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Effect of EGCG on bronchial epithelial cell premalignant lesions induced by cigarette smoke and on its CYP1A1 expression

ABSTRACT: Epigallocatechin-3-gallate (EGCG) has been demonstrated to exhibit anticancer effects; however, the mechanisms behind these are not yet clear. The objective of the present study was to assess the effect of EGCG on smoking-induced, precancerous, bronchial epithelial cell lesions and determine a potential protective mechanism. Human bronchial epithelial (HBE) cells were treated with cigarette smoke extract (CSE). Benzopyrene-DNA adducts were detected by immunofluorescence cytochemistry. Changes to microRNA (miRNA) expression levels were detected via microarray. The effects of EGCG on smoke-induced benzopyrene-DNA adduct formation and the subsequent change in miRNA expression were analyzed. Subsequently, the protective effect of EGCG on smoke inhalation-induced precancerous lesions was investigated. The expression levels of miRNA target genes were also analyzed. After CSE treatment, benzopyrene-DNA adducts appeared in HBE cells, along with a resultant change in miRNA expression. EGCG inhibited the effects of CSE exposure; benzopyrene-DNA adduct formation was reduced and miRNA expression changes were suppressed. In vivo, EGCG significantly reduced benzopyrene-DNA adduct formation and the subsequent development of precancerous lesions in rat lungs induced by cigarette smoke inhalation. Moreover, EGCG downregulated CYP1A1 overexpression, a target gene of multiple smoking-induced miRNAs, in rat lungs. EGCG may reduce the risk of lung cancer by downregulating the expression of the key gene CYP1A1, preventing the formation of smoking-induced benzopyrene-DNA adducts and alleviating smoking-induced bronchial epithelial dysplasia and heterogeneity.

SUBMITTER: Gu Q

PROVIDER: S-EPMC8559702 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study analyzes the correlation and interaction of miRNAs and mRNAs and their biological function in the malignant transformation of BEAS-2B cells induced by cigarette smoke (CS). Normal human bronchial epithelial cells (BEAS-2B) were continuously exposed to CS for 30 passages (S30) to establish an in vitro cell model of malignant transformation. The transformed cells were validated by scratch wound healing assay, transwell migration assay, colony formation and tumorigenicity assay. The miRNA and mRNA sequencing analysis were performed to identify differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) between normal BEAS-2B and S30 cells. The miRNA-seq data of lung cancer with corresponding clinical data obtained from TCGA was used to further identify lung cancer-related DEMs and their correlations with smoking history. The target genes of these DEMs were predicted using the miRDB database, and their functions were analyzed using the online tool "Metascape." It was found that the migration ability, colony formation rate and tumorigenicity of S30 cells enhanced. A total of 42 miRNAs and 753 mRNAs were dysregulated in S30 cells. The change of expression of top five DEGs and DEMs were consistent with our sequencing results. Among these DEMs, eight miRNAs were found dysregulated in lung cancer tissues based on TCGA data. In these eight miRNAs, six of them including miR-96-5p, miR-93-5p, miR-106-5p, miR-190a-5p, miR-195-5p, and miR-1-3p, were found to be associated with smoking history. Several DEGs, including THBS1, FN1, PIK3R1, CSF1, CORO2B, and PREX1, were involved in many biological processes by enrichment analysis of miRNA and mRNA interaction. We identified the negatively regulated miRNA-mRNA pairs in the CS-induced lung cancer, which were implicated in several cancer-related (especially EMT-related) biological process and KEGG pathways in the malignant transformation progress of lung cells induced by CS. Our result demonstrated the dysregulation of miRNA-mRNA profiles in cigarette smoke-induced malignant transformed cells, suggesting that these miRNAs might contribute to cigarette smoke-induced lung cancer. These genes may serve as biomarkers for predicting lung cancer pathogenesis and progression. They can also be targets of novel anticancer drug development.

Project description:While lung cancer is the leading cause of cancer death in the US, we have a limited understanding of the earliest molecular events preceding the onset of disease. Prior work has demonstrated that cigarette smoke creates a molecular “field of injury” throughout the airway epithelium and that there are distinct alterations in the airway transcriptome among smokers who have lung cancer. Molecular characterization of this airway “field of injury” in current and former smokers with premalignant lesions (PMLs) could provide novel insights into the earliest molecular events associated with lung carcinogenesis and identify relatively accessible biomarkers to guide lung cancer detection and early intervention. Using mRNA sequencing (mRNA-Seq), we profiled 82 cytologically normal bronchial airway epithelial cells collected during autofluorescence bronchoscopy from high-risk smokers with and without bronchial PMLs, 75 of which were used in downstream analyses. We identified 280 genes differentially expressed in the “field of injury” between subjects with (n=50) and without (n=25) PMLs (FDR<0.002), 81 of which were up-regulated in subjects with PMLs. Oxidative phosphorylation (OXPHOS), the electron transport chain (ETC), and mitochondrial protein transport pathways were strongly enriched among these up-regulated genes (FDR<0.05). We next demonstrated that OXPHOS activation is shared between the “field” and the PMLs with increased oxygen consumption and increased staining for mitochondrial markers in biopsies of PMLs from patients as well as an animal model of lung squamous cell carcinoma (SCC) premalignancy. The 280-gene signature also has a significant concordant relationship to gene expression changes identified in PMLs adjacent to lung SCC tumors, in lung SCC tumors, and in the cytologically normal airway of individuals with lung cancer (FDR<0.05). These findings suggest that these expression changes are reflective of early cancer-associated changes occurring throughout the respiratory tract, and that pathways such as OXPHOS may be targets for chemoprevention. We subsequently developed an airway gene expression biomarker that predicts the presence of PMLs (AUC=0.92, n=17 samples in test set) and show that changes in the biomarker score are associated with progression and regression of PMLs in an independent cohort (AUC=0.75, n=51 samples). The biomarker results indicate that molecular alterations in the field of injury are dynamic with progression or regression of PMLs, suggesting that these changes may be leveraged to stratify high-risk smokers with progressive disease into early intervention trials and monitor disease progression or recurrence.

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Effect of EGCG on bronchial epithelial cell premalignant lesions induced by cigarette smoke and on its CYP1A1 expression

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