Research for esophageal carcinogenesis and proliferation, by characterization of cancer stem cells and analysis of the inactivation mechanism for suppressor genes in normal esophageal epithelial cells.

通过癌症干细胞的表征和正常食管上皮细胞抑制基因失活机制的分析来研究食管癌发生和增殖。

• 批准号: 17390363
• 负责人: SHIMADA Yutaka
• 金额: $ 9.79万
• 依托单位: Hyogo College of Medicine (2006)Kyoto University (2005)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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/grant/KAKENHI-PROJECT-17390363/
• 关键词: Cancer stem cell; Normal esophageal epithelial cell; p75NTR; ABCG2; Hedgeho; Gli-1; NGF; FHIT; Hedgehog; 癌抑制遺伝子

p75NTRp75NTR was expressed in all examined esophageal squamous cell carcinoma (ESCC) and the mean proportion of the p75NTR-positive fraction was 30.1%. The size of p75NTR-positive colonies was larger than that of p75NTR-negative colonies (p<0.0001). Down regulation of p75NTR expression by SiRNA resulted in marked growth inhibition with induction of apoptosis. Our findings suggest that p75NTR was expressed in a small number of cells in ESCC cell lines and p75NTR is necessary for survival and maintenance of ESCC tumors.ABCG2ABCG2 expression was detectable in 61% of patients and the proportion of ABCG2 positive cells was variable (0% to 100%). The presence of ABCG2 positive cells in the tumor was revealed to be an independent prognostic factor along with the extent of the primary tumor and positive lymph node metastasis in multivariate analysis. Our data suggests that ABCG2 plays an underlying role in malignant characteristics of ESCC.GlilCell proliferation and migration were significantly inhibited by Cyclopamine in the cell lines that expressed all Hedgehog (Hh) pathway molecules, while cell proliferation was not affected in the cell lines lacking Shh and Gli-1 expression. SiRNA target for Gli-1 inhibited the cell growth of ESCC cells.FHITNicotine induced methylation of the FHIT gene and attenuated Fhit protein, associated with DNMT3a expression in normal esophageal epithelial cells (HEEC). Furthermore, re-expression of Fhit protein of HEECs was found after cessation of moderate- to long-term exposure to nicotine.NGFNGF overexpression was associated with lymph node metastasis, distant metastasis, higher TNM stage, poorer tumour differentiation and poorer survival of esophageal cancer patients. The motility of HSA/c, one of the ESCC cell lines overexpressing NGF, was significantly decreased by either neutralizing NGF antibody, an inhibitor of TrkA, or NGF-small interfering RNA in transwell migration assay.

p75NTR p75NTR 在所有检查的食管鳞状细胞癌 (ESCC) 中表达，p75NTR 阳性部分的平均比例为 30.1%。 p75NTR 阳性集落的大小大于 p75NTR 阴性集落的大小 (p<0.0001)。 SiRNA 下调 p75NTR 表达导致显着的生长抑制并诱导细胞凋亡。我们的研究结果表明，p75NTR 在 ESCC 细胞系中的少数细胞中表达，并且 p75NTR 对于 ESCC 肿瘤的生存和维持是必需的。ABCG2ABCG2 表达在 61% 的患者中可检测到，并且 ABCG2 阳性细胞的比例是可变的（0%至 100%）。多变量分析表明，肿瘤中 ABCG2 阳性细胞的存在与原发肿瘤的范围和阳性淋巴结转移一起是一个独立的预后因素。我们的数据表明ABCG2在ESCC的恶性特征中发挥潜在作用。在表达所有Hedgehog（Hh）途径分子的细胞系中，Glil细胞增殖和迁移被环巴明显着抑制，而在缺乏Shh的细胞系中，细胞增殖不受影响和Gli-1表达。 Gli-1 的 SiRNA 靶标抑制 ESCC 细胞的生长。FHITN 尼古丁诱导 FHIT 基因甲基化并减弱 Fhit 蛋白，与正常食管上皮细胞 (HEEC) 中 DNMT3a 的表达相关。此外，停止中长期接触尼古丁后，HEECs中的Fhit蛋白重新表达。NGFNGF过表达与食管癌淋巴结转移、远处转移、TNM分期较高、肿瘤分化较差以及生存较差有关患者。 HSA/c（过度表达 NGF 的 ESCC 细胞系之一）的运动性在 Transwell 迁移测定中通过中和 NGF 抗体（TrkA 抑制剂）或 NGF 小干扰 RNA 显着降低。

项目成果

ABCG2 Expression Is an Independent Unfavorable Prognostic Factor in Esophageal Squamous Cell Carcinoma

ABCG2表达是食管鳞状细胞癌的独立不良预后因素

• 发表时间: 2007
• 作者: Tsunoda S

An Inducible Short-Hairpin RNA Vector against Osteopontin Reduces Metastatic Potential of Human Esophageal Squamous Cell Carcinoma In vitro and In vivo

一种针对骨桥蛋白的诱导型短发夹 RNA 载体可降低人食管鳞状细胞癌的体外和体内转移潜力

• 发表时间: 2006
• 作者: Tetsuo Ito; Yosuke Hashimoto; Eiji Tanaka; Takatsugu Kan; Shigeru Tsunoda; Fumiaki Sato; Motoshige Higashiyama; Tomoyuki Okumura; Yutaka Shimada.
• 通讯作者: Yutaka Shimada.

The biological role of the low affinity neurotrophin receptor(p75NTR) in esophageal squamous cell carcinoma

低亲和力神经营养蛋白受体（p75NTR）在食管鳞癌中的生物学作用

• 发表时间: 2006
• 作者: Okumura T

The Clinical Significance of Aurora-A/STK15/BTAK Expression in Human Esophageal Squamous Cell Carcinoma

Aurora-A/STK15/BTAK在人食管鳞癌中表达的临床意义

• DOI: 10.1158/1078-0432.ccr-04-1627
• 发表时间: 2005-03-01
• 期刊: Clinical Cancer Research
• 影响因子: 11.5
• 作者: E. Tanaka;Y. Hashimoto;Tetsuo Ito;T. Okumura;T. Kan;G. Watanabe;M. Imamura;J. Inazawa;Y. Shimada
• 通讯作者: Y. Shimada

Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma

神经生长因子过表达及其自分泌环路在食管鳞癌中的意义

• 发表时间: 2006
• 作者: Shigeru Tsunoda; Tomoyuki Okumura; Tetsuo Ito; Yukiko Mori; Toshiya Soma; Go Watanabe; Junichi Kaganoi; Atsushi Itami; Yoshiharu Sakai; Yutaka Shimada.
• 通讯作者: Yutaka Shimada.