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子宫内膜癌中转化生长因子βⅡ型受体基因的异常表达与突变

Aberrant expression and mutations of TGF-beta receptor type II gene in endometrial cancer.

作者信息

Sakaguchi Junko, Kyo Satoru, Kanaya Taro, Maida Yoshiko, Hashimoto Manabu, Nakamura Mitsuhiro, Yamada Kiyofumi, Inoue Masaki

机构信息

Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.

出版信息

Gynecol Oncol. 2005 Sep;98(3):427-33. doi: 10.1016/j.ygyno.2005.04.031.

Abstract

OBJECTIVE

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that strongly inhibits epithelial cell growth. Disabling of TGF-beta signaling is thought to be involved in development of a variety of tumors in which abnormal expression or function of TGF-beta receptor plays critical roles. In the present study, we examined aberrant expression and mutation of the gene TGF-beta receptor type II (TbetaRII) in endometrial cancers of endometrioid subtype.

METHODS AND RESULTS

Real-time PCR analysis using surgical tissue specimens of 27 endometrial cancers and 24 normal endometria revealed that endometrial cancers had significantly decreased levels of TbetaRII mRNA expression (mean level 2.44 +/- 2.65), compared to normal endometria (mean level 7.23 +/- 6.07) (P < 0.001). Methylation status of TbetaRII promoter containing 30 CpGs was examined by bisulfite sequencing analysis, and 98% (51/52) of the patients were found to have unmethylated TbetaRII promoter, indicating that promoter hypermethylation is not the major cause of decreased expression of TbetaRII in endometrial cancers. Mutational analysis revealed that 15.1% (8/53) of endometrial cancers had frameshift mutations at polyadenine repeats in exon 3 of the TbetaRII gene. Notably, these mutations were preferentially accumulated in patients with MSI-H phenotype (7/19:37%) (P < 0.001) or with those with methylated MLH1 promoters (6/16:38%) (P < 0.01). Thus, it appears that the TbetaRII gene is a target of mismatch repair deficiency.

CONCLUSION

Taken together, we found that the decreased expression of TbetaRII as well as frameshift mutation of TbetaRII via mismatch repair deficiency frequently occurs in this tumor type, possibly causing loss of receptor function and unresponsiveness of TGF-beta signaling that may lead to endometrial carcinogenesis.

摘要

目的

转化生长因子β(TGF-β)是一种多功能细胞因子,可强烈抑制上皮细胞生长。TGF-β信号传导功能丧失被认为与多种肿瘤的发生有关,其中TGF-β受体的异常表达或功能起着关键作用。在本研究中,我们检测了子宫内膜样亚型子宫内膜癌中II型TGF-β受体(TbetaRII)基因的异常表达和突变情况。

方法与结果

使用27例子宫内膜癌和24例正常子宫内膜的手术组织标本进行实时PCR分析,结果显示,与正常子宫内膜(平均水平7.23±6.07)相比,子宫内膜癌的TbetaRII mRNA表达水平显著降低(平均水平2.44±2.65)(P<0.001)。通过亚硫酸氢盐测序分析检测了包含30个CpG的TbetaRII启动子的甲基化状态,发现98%(51/52)的患者TbetaRII启动子未甲基化,表明启动子高甲基化不是子宫内膜癌中TbetaRII表达降低的主要原因。突变分析显示,15.1%(8/53)的子宫内膜癌在TbetaRII基因外显子3的多聚腺嘌呤重复序列处发生移码突变。值得注意的是,这些突变在微卫星高度不稳定(MSI-H)表型的患者中优先积累(7/19:37%)(P<0.001),或在MLH1启动子甲基化的患者中优先积累(6/16:38%)(P<0.01)。因此,TbetaRII基因似乎是错配修复缺陷的靶点。

结论

综上所述,我们发现TbetaRII表达降低以及通过错配修复缺陷导致的TbetaRII移码突变在这种肿瘤类型中频繁发生,这可能导致受体功能丧失和TGF-β信号传导无反应,进而可能导致子宫内膜癌的发生。

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