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肺癌中MARVELD1基因表观遗传沉默的生物学及临床意义

Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer.

作者信息

Shi Ming, Wang Shan, Yao Yuanfei, Li Yiqun, Zhang Hao, Han Fang, Nie Huan, Su Jie, Wang Zeyu, Yue Lei, Cao Jingyan, Li Yu

机构信息

School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.

Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.

出版信息

Sci Rep. 2014 Dec 18;4:7545. doi: 10.1038/srep07545.

DOI:10.1038/srep07545
PMID:25520033
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4269892/
Abstract

Epigenetic silence in cancer frequently altered signal-transduction pathways during the early stages of tumor development. Recent progress in the field of cancer epigenetics has led to new opportunities for diagnosis and treatment of cancer. We previously demonstrated that novel identified nuclear factor MARVELD1 was widely expressed in human tissues, but down-regulated by promoter methylation in multiple cancers. This study was carried out to determine the biological and clinical significance of MARVELD1 gene silencing in lung cancer. Here, we found the reduced MARVELD1 expression significantly correlated with diagnostic histopathology and malignant degree of lung cancers. DNA hypermethylation and histone deacetylation synergistically inactivated MARVELD1 gene in lung cancer cells. Moreover, MARVELD1 modulated the efficiency of nonsense-mediated mRNA decay (NMD) through interaction with NMD core factor SMG1. The decreased MARVELD1 level in lung cancer reduces NMD efficiency through diminishing the association between NMD complex component UPF1/SMG1 and premature termination codons containing mRNA (PTC-mRNA). The results suggested that MARVELD1 silencing is an appealing diagnostic biomarker for lung cancer and epigenetic silencing of MARVELD1 gene links with the regulatory mechanism of NMD pathway in lung cancer, which may be required for tumorigenesis.

摘要

癌症中的表观遗传沉默在肿瘤发展早期经常改变信号转导通路。癌症表观遗传学领域的最新进展为癌症的诊断和治疗带来了新机遇。我们先前证明，新鉴定出的核因子MARVELD1在人体组织中广泛表达，但在多种癌症中因启动子甲基化而下调。本研究旨在确定MARVELD1基因沉默在肺癌中的生物学和临床意义。在此，我们发现MARVELD1表达降低与肺癌的诊断组织病理学和恶性程度显著相关。DNA高甲基化和组蛋白去乙酰化协同作用使肺癌细胞中的MARVELD1基因失活。此外，MARVELD1通过与NMD核心因子SMG1相互作用来调节无义介导的mRNA降解（NMD）效率。肺癌中MARVELD1水平降低通过减少NMD复合物组分UPF1/SMG1与含过早终止密码子的mRNA（PTC-mRNA）之间的关联而降低NMD效率。结果表明，MARVELD1沉默是一种有吸引力的肺癌诊断生物标志物，且MARVELD1基因的表观遗传沉默与肺癌中NMD途径的调控机制相关联，这可能是肿瘤发生所必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/70d4101bc5e8/srep07545-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/ffa7cd64aafb/srep07545-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/9092514505d8/srep07545-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/97ad52d2b574/srep07545-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/6192b1ff1966/srep07545-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/cc269a93c9f0/srep07545-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/70d4101bc5e8/srep07545-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/ffa7cd64aafb/srep07545-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/9092514505d8/srep07545-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/97ad52d2b574/srep07545-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/6192b1ff1966/srep07545-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/cc269a93c9f0/srep07545-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b861/4269892/70d4101bc5e8/srep07545-f6.jpg

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