Clarification of control mechanisms for metastasis/invasion in pancreatic cancer

阐明胰腺癌转移/侵袭的控制机制

• 批准号: 16390383
• 负责人: MANABE Tadao
• 金额: $ 9.09万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390383/
• 关键词: neurotrophic factor; pancreatic cancer; integrin; interleukin-lalpha; NF-kappaB; integtin

We previously reported that the neurotrophic factor, GDNF, has an important role in the invasive capability of pancreatic cancer cells. Furthermore, we confirmed that increased IL-lalpha expression is a feature of liver-metastatic pancreatic cancer cell lines and that IL-lalpha enhances adhesion molecule integrins expression and metastatic potential in pancreatic cancer cell lines via IL-1 receptor type I (IL-1RI). The aims of this study were to identify the role of GDNF and inflammatory cytokines for pancreatic cancer cell proliferative, adhesive, and invasive capabilities.We report the results that we acquired till now as follows.1. GDNF and IL-lalpha significantly enhanced the expression of a6β1 and a5β1-integrins through the activation of transcription factors such as NF-kB and AP-1.2. In all intrapancreatic nerves GDNF was expressed strongly. In pancreatic cancer tissues, the expression of RET was stronger than that seen in normal ductal cells and was significantly related to the survival rate after resection and lymphatic invasion.3. Alteration of ILK kinase activity controlled p38 MAPK phosphorylation with subsequent regulation of pancreatic cancer cell adhesion and invasion. Overexpressed ILK enhances the p38 MAPK phosphorylation strongly through GSK-3 activation which promotes aggressive capabilities of pancreatic cancer cells. In immunohistochemical analysis, statistically significant association between strong expression of ILK and poor prognosis of pancreatic cancer patients were observed.4. FAK activation correlated with the activation of Ras/ERK signaling pathways in pancreatic cancer cells and activation of these signaling pathways can be inhibited by knockdown of FAK expression with siRNA, consistent with the inhibition of adhesive and invasive capabilities of pancreatic cancer cells.

我们以前报道过，神经营养因子GDNF在胰腺癌细胞的侵袭能力中具有重要作用。此外，我们证实IL-1 α表达增加是肝转移性胰腺癌细胞系的特征，并且IL-1 α通过IL-1受体I型（IL-1 RI）增强胰腺癌细胞系中粘附分子整合素的表达和转移潜力。本研究旨在探讨GDNF和炎症因子对胰腺癌细胞增殖、粘附和侵袭能力的影响，现将研究结果报道如下：1. GDNF和IL-1 α通过激活转录因子如NF-κ B和AP-1显著增强α 6 β1和α 5 β1-整联蛋白的表达。GDNF在胰腺内神经均呈强阳性表达。RET在胰腺癌组织中的表达强于正常导管细胞，且与术后生存率和淋巴管浸润密切相关. ILK激酶活性的改变控制p38 MAPK磷酸化，随后调节胰腺癌细胞的粘附和侵袭。过表达的ILK通过GSK-3的激活而增强p38 MAPK的磷酸化，从而促进胰腺癌细胞的侵袭能力。免疫组化分析显示ILK强表达与胰腺癌患者预后不良有统计学意义. FAK激活与胰腺癌细胞中Ras/ERK信号通路的激活相关，并且这些信号通路的激活可以通过用SiRNA敲低FAK表达来抑制，这与胰腺癌细胞粘附和侵袭能力的抑制一致。

项目成果

Expression of α_6 integrin subunit is associated with malignancy in gastric gastrointestinal stromal tumors

α_6整合素亚基的表达与胃胃肠道间质瘤的恶性相关

• 发表时间: 2007
• 期刊: Medical Science Monitor 13
• 作者: Takeyama;H
• 通讯作者: H

Integrin-linked kinase activity is associated with interleukin-la-induced progressive behavior of pancreatic cancer and poor patient survival

整合素连接激酶活性与白细胞介素-1α诱导的胰腺癌进展行为和患者较差的生存率相关

• 发表时间: 2006
• 期刊: Oncogene 25
• 作者: Ozaki;K.;Nagasaka;T.;Notohara;K.;Kambara;T.;Takeda;M.;Sasamoto;H.;Jass;J.R.;Tanaka;N.;Matsubara;N.;Hirozumi Sawai;Yu Maki et al.;Hirozumi Sawai
• 通讯作者: Hirozumi Sawai

Activation of focal adhesion kinase enhances the adhesion and invasion of pancreatic cancer cells via extracellular signal-regulated kinase-1/2 signaling pathway activation.

局灶性粘附激酶的激活通过细胞外信号调节的激酶-1/2信号传导途径激活来增强胰腺癌细胞的粘附和侵袭。

• DOI: 10.1186/1476-4598-4-37
• 发表时间: 2005-10-06
• 期刊: MOLECULAR CANCER
• 影响因子: 37.3
• 作者: Sawai, Hirozumi;Okada, Yuji;Funahashi, Hitoshi;Matsuo, Yoichi;Takahashi, Hiroki;Takeyama, Hiromitsu;Manabe, Tadao
• 通讯作者: Manabe, Tadao

Stem Cell Factor/c-kit Receptor Signaling Enhances the Proliferation and Invasion of Colorectal Cancer Cells Through the PI3K/Akt Pathway

• DOI: 10.1007/s10620-007-9759-7
• 发表时间: 2007-04
• 期刊: Digestive Diseases and Sciences
• 影响因子: 3.1
• 作者: Akira Yasuda;H. Sawai;Hiroki Takahashi;N. Ochi;Y. Matsuo;H. Funahashi;Mikinori Sato;Y. Okada;H. Takeyama;T. Manabe

The stem cell factor/c-kit receptor pathway enhances proliferation and invasion of pancreatic cancer cells.

干细胞因子/C-KIT受体途径增强了胰腺癌细胞的增殖和侵袭。

• DOI: 10.1186/1476-4598-5-46
• 发表时间: 2006-10-18
• 期刊: Molecular cancer
• 影响因子: 37.3