scholarly journals Methyl DNA phosphate adduct formation in lung tumor tissue and adjacent normal tissue of lung cancer patients

2019 ◽  
Vol 40 (11) ◽  
pp. 1387-1394 ◽  
Author(s):  
Bin Ma ◽  
Peter W Villalta ◽  
J Bradley Hochalter ◽  
Irina Stepanov ◽  
Stephen S Hecht
Keyword(s):  
Lung Cancer ◽  
Dna Adducts ◽  
Human Lung ◽  
Lung Tumor ◽  
Normal Lung ◽  
Lung Cancer Patients ◽  
Normal Tissues ◽  
Phosphate Backbone ◽  
Limit Of Quantitation ◽  
Methylating Carcinogens

Abstract The formation of methyl DNA adducts is a critical step in carcinogenesis initiated by the exposure to methylating carcinogens. Methyl DNA phosphate adducts, formed by methylation of the oxygen atoms of the DNA phosphate backbone, have been detected in animals treated with methylating carcinogens. However, detection of these adducts in human tissues has not been reported. We developed an ultrasensitive liquid chromatography–nanoelectrospray ionization–high resolution tandem mass spectrometry method for detecting methyl DNA phosphate adducts. Using 50 μg of human lung DNA, a limit of quantitation of two adducts/1010 nucleobases was achieved. Twenty-two structurally unique methyl DNA phosphate adducts were detected in human lung DNA. The adduct levels were measured in both tumor and adjacent normal tissues from 30 patients with lung cancer, including 13 current smokers and 17 current non-smokers, as confirmed by measurements of urinary cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Levels of total methyl DNA phosphate adducts in normal lung tissues were higher in smokers than non-smokers, with an average of 13 and 8 adducts/109 nucleobases, respectively. Methyl DNA phosphate adducts were also detected in lung tissues from untreated rats with steady-state levels of 5–7 adducts/109 nucleobases over a period of 70 weeks. This is the first study to report the detection of methyl DNA phosphate adducts in human lung tissues. The results provide new insights toward using these DNA adducts as potential biomarkers to study human exposure to environmental methylating carcinogens.

Decreased Expression of Decorin and p57(KIP2) Correlates with Poor Survival and Lymphatic Metastasis in Lung Cancer Patients

2011 ◽  
Vol 26 (1) ◽  
pp. 9-21 ◽  
Author(s):  
Rong Biaoxue ◽  
Cai Xiguang ◽  
Liu Hua ◽  
Ma Hui ◽  
Yang Shuanying ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Lymphatic Metastasis ◽  
Expression Level ◽  
Normal Lung ◽  
Tgf Beta ◽  
Expression Levels ◽  
Lung Cancer Patients ◽  
Normal Tissues ◽  
Tumor Tissues

Purpose Decorin, p57(KIP2), and TGF-beta 1 have been investigated as prognostic factors because they appear to be associated with tumorigenesis; however, the effect of decorin and p57(KIP2) in lung cancer remains poorly understood. The purpose of this study was to examine the expression of decorin, p57(KIP2), and TGF-beta 1 in 64 lung cancer specimens and 36 normal lung specimens, and to analyze the relationships with respect to clinicopathological features and patient survival in lung cancer. Methods The expression levels of decorin, p57(KIP2), and TGF-beta 1 were examined by in situ hybridization and immunohistochemistry. Results Normal tissues exhibited a higher expression level of decorin than tumor tissues (P<0.05) and tumor tissues exhibited a higher expression level of TGF-beta 1 than normal tissues (P<0.05). The expression levels of p57(KIP2) and TGF-beta 1 were significantly associated with histological types of lung cancer (P<0.05), and the expression levels of decorin and p57(KIP2) were significantly associated with lymphatic invasion (P<0.05). Moreover, increased expression of decorin and p57(KIP2) correlated with increased survival (decorin, p=0.018; p57(KIP2), p=0.012). Conclusion Decreased expression levels of decorin and p57(KIP2) were associated with poor postsurgical survival time and lymphatic metastasis in lung cancer patients; moreover, low expression was an adverse prognostic factor.

scholarly journals Targeting HSP90 Inhibits Proliferation and Induces Apoptosis Through AKT1/ERK Pathway in Lung Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Mengyuan Niu ◽  
Bin Zhang ◽  
Li Li ◽  
Zhonglan Su ◽  
Wenyuan Pu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cell ◽  
Lung Tumor ◽  
Hsp90 Inhibitor ◽  
Tumor Xenograft ◽  
Mouse Lung ◽  
Lung Cancer Cell ◽  
Lung Cancer Patients ◽  
Normal Tissues

Lung cancer is one of the most common malignant cancers worldwide. Searching for specific cancer targets and developing efficient therapies with lower toxicity is urgently needed. HPS90 is a key chaperon protein that has multiple client proteins involved in the development of cancer. In this study, we investigated the transcriptional levels of HSP90 isoforms in cancerous and normal tissues of lung cancer patients in multiple datasets. The higher expression of HSP90AA1 in cancer tissues correlated with poorer overall survival was observed. The higher levels of transcription and expression of HSP90AA1 and the activity of AKT1/ERK pathways were confirmed in lung cancer patient tissues. In both human and mouse lung cancer cell lines, knocking down HSP90AA1 promoted cell apoptosis through the inhibition of the pro-survival effect of AKT1 by decreasing the phosphorylation of itself and its downstream factors of mTOR and BAD, as well as downregulating Mcl1, Bcl-xl, and Survivin. The knockdown also suppressed lung cancer cell proliferation by inhibiting ERK activation and downregulating CyclinD1 expression. The treatment of 17-DMAG, an HSP90 inhibitor, recaptured these effects in vitro and inhibited tumor cell growth, and induced apoptosis without obvious side effects in lung tumor xenograft mouse models. This study suggests that targeting HSP90 by 17-DMAG could be a potential therapy for the treatment of lung cancer.

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

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.

scholarly journals Single-Cell Expression Landscape of SARS-CoV-2 Receptor ACE2 and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1250
Author(s):  
Guangchun Han ◽  
Ansam Sinjab ◽  
Kieko Hara ◽  
Warapen Treekitkarnmongkol ◽  
Patrick Brennan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Single Cell ◽  
Cancer Patients ◽  
Expression Profiles ◽  
Lung Cells ◽  
Alveolar Type ◽  
Specific Expression ◽  
Lung Cancer Patients ◽  
Normal Tissues ◽  
Cell Expression

The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of ACE2 and SARS-CoV-2-priming proteases TMPRSS2 and TMPRSS4 in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of ACE2, TMPRSS2, and TMPRSS4. Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that ACE2 levels were highest in normal alveolar type 2 (AT2) cells and that TMPRSS2 was expressed in 65% of normal AT2 cells. Conversely, the expression of TMPRSS4 was highest and most frequently detected (75%) in lung cells with malignant features. ACE2-positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated HHIP, and the scavengers CD36 and DMBT1. Notably, the viral scavenger DMBT1 was significantly positively correlated with ACE2 expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.

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

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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