Role of the c-kit tyrosine kinase in the genesis of gastrointestinal stromal tumors.

c-kit 酪氨酸激酶在胃肠道间质瘤发生中的作用。

• 批准号: 09671305
• 负责人: NISHIDA Toshirou
• 金额: $ 2.3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671305/
• 关键词: gastrointestinal tract; proto-oncogene; gain-of-function mutation; stromal tumors; recurrence; prognosis; c-kit; 消化管平滑筋腫; Interstitial Cells Cajal; 再発

The etiology and cellular origin of gastrointestinal stroma tumors (GISTs) are unknown.Sequencing of c-kil complementary DNA from five GISTs revealed mutations in the juxtamembrane domain.All corresponding mutant KIT proteins were constitutively activated without KIT ligand, the stem cell factor (SCF).Stable transfection of the mutant c-kil complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells.Because the development of the interstitial cells of Cajal (ICCs) is dependent on the SCF-KlT interaction and because both GISTs and ICCs express KIT and CD 34, GISTs may originate from the ICCs.We have found a family with multiple GISTs, of which many family members suffered from multiple GISTs and related symptoms.The family members with multiple GISTs showed the same c-kil mutation in the juxtamembrance domain.The c-kil mutation of this family was detected not only in GISTs but also in leukocytes, thus, familial GISTs appeared to be a cancer syndrome.Next we examined the correlation between the presence of c-kil mutation and the prognosis of GISTs.One hundred and twenty four patients with GIST were analyzed.Most GISTs (89%) express the c-kil protein, and missense mutations of exon 11 were found in 71 out of 124 GISTs.These 71 mutation-positive (+) GISTs were larger in size and invaded more frequently to adjacent tissues compared with the 53 mutation-negative (-) GISTs.Histologically, the mutation (+) GISTs showed higher mitotic figures and more necrosis and hemorrhage.The patients with mutation (+) GISTs showed more frequent recurrences and higher mortality than those with mutation (-) GISTs.The c-kil mutation was an independent prognostic factor for overall and cause-specific survival of the patients with GISTs.

胃肠道间质瘤(GIST)的病因和细胞起源尚不清楚。5个GIST的c-kil互补DNA测序显示膜旁区域有突变。所有突变的KIT蛋白都是在没有KIT配体干细胞因子(SCF)的情况下被结构性激活的。我们发现了一个突变的c-kil互补DNA诱导BA/F3小鼠淋巴样细胞恶性转化。由于Cajal间质细胞(ICCs)的发育依赖于SCF-KLT的相互作用，而且GIST和ICCs都表达KIT和CD34，GIST可能起源于ICCs。我们发现了一个具有多个GIST的家族，家族性GIST不仅在GIST中检测到c-kil突变，而且在白细胞中也检测到c-kil突变，提示家族性GIST是一种癌症综合征。接下来，我们研究了c-kil突变与GIST预后的关系。对124例GIST患者进行了分析。大多数GIST(89%)表达c-kil蛋白，突变阳性(+)的GIST与突变阴性(-)的GIST相比，体积更大，侵犯周围组织的频率更高。组织学上，突变(+)的GIST表现出更多的有丝分裂像和更多的坏死和出血。突变(+)的GIST患者的复发频率和死亡率高于突变(-)的GIST。c-kil突变是影响GIST患者总体和病因特异性生存的独立预后因素。

项目成果

Nishida T,Nakao K,Hamaji M,Nakahara M,Tsujimoto M.: "Prognostic Significance of Proliferative Cell Nuclear Antigen in Carcinoma of the Extrahepatic Bile Duct." World J Surg. 21. 634-639 (1997)

Nishida T，Nakao K，Hamaji M，Nakahara M，Tsujimoto M.：“增殖细胞核抗原在肝外胆管癌中的预后意义”。

Hirota S.et al.: "Gain-of-function mutation of c-kit in human gastrointestinal stromal tumors." Science. 279. 577-580 (1998)

Hirota S.et al.：“人胃肠道间质瘤中 c-kit 的功能获得突变。”

Nishida T.et al.: "Prognostic Significance of Proliferative Cell Nuclear Antigen in Carcinoma of the Extrahepatic Bile Duct." World J Surg. 21. 634-639 (1997)

Nishida T.et al.：“增殖细胞核抗原在肝外胆管癌中的预后意义。”

Nishida T,Hirota S,Taniguchi M,Hashimoto K,et al.: "Familial Gastrointestinal Stromal Tumors with Germ Line Mutation of the KIT gene." Nature Genetics. 19. 323-324 (1998)

Nishida T、Hirota S、Taniguchi M、Hashimoto K 等人：“具有 KIT 基因种系突变的家族性胃肠道间质肿瘤。”

Nishida T.et al.: "Endothelin A receptor blockade worsens endotoxin induced hepatic microcirculatory changes and necrosis." Gastroenterology. 115. 412-420 (1998)

Nishida T.等人：“内皮素 A 受体阻断会加重内毒素引起的肝脏微循环变化和坏死。”