title: 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.
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.|b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.|b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.|b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Gu
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Xie
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.|b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Che
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Lung-Chi
authors.initials: LC
authors.lastname: Chen
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lyu
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.affiliation: a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.|b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D001980:Bronchi / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009532:Nickel / Q000009:adverse effects*; D000071456:Sequestosome-1 Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000071186:Beclin-1; D047908:Intracellular Signaling Peptides and Proteins; D018942:Macrolides; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014409:Tumor Necrosis Factor-alpha; C025946:3-methyladenine; D009532:Nickel; C040929:bafilomycin A1; D000071189:Autophagy-Related Protein-1 Homolog; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D000225:Adenine
keywords: RELA; SQSTM1/p62; autophagy; malignant transformation; nickel