The Role of Fibroblast Activation in Uterine Fibroid
关键词
抽象
描述
- Uterine fibroids (UFs) are steroid hormone-responsive, benign tumors of the smooth muscle compartment (myometrium) of the uterus .They are the most common neoplasm affecting women in their reproductive age. UFs are mainly composed of fibroid cells and a significant ECM component which principally consists of fibroblasts. Previous studies on the pathogenesis of uterine UF have mainly focused on the differentiation and proliferation of fibroid cells. However, the histologic features of fibroid tissue suggest that fibroblasts may play an important role in the generation of UF.
- Fibroblast activation protein (FAP), fibroblast-specific marker, is a 95 kDa cell surface glycoprotein. It is a type II transmembrane serine protease and a member of proline-specific proteases family. Recent studies showed that the high expression of FAP is closely related to the occurrence of UF .Luo et al 2015 were the first who suggested that estrogen could stimulate fibroblast activation. In addition, they revealed that proliferative activity of fibroblast and the expression of FAP were significantly increased after estrogen stimulation. They also found that estrogen could promote the release of cytokines (TGFβ and IGF-1) and ECM components (collagen I, fibronectin, and laminin) from fibroblasts. Furthermore they found that silencing of FAP expression significantly decreased promotion effects of estrogen on TAF suggesting that FAP plays an important role in estrogen-mediated fibroblast activation.
- Autophag (eating of self) is a collection of processes that enables the cells to digest and recycle their cytoplasmic contents, such as toxic protein aggregates, disused organelles and invading microorganisms. Dysregulation in autophagy process have been recently described in many neoplasms. However the role of autophagy in the pathogenesis of UFs is still unclear and further understanding of its regulation and significance will be needed.
- The PI3K/AKT/mTOR signalling pathway is considered the main pathway involved in the initiation and regulation of autophagy. Previous studies found that reduced FAP significantly decreased the expression of phosphorylated AKT suggesting that FAP is an upstream factor modulating the PI3K/AkT. This study will be the first to study the link between fibroblast activation and autophagy in pathogenesis of UF through PI3K/AKT signaling pathway. Although several types of drugs (mostly antiproliferative agents) are available for UF treatment, none of them were introduced specifically as antifibrotic agents. Targeting such novel signaling pathway may be considered useful for future non surgical treatment of UF affecting both proliferative and fibrotic changes.
日期
| 最后验证: | 04/30/2020 |
| 首次提交: | 02/19/2018 |
| 提交的预估入学人数: | 02/19/2018 |
| 首次发布: | 02/25/2018 |
| 上次提交的更新: | 05/10/2020 |
| 最近更新发布: | 05/12/2020 |
| 实际学习开始日期: | 02/28/2018 |
| 预计主要完成日期: | 10/31/2019 |
| 预计完成日期: | 02/29/2020 |
状况或疾病
干预/治疗
Genetic: Measurement of protein expression in tissue and /or blood samples.
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| patients group include 40 premenopausal women (age ˂ 45 year) with uterine fibroids who are diagnosed through clinical gynecological, ultrasound and other auxiliary examinations.
The protein expression of the followings markers will be estimated in tumor tissue samples:
Fibroblast activation protein (FAP) will be measured by quantitative real time polymerase chain reaction qRTPCR (mRNA level) and ELISA (protein level).
Autophagy markers level (LC3 and p62) will be measured by qRTPCR (mRNA level) and by immunohistochemical analysis.
Phosphorylated protein kinase B (pAKT) level will be measured by western blot analysis.
Circulating (cFAP) will be measured using ELISA in blood of UF patients. | |
| Control group include 40 (age, BMI) matched healthy females
The protein expression followings markers will be estimated in normal myometrial tissue samples( 1cm from UF lesions):
Fibroblast activation protein (FAP) will be measured by quantitative real time polymerase chain reaction qRTPCR (mRNA level) and ELISA (protein level).
Autophagy markers level (LC3 and p62) will be measured by qRTPCR (mRNA level) and by immunohistochemical analysis.
Phosphorylated protein kinase B (pAKT) level will be measured by western blot analysis.
Circulating (cFAP) will be measured using ELISA in blood of healthy controls |
资格标准
| 有资格学习的性别 | Female |
| 取样方式 | Non-Probability Sample |
| 接受健康志愿者 | 是 |
| 标准 | Inclusion Criteria: i. Premenopausal women (age ˂ 45) with uterine fibroids who are diagnosed through clinical gynecological, ultrasound and other auxiliary examinations. ii. Patients who exhibit a normal coagulation function. Exclusion Criteria - i. Patients who have a previous history of myomectomy or with ovarian malignancy and borderline tumors ii. Patients who are subsequently diagnosed with uterine adenomyosis. iii. Pregnant women. iv. Patients who receive hormonal treatment within three months before surgery. v. Patients with history of coronary artery disease, hypertension, liver cirrhosis or hematologic disorders. |
结果
主要结果指标
1. Comparing FAP and autophagy markers in patient and control groups. [1 year]
次要成果指标
1. Study signaling pathway linking FAP and autophagy which ma considered as a therapeutic target [1 year]
