https://scholars.lib.ntu.edu.tw/handle/123456789/160281
標題: | PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation of MMP2 | 作者: | Kuo, Hong-Yi Huang, Yen-Sung Tseng, Chin-Hsiu Chen, Yi-Chen Chang, Yu-Wei Shih, Hsiu-Ming Wu, Cheng-Wen |
關鍵字: | ATRS;Interferon-;lung adenocarcinoma;MMP2;nuclear EGFR;PML;STAT3;promyelocytic leukemia protein;EGFR;EGF receptor;LAC;nEGFR;matrix metalloprotease-2;AT-rich sequence;IFN;interferon-;INM;inner nuclear membrane | 公開日期: | 2014 | 起(迄)頁: | 3132-3142 | 來源出版物: | Cell Cycle | 摘要: | Promyelocytic leukemia protein (PML) is emerging as an important tumor suppressor. Its expression is lost during the progression of several types of cancer, including lung cancer. The EGF receptor (EGFR), a membrane-bound receptor tyrosine kinase, transduces intracellular signals responsible for cell proliferation, differentiation and migration. EGFR activity is frequently abnormally upregulated in lung adenocarcinoma (LAC) and thus is considered to be a driving oncogene for LAC. EGFR translocates into the nucleus and transcriptionally activates genes, such as CCND1, that promote cell growth. Recently, we demonstrated that PML interacted with nuclear EGFR (nEGFR) and suppressed the nEGFR-mediated transcriptional activation of CCND1 in lung cancer cells, thereby restraining cell growth. When we further investigated the interplay between PML and EGFR in lung cancer metastasis, we found that the matrix metalloprotease-2 gene (MMP2) was a novel nEGFR target gene and was repressed by PML. We provide evidence that nEGFR bound to the AT-rich sequence (ATRS) in the MMP2 promoter and enhanced its transcriptional activity. In addition, we demonstrated that PML repressed nEGFR-induced MMP2 transcription and reduced cell invasion. PML was recruited by nEGFR to the MMP2 promoter where it reduced histone acetylation, leading to the transcriptional repression of MMP2. Finally, we demonstrated that PML upregulation by interferon- (IFN) in lung cancer cells decreased MMP2 expression and cell invasion. Together, our results suggested that IFN induced PML to inhibit lung cancer metastasis by repressing the nEGFR-mediated transcriptional activation of MMP2. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/278978 | DOI: | 10.4161/15384101.2014.949212 | SDG/關鍵字: | beta interferon; epidermal growth factor receptor; gelatinase A; promyelocytic leukemia protein; STAT3 protein; beta interferon; cyclin D1; epidermal growth factor; epidermal growth factor receptor; gelatinase A; histone; nuclear protein; PML protein, human; small interfering RNA; STAT3 protein; transcription factor; tumor suppressor protein; animal experiment; animal model; Article; AT rich sequence; cancer inhibition; controlled study; enzyme activation; gene repression; histone acetylation; human; human cell; lung cancer; lung cancer cell line; metastasis; mouse; nonhuman; promoter region; protein analysis; protein expression; tumor invasion; upregulation; adenocarcinoma; animal; antagonists and inhibitors; binding site; cell nucleus; drug effects; genetics; HEK293 cell line; lung tumor; male; metabolism; metastasis; nonobese diabetic mouse; nucleotide sequence; pathology; SCID mouse; transcription initiation; tumor cell line; Adenocarcinoma; Animals; Base Sequence; Binding Sites; Cell Line, Tumor; Cell Nucleus; Cyclin D1; Epidermal Growth Factor; HEK293 Cells; Histones; Humans; Interferon-beta; Lung Neoplasms; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Nuclear Proteins; Promoter Regions, Genetic; Receptor, Epidermal Growth Factor; RNA, Small Interfering; STAT3 Transcription Factor; Transcription Factors; Transcriptional Activation; Tumor Suppressor Proteins; Up-Regulation |
顯示於: | 分子醫學研究所 |
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