The role of restored expression of RECK gene in regulating carcinogenesis and invasion by demethylation agent in oral squamous cell carcinoma cell lines

RECK基因恢复表达在去甲基化剂调控口腔鳞癌细胞系癌变和侵袭中的作用

• 批准号: 17592070
• 负责人: KATO Keizo
• 金额: $ 1.54万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17592070/
• 关键词: oral cancer; hypermethylation; RECK; demethylation; 口腔願

We have previously reported that MMP-2active form correlated with lymph node metastasis. RECK, a novel tumor suppressor gene, was recently found to regulate the activity of MMPs and MT1-MMP. Down regulation of RECK gene plays an important role in malignant progress of cancer cells. Furthermore, hypermethylation is known as the epigenetic change that is associated with cancer development. Therefore determination of hypermethylation is important in carcinogenesis process. However, study on methylation status of RECK gene in oral squamous cell carcinoma has not yet been reported. We investigate that reversal of hypermethylation of RECK gene may relate to inhibition of MMPs activity and cancer invasive ability.The present results showed that hypermethylation occurred in RECK gene promoter in oral squamous cell carcinoma cell lines. In addition, enhanced expression of RECK mRNA was confirmed by RT-PCR and mRNA levels were clearly associated with reversal of hypermethylation of RECK in these cell lines after treatment with 5-aza-2'-deoxycytidine. Furthermore, the inhibition of MMP-2 and MMP-9 activities was also observed in cancer cells after treatment with demethylation agent. Interestingly, 5-aza-2'-deoxycytidine significantly suppressed cancer cell invasive ability by decreasing the number of invasive foci in three-dimensional collagen invasion model.Our findings support the conclusion that demethylation agent plays a crucial role in inhibiting MMPs activities and cell invasive ability possibly by demethylation effect of MMPs inhibitors such as RECK.

我们先前已经报道了MMP-2活动形式与淋巴结转移相关。 RECK是一种新型的肿瘤抑制基因，最近被发现可以调节MMP和MT1-MMP的活性。降低RECK基因在癌细胞的恶性进展中起重要作用。此外，高甲基化被称为与癌症发展相关的表观遗传变化。因此，确定高甲基化在癌变过程中很重要。然而，尚未报道对口服鳞状细胞癌中RECK基因的甲基化状态的研究。我们研究了RECK基因高甲基化的逆转可能与MMPS活性和癌症侵入性能力的抑制有关。目前的结果表明，在口服鳞状细胞癌细胞系中的Reck Gene启动子中发生了高甲基化。此外，通过RT-PCR证实了RECK mRNA的增强表达，mRNA水平显然与5-aza-2'-脱氧胞苷处理后，在这些细胞系中，在这些细胞系中的高甲基化逆转有关。此外，在用脱甲基化剂治疗后，在癌细胞中还观察到了MMP-2和MMP-9活性的抑制作用。有趣的是，5-aza-2'-脱氧胞苷丁丁通过减少三维胶原入侵模型的侵入性焦点的数量来显着抑制癌细胞的侵入性能力。它支持这样的结论，即脱甲基化剂在抑制MMP的活性和细胞侵入能力中可能通过脱甲基化效应的MMPS活性和细胞侵入能力在MMMMMMMMMMMMMMMMMMMMS中起着至关重要的作用。

项目成果

Recent Advances in Gastrointestinal Carcinogenesis

胃肠癌发生的最新进展

• 发表时间: 2006
• 作者: Higashi;H.
• 通讯作者: H.

Multistep carcinogenesis of the colon in Apcmi^<min/+> mouse

Apcmi^<min/> 小鼠结肠多步癌变

• 发表时间: 2007
• 期刊: Cancer Science 98・1
• 作者: Yasuhiro Yamada;Hideki Mori
• 通讯作者: Hideki Mori

Chemopreventive effect of fermented brown rice and bran on 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rat

发酵糙米和麸皮对4-硝基喹啉1-氧化物诱导的大鼠口腔癌的化学预防作用

• 发表时间: 2007
• 期刊: Oncology Reports 17 (4)
• 作者: Yasuhiro Yamada;Hideki Mori;Nguyen Khanh Long
• 通讯作者: Nguyen Khanh Long

Chemopreventive effect of fermented brown rice and bran on 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats

发酵糙米和麸皮对4-硝基喹啉1-氧化物诱导的大鼠口腔癌的化学预防作用

• 发表时间: 2007
• 期刊: Oncology Reports 17・4
• 作者: Nguyen Khanh Long;Hiroki Makita;Tomomi Yamashita;Makoto Toida;Keizo Kato;Daijiro Hatakeyama;Toshiyuki Shibata
• 通讯作者: Toshiyuki Shibata

Inhibitory effects of fermented brown rice and bran on the development of acute hepatitis in Long-Evans Cinnamon rats

发酵糙米和麸皮对肉桂大鼠急性肝炎的抑制作用

• 发表时间: 2006
• 期刊: Oncology Reports 15・4
• 作者: Toshiyuki Shibata;Hiroki Nagayasu;Hiroyuki Kitajo;Makoto Arisue;Tomomi Yamashita;Daijiro Hatakeyama;Teruaki Iwasaki;Hiroshi Kobayashi
• 通讯作者: Hiroshi Kobayashi