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Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.

ABSTRACT: Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.

SUBMITTER: Huang H

PROVIDER: S-EPMC5079680 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.

Huang Haishan H Zhu Junlan J Li Yang Y Zhang Liping L Gu Jiayan J Xie Qipeng Q Jin Honglei H Che Xun X Li Jingxia J Huang Chao C Chen Lung-Chi LC Lyu Jianxin J Gao Jimin J Huang Chuanshu C

Autophagy 20160728 10

Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulti ...[more]

PMID: 27467530

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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:BackgroundIFN-γ has been traditionally recognized as an inflammatory cytokine that involves in inflammation and autoimmune diseases. Previously we have shown that sustained IFN-γ induced malignant transformation of bovine mammary epithelial cells (BMECs) via arginine depletion. However, the molecular mechanism underlying this is still unknown.MethodsIn this study, the amino acids contents in BMECs were quantified by a targeted metabolomics method. The acquisition of differentially expressed genes was mined from RNA-seq dataset and analyzed bioinformatically. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry (IHC) assay were performed to detect gene mRNA and protein expression levels. CCK-8 and would healing assays were used to detect cell proliferation and migration abilities, respectively. Cell cycle phase alternations were analyzed by flow cytometry.ResultsThe targeted metabolomics analysis specifically discovered IFN-γ induced arginine depletion through accelerating arginine catabolism and inhibiting arginine anabolism in BMECs. Transcriptome analysis identified leucine aminopeptidase 3 (LAP3), which was regulated by p38 and ERK MAPKs, to downregulate arginine level through interfering with argininosuccinate synthetase (ASS1) as IFN-γ stimulated. Moreover, LAP3 also contributed to IFN-γ-induced malignant transformation of BMECs by upregulation of HDAC2 (histone deacetylase 2) expression and promotion of cell cycle proteins cyclin A1 and D1 expressions. Arginine supplementation did not affect LAP3 and HDAC2 expressions, but slowed down cell cycle process of malignant BMECs. In clinical samples of patients with breast cancer, LAP3 was confirmed to be upregulated, while ASS1 was downregulated compared with healthy control.ConclusionsThese results demonstrated that LAP3 mediated IFN-γ-induced arginine depletion to malignant transformation of BMECs. Our findings provide a potential therapeutic target for breast cancer both in humans and dairy cows.

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Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.

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Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.

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