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博士論文 / RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-кB signaling pathway in nasopharyngeal carcinoma

著者

書誌事項

タイトル

RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-кB signaling pathway in nasopharyngeal carcinoma

著者名

Zhao Weilin

学位授与大学

三重大学 (大学ID:0046) (CAT機関ID:KI000538)

取得学位

博士(医学)

学位授与番号

甲医学第1855号

学位授与年月日

2017-09-20

注記・抄録

Background: Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck that is prevalent in Southeast Asia and southern China. Recent studies in epigenetics suggest that DNA methylation plays a pivotal role in the onset and progression of cancer. Combining the methyl- DNA binding domain capture technique and cDNA microarray analysis, we identified a unique hypermethylated gene, RERG (Ras-like estrogen-regulated growth inhibitor), that was downregulated in NPC tissues. RERG is a tumor suppressor gene that was first reported in breast cancer. However, the functions of RERG are largely unknown in other tumor types. Methods: RERG expression was assessed in human subjects (NPC primary tissues and noncancer tissues) and cell lines (NPC cell lines and an immortalized epithelial cell line NP460). Further, we investigated the methylation rate of RERG in both human subject and cell lines. 5- Aza-2’-deoxycytidine (Aza) or combined with trichostatin A (TSA) were treated to three NPC cell lines (HK1, C666-1 and HK1_EBV). In addition, the role of RERG in NPC cells and its underlying mechanisms were explored by overexpression of RERG in NPC cell lines. Results: RERG was significantly down-regulated in NPC cancer nests compared to normal nasopharyngeal epithelium cells. Furthermore, the RERG promoter was frequently methylated in NPC tissues and cell lines. The RERGmethylation rate yielded an area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.897 (95%CI: 0.818–0.976). The downregulation of RERG was restored in NPC cells treated with Aza and TSA. In addition, ectopic expression of RERG in NPC cell lines resulted in a significant suppression of cell proliferation, clonogenicity,migration and invasion. RERG-overexpressing cells showed significantly slower growth and less angiogenesis in tumor xenografts in nude mice. RERG suppressed the ERK/NF-κB signaling pathway and inhibited tumor growth and angiogenesis with downregulation of MMPs and IL8 in tumors of nude mouse xenografts. Conclusions: Our results suggest that RERG is frequently silenced by promoter CpG methylation in NPC, and acts as a functional tumor suppressor by suppressing the ERK/NF- κB signaling pathway. These findings support the potential use of RERG as a novel molecular target in NPC therapy.

本文 / Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine; Department of Otorhinolaryngology - Head and Neck Surgery, Mie University Graduate School of Medicine; Department of Otolaryngology Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University

47p

内容の要旨・審査結果の要旨 / 三重大学大学院医学系研究科 生命医科学専攻 臨床医学系講座 耳鼻咽喉・頭頸部外科学分野

キーワード

angiogenesis, DNA methylation, tumor suppressor gene, RERG, Nasopharyngeal carcinoma

各種コード

NII論文ID(NAID)

500001048743

NII著者ID(NRID)
  • 8000001159315
DOI (出版社)

10.1186/s13046-017-0554-9

本文言語コード

eng

データ提供元

機関リポジトリ / NDLデジタルコレクション

外部リンク

博士論文 / 三重大学 / 医学

博士論文 / 三重大学

博士論文 / 医学

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