Functional analysis and clinical application of PHD3 in renal cell carcinoma

PHD3在肾细胞癌中的功能分析及临床应用

• 批准号: 22791477
• 负责人: TANAKA Toshiaki
• 金额: $ 2.16万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22791477/
• 关键词: 腎細胞癌; 腫瘍生物学; 分子生物学; 腫瘍免疫学; シグナル伝達; 腫瘍マーカー

VHL gene-mutant cell lines of renal cell carcinoma(RCC), SMKT-R2 and SMKT-R3 had stable overexpression of PHD3. In Caki-1, a VHL-wild type RCC cell line, PHD3 expression was induced in the non-confluent state. In Caki-1, in the nonconfluent state, the PI3K/Akt/mTOR pathway was activated, and inhibition of the pathway with LY294002 reduced PHD3 expression. Even in HIF-la/2a double-knockdown Caki-1, activation of the PI3k/Akt/mTOR pathway induced overexpression of PHD3. In addition, PHD3 siRNA promoted cell proliferation compared with control siRNA in Caki-1 without induction of HIF protein expression. Even in VHL-mutant SMKT-R2 and SMKT-R3, PHD3 siRNA showed the same effect. On the other hand, PHD3-expressing plasmid transfection into ACHN, a RCC cell line with no expression of PHD3 under normoxia, reduced cell proliferation compared with empty vector transfection.In 22 patients with RCC, preoperative serum anti-PHD3 Ab titers were significantly higher in RCC patients than in healthy volunteers. Both pre-and postoperative serum samples were obtained from 17 patients at least 1 month after tumor removal. In all 17 patients, titers of serum anti-PHD3 were decreased after the surgical resection compared with those before operation. The result suggests that the anti-PHD3 Ab may be a novel serological marker for RCC, and the titer may reflect the tumor burden in each individual.

VHL基因突变的肾癌细胞系SMKT-R2和SMKT-R3均稳定过表达PHD3。在VHL野生型肾癌细胞株CAKI-1中，PHD3在非融合状态下被诱导表达。在Caki-1细胞中，在非融合状态下，PI3K/Akt/mTOR通路被激活，LY294002抑制该通路可降低PHD3的表达。即使在HIF-1a/2a双敲除的Caki-1中，PI3K/Akt/mTOR通路的激活也诱导了PHD3的过度表达。此外，与对照siRNA相比，PHD3 siRNA促进了Caki-1细胞的增殖，而不诱导HIF蛋白表达。即使在VHL突变体SMKT-R2和SMKT-R3中，PHD3 siRNA也显示出相同的作用。另一方面，将PHD3表达的真核表达载体转入常氧下不表达PHD3的肾癌细胞株ACHN，与空载体转染组相比，细胞增殖抑制。22例肾癌患者术前血清抗PHD3抗体滴度明显高于正常对照组。17例患者在肿瘤切除后至少1个月采集了手术前和术后的血清样本。17例患者手术切除后血清抗PHD3滴度均较术前降低。提示抗PHD3抗体可能是肾癌的一种新的血清学标志物，其滴度可反映个体的肿瘤负荷。

项目成果

腎細胞癌におけるPHD3の増殖抑制効果

PHD3对肾细胞癌的生长抑制作用

• 发表时间: 2010
• 作者: Tanaka T;TorigoeT;Hirohashi Y;Sato E;Honma I;Kitamura H;Masumori N;Sato N;Tsukamoto T;Toshiaki Tanaka;Toshiaki Tanaka;田中俊明
• 通讯作者: 田中俊明

American Urology Association 2010. PHD3 has a HIF-independent-antiproliferative function in renal cell carcinoma

美国泌尿外科协会 2010。PHD3 在肾细胞癌中具有不依赖 HIF 的抗增殖功能

• 发表时间: 2010
• 作者: Tanaka T;TorigoeT;Hirohashi Y;Sato E;Honma I;Kitamura H;Masumori N;Sato N;Tsukamoto T
• 通讯作者: Tsukamoto T

Autoantibody against hypoxia-inducible factor prolyl hydroxylase-3 is a potential serological marker for renal cell carcinoma

抗缺氧诱导因子脯氨酰羟化酶 3 的自身抗体是肾细胞癌的潜在血清学标志物

• DOI: 10.1007/s00432-010-0940-6
• 发表时间: 2011
• 期刊: J. Cancer Res. Clin. Oncol
• 作者: Tanaka;T.;Kitamura;H.;Torigoe;T.;Hirohashi;Y.;Masumori;N.;Sato;N. and Tsukamoto;T.
• 通讯作者: T.

PHD3 expression is a predictor of progression-free survival in clear cell renal cell carcinoma

PHD3 表达是透明细胞肾细胞癌无进展生存的预测因子

• 发表时间: 2012
• 作者: Tanaka;T.;Kitamura;H.;Torigoe;T.;Hirohashi;Y.;Masumori;N.;Sato;N. and Tsukamoto;T.;Toshiaki Tanaka;Toshiaki Tanaka
• 通讯作者: Toshiaki Tanaka

HIF prolyl hydroxylase-3 has a HIF-independent-antiproliferative function in renal cell carcinoma

HIF 脯氨酰羟化酶 3 在肾细胞癌中具有不依赖 HIF 的抗增殖功能

• 发表时间: 2010
• 作者: Tanaka T;Torigoe T;Hirohashi Y;Kitamura H;Masumori N;Tsukamoto T;Sato N;田中俊明
• 通讯作者: 田中俊明