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MEST Promotes Lung Cancer Invasion and Metastasis by Interacting with VCP to Activate NF-κB Signaling

ABSTRACT: Active cell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcome. We here established high-invasive lung cancer cell models, A549-i8 and H1299-i8, and identified mesoderm-specific transcript (MEST) as a novel invasive regulator for lung cancer. MEST overexpression promoted the metastasis of lung cancer cells in vivo and in vitro by activating NF-κB signaling. MEST enhanced the interaction of VCP with IκBα, which accelerated IκBα degradation and NF-κB activation. Such an acceleration could be abrogated by VCP silencing, indicating that MEST is an upstream regulator to induce the sequential VCP/IκBα/NF-κB signaling. Furthermore, high MEST and VCP expressions were associated with poor survival of lung cancer patients. Collectively, we demonstrated that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP, coordinating IκBα/NF-κB pathway. Targeting MEST/VCP/IκBα/NF-κB signaling may represent a promising therapeutic strategy for lung cancer.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yang Wang

PROVIDER: PXD026409 | iProX | Wed Jun 02 00:00:00 BST 2021

REPOSITORIES: iProX

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MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling.

Wang Yang Y Zhang Jing J Li Yang-Jia YJ Yu Nan-Nan NN Liu Wan-Ting WT Liang Jun-Ze JZ Xu Wen Wen WW Sun Zheng-Hua ZH Li Bin B He Qing-Yu QY

Journal of experimental & clinical cancer research : CR 20210924 1

<h4>Background</h4>Cell 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.<h4>Methods</h4>Transwell invasion assay was performed to establish high-invasive lung cancer ce ...[more]

PMID: 34560900

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Project description:Background: JAG-1 is a ligand of Notch signaling and can regulate cell differentiation and proliferation in cancers. Recent studies indicated that JAG1 is a gene associated with cancer progression. Therefore, we investigated the role of JAG1 in lung cancer progression. Methods: The expression of JAG1 was manipulated by overexpression or RNA silencing in several human lung cell lines. The effect of JAG1 on tumorigenesis and invasion was assessed by the cell anchorage-independent growth, cell proliferation, cell migration and invasion assays in vitro as well as metastasis in vivo. The potential downstream genes of JAG1 were identified by oligonucleotide microarrays and quantitative reverse transcriptionÂ¡Vpolymerase chain reaction (RT-PCR). We further measured JAG1 expression in lung cancer specimens by RT-PCR. Correlation between JAG1 expression and overall survival of lung cancer patients was determined by using the log-rank test and multivariable Cox proportional hazards regression analysis. All statistical tests were two-sided. Results: JAG1 enhanced anchorage-independent growth, cell migration, invasion in the lower invasive cells, CL1-0. JAG1 also increased the capability of migration and invasion in the other two lung cancer cell lines (A549 and NCI-H226). The silencing of JAG1 inhibited migration and invasion activities of the higher invasive cells, CL1-5, by siRNA technology. The invasion-promoting activity of JAG1 was also demonstrated in vivo by using a mouse metastasis model. By microarray analysis, we found that the expression of heat shock 70kDa protein 2 (HSPA2) was activated by JAG1 overexpression and eliminated by JAG1 silencing. Moreover, lung cancer patients with high JAG1 expressing tumors had shorter overall survival than those with low-expressing tumors. Conclusion: JAG1 might be an oncogene which promotes colonogenesis and metastasis, and high JAG1 expression is associated with shorten survival in lung cancer. In this investigation, we used a lung cancer invasion cell model to identify the genes involved in cancer progression. JAG1 is a potential oncogene whose expression is correlated to the survival of patients with breast, prostate and liver cancers. However, the role of JAG1 in lung caner progression has not been reported, particularly in metastasis. Here, JAG1 was ectopically expressed in lower invasive lung cancer cell line its impact on colonogenesis, migration and invasiveness was assessed. The underlying mechanism was explored by JAG1-expressed transfectants and microarrays and the clinical relevance was evaluated by quantitative RT-PCR.

Dataset Information

MEST Promotes Lung Cancer Invasion and Metastasis by Interacting with VCP to Activate NF-κB Signaling

Publications

MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling.

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