MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling.
MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling.
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MEST通过与VCP相互作用激活NF-κB信号促进肺癌侵袭和转移
DOI：
10.1186/s13046-021-02107-1
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发表时间：
2021-09-24
期刊：
影响因子：
--
通讯作者：
He QY
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang J;Li YJ;Yu NN;Liu WT;Liang JZ;Xu WW;Sun ZH;Li B;He QY
背景细胞侵袭是转移性肿瘤的标志，导致不良的临床结果。在本研究中，我们建立了两种高侵袭性肺癌细胞模型（A549-i8和H1299-i8），并鉴定了中胚层特异性转录物（MEST）作为肺癌侵袭性调节因子。目的探讨其生物学功能及其在肺癌转移中的临床意义。免疫组化法检测MEST在肿瘤组织中的表达。质谱和生物信息学分析用于鉴定MEST调节的蛋白质和结合伴侣。免疫共沉淀法检测MEST与VCP的相互作用。在体外和体内研究了MEST的生物学功能。结果MEST过表达通过激活NF-κB信号通路促进肺癌细胞的体内外转移。MEST增强了VCP与IκBα的相互作用，从而加速了IκBα的降解和NF-κB的激活。这种加速作用被VCP沉默消除，表明MEST是VCP/IκBα/NF-κB信号通路的上游激活剂。结论MEST通过与VCP相互作用协调IκBα/NF-κB α通路，在肺癌侵袭转移中发挥重要作用。靶向MEST/VCP/IκBα/NF-κB信号通路可能是治疗肺癌的一个有希望的策略。
BackgroundCell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcomes. In this study, we established two highly invasive lung cancer cell models (A549-i8 and H1299-i8) and identified mesoderm-specific transcript (MEST) as a novel invasive regulator of lung cancer. We aim to characterize its biological function and clinical significance in lung cancer metastasis.MethodsTranswell invasion assay was performed to establish high-invasive lung cancer cell model. Immunohistochemistry (IHC) was used to detect MEST expression in tumor tissues. Mass spectrometry and bioinformatic analyses were used to identify MEST-regulated proteins and binding partners. Co-immunoprecipitation assay was performed to detect the interaction of MEST and VCP. The biological functions of MEST were investigated in vitro and in vivo. Immunofluorescence staining was conducted to explore the colocalization of MEST and VCP.ResultsMEST overexpression promoted metastasis of lung cancer cells in vivo and in vitro by activating NF-κB signaling. MEST increased the interaction between VCP and IκBα, which accelerated IκBα degradation and NF-κB activation. Such acceleration was abrogated by VCP silencing, indicating that MEST is an upstream activator of the VCP/IκBα/NF-κB signaling pathway. Furthermore, high expressions of MEST and VCP were associated with poor survival of lung cancer patients.ConclusionCollectively, these results demonstrate that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP to coordinate the IκBα/NF-κB pathway. Targeting the MEST/VCP/IκBα/NF-κB signaling pathway may be a promising strategy to treat lung cancer.
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DOI：
10.1084/jem.188.6.1055
发表时间：
1998-09-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cheng JD;Ryseck RP;Attar RM;Dambach D;Bravo R
通讯作者：
Bravo R
影响因子：
11.5
作者：
Li, Bin;Tsao, Sai Wah;Cheung, Annie L. M.
通讯作者：
Cheung, Annie L. M.
DOI：
10.1016/j.biopha.2020.110569
发表时间：
2020-10-01
期刊：
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
影响因子：
--
作者：
Rasmi, Rajan Radha;Sakthivel, Kunnathur Murugesan;Guruvayoorappan, Chandrasekaran
通讯作者：
Guruvayoorappan, Chandrasekaran
影响因子：
56.9
作者：
BROWN, K;GERSTBERGER, S;SIEBENLIST, U
通讯作者：
SIEBENLIST, U
影响因子：
5.7
作者：
Li, Bin;Li, Yuk Yin;Cheung, Annie L. M.
通讯作者：
Cheung, Annie L. M.