Development of new therapeutic modalities based on the analysis of the pathogenesis and biological features of leiomyoma

基于平滑肌瘤发病机制和生物学特征的分析开发新的治疗方式

• 批准号: 13307047
• 负责人: FUJII Shingo
• 金额: $ 31.45万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307047/
• 关键词: Uterus; leiomyoma; Ref-1; mast cell; p53; sFRP-1; pathogenesis; treatment; 子宮筋腫; Wntシグナル; MnSOD; PEP-19; S100蛋白; 虚血再還流ストレス; 肥満細胞; トラニラスト; 子宮平滑筋; Frizzled related protein 1; アポトーシス; redox factor 1; リン酸化; 翻訳後修飾; 増殖

Regarding the proliferation of uterine leiomyoma, the posttranscriptional modification of Ref-1 was revealed to associate with the proliferation of leiomyoma cells in vivo and in vitro. Mast cells in the uterus were suggested to enhance the proliferation of smooth muscle cells. Apoptosis-resistant character of leiomyoma cells was suggested through the studies of sFRP1 (a modulator of Wnt signaling), S100A11 (S100 protein family), and PEP-19. In addition, Ref-1, S100A11, and β catenin were suggested to be involved in the pathophysiology of leiomyosarcoma.Regarding the pathogenesis of leiomyoma, we hypothesize that leiomyomas resale from proliferation of smooth muscle cells is the myometrial tissue that survives the repeated ischemic-reperfusion stress experienced during the menstrual cycle. The blood supply to the myometrium in vivo is knows to decrease daring uterine contraction, particularly daring menstruation. In each luteal phase of the menstrual cycle, myometrial smooth muscles ex … More hibit proliferative activity, in preparation for pregnancy. However, if pregnancy does not occur, the proliferative activity of the myometrial smooth muscle colts may be interrupted at the time of menstruation. Myometrial contraction, winch results in the cessation of menstrual blinding, probably induces an ischemic / hypoxic state in the myometrial smooth muscle cells. Ischemic injury could occur in these cells which are in the proliferative phase. It is suggested that them injured colts could become candidates for progenitor cells of leiomyomas. Somatic mutation could well be induced in these cells after surviving many repeats of the menstrual cycle. In this respect, immunohistochemically we found e few p53- or p21-positive cells in the myometrium exclusively in the follicular phase of the menstrual cycle. This highly suggests that there exists smooth muscle cells that were injured their DNA during the menses, and these cells would be repaired during the cell-cycle arrest or eliminated through apoptosis. If the cells with injured DNA may acquire apoptosis-resistance expressing molecules such as sFRP1 and S100A11, these cells become the candidates of the precursor of leiomyoma cell.Regarding the treatment, tranilast that suppresses fibrosis or arts as a mast cell stabilizer, became a candidate of a new therapeutic agent. Tranilast inhibited the proliferation of cultured leiomyoma cells in a dose-dependent manner without any cytotoxic effort. We also demonstrated that uterine arterial embolization successfully reduced the uterine size of diffuse leiomyomatosis, suggesting that this procedure may be a premising new therapeutic modality for this intractable disease without loss of fertility. Less

关于子宫肌瘤的增殖，Ref-1的转录后修饰被揭示与体内和体外子宫肌瘤细胞的增殖有关。提示子宫肥大细胞可促进平滑肌细胞增殖。通过对sFRP 1（Wnt信号的调节剂）、S100 A11（S100蛋白家族）和PEP-19的研究，提出了平滑肌瘤细胞的抗凋亡特性。此外，Ref-1、S100 A11和β catenin被认为参与了平滑肌肉瘤的病理生理过程。关于平滑肌瘤的发病机制，我们假设平滑肌细胞增殖导致的平滑肌瘤再发是子宫肌层组织在月经周期反复缺血-再灌注应激中存活下来。已知体内子宫肌层的血液供应减少子宫收缩，特别是月经。在月经周期的每一个黄体期，子宫肌层平滑肌细胞都能从子宫内膜中分离出来。 ...更多信息 增殖活性，为怀孕做准备。然而，如果没有怀孕，子宫肌层平滑肌的增殖活性可能在月经时中断。子宫肌层收缩，其导致月经盲的停止，可能诱导子宫肌层平滑肌细胞的缺血/缺氧状态。缺血性损伤可发生在这些处于增殖期的细胞中。这表明，他们受伤的小马可能成为候选人的平滑肌瘤祖细胞。这些细胞在经历多次月经周期后仍能存活，很可能诱发体细胞突变。在这方面，我们用免疫化学方法发现，在月经周期的卵泡期，子宫肌层中仅有少数p53或p21阳性细胞。提示月经期存在DNA损伤的平滑肌细胞，这些细胞在细胞周期停滞时修复或通过凋亡消除。如果DNA损伤的细胞能够获得sFRP 1和S100 A11等抗凋亡表达分子，则这些细胞成为平滑肌瘤细胞前体的候选者。在治疗方面，抑制纤维化或作为肥大细胞稳定剂的曲尼司特成为新的治疗药物的候选者。曲尼司特以剂量依赖性方式抑制培养的平滑肌瘤细胞的增殖，而没有任何细胞毒性作用。我们还证实了子宫动脉栓塞术成功地缩小了弥漫性平滑肌瘤病的子宫大小，这表明这种手术可能是这种难治性疾病的一种新的治疗方式，而不会丧失生育能力。少

项目成果

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Chie Kuragaki、Takayuki Enomoto、Yuko Ueno、hongbo Sun、Masami Fujita、Ryuichi Nakashima、Yutaka Ueda、Hiroko Wada、Yuji Murata、Toshihiko Toki、Ikuo Konishi、Shingo Fujii：“STK11 基因突变表征了微小偏差腺癌

Orii A: "Altered post-translational modification of redox factor 1 protein in human uterine smooth muscle tumors"J Clin Endocrinol Metab. 87. 3754-3759 (2002)

Orii A：“人子宫平滑肌肿瘤中氧化还原因子 1 蛋白的翻译后修饰发生改变”J Clin Endocrinol Metab。

Fukuhara, K. et al.: "Secreted frizzled related protein 1 is over-expressed in uterine leiomyoas associated with a high estrogenic environment and is unrelated to proliferative activity"J Clin Endocr Met. (in press).

Fukuhara, K. 等人：“分泌性卷曲相关蛋白 1 在与高雌激素环境相关的子宫平滑肌中过度表达，并且与增殖活性无关”J Clin Endocr Met。

Hiroaki Shime, et al.: "Tranilast Inhibits the Proliferation of Uterine Leiomyoma Cells in Vitro through G1 Arrest Associated with the Induction of p21 (wafl) and p53"J Clin Endocrinol Metab. 87. 5610-5617 (2002)

Hiroaki Shime 等人：“曲尼司特通过与 p21 (wafl) 和 p53 诱导相关的 G1 期停滞来抑制体外子宫平滑肌瘤细胞的增殖”J Clin Endocrinol Metab。