings will shed light on the molecular mechanism of lycopene action against lung cancer.

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