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.

LncRNA MEG3 downregulation mediated by DNMT3b contributes to nickel malignant transformation of human bronchial epithelial cells via modulating PHLPP1 transcription and HIF-1α translation

“…The effect of MEG3 on the expression of c-Jun and c-Myc was further validated in Beas2B(shMEG3) cells(Figure 5F). These results are also consistent with our most recently findings that nickel exposure leads to a marked nuclear translocation of c-Jun and c-Myc 26 . Therefore, we proposed that c-Jun and c-Myc might be the transcription factors for negative regulation of phlpp1 promoter transactivation through direct binding.…”

Trichoplein controls endothelial cell function by regulating autophagy

“…An NF-kB response element has been identified in the p62 promoter (Vadlamudi & Shin, 1998). Our work showed, in agreement with previous studies (Huang et al, 2016), that NF-kB/p65 binds p62 promoter and plays an important role for p62 transcriptional regulation.…”

RhoGDIβ promotes Sp1/MMP‐2 expression and bladder cancer invasion through perturbing miR‐200c‐targeted JNK2 protein translation

“…The primers used in this study were: human mmp‐2 (Forward: 5′‐caa gtg gga caa gaa cca ga‐3′, Reverse: 5′‐cca aag ttg atc atg atg tc‐3′), human sp1 (Forward: 5′‐att aac ctc agt gca ttg ggt a‐3′, Reverse: 5′‐agg gca ggc aaa ttt ctt ctc‐3′), human jnk2 (Forward: 5′‐atg aag aaa ctt cag cca act gt‐3′, Reverse: 5′‐aca gat ctc tgg ctt gac tt ‐3′) and human gapdh (Forward: 5′‐gat gat ctt gag gct gtt gtc‐3′, Reverse: 5′‐cag ggc tgc ttt taa ctc tg‐3′). Real‐time PCR was conducted following the protocol for Fast SYBR Green Master Mix kit (Applied Biosystems, Foster City, CA, USA; 4385614) in the 7900HT Fast Real‐Time PCR System (Applied Biosystems) using the same cDNs used for RT‐PCR as described in our previous publication (Huang et al ., ).…”