JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
·
2020
·Vol. 106
·期 2
·526-538
·
IF 5.399
Wu Ying-Ting,Ma Si-Yu,Sun Wen-Qin,Shen Wei-Wei,Zhu Hui-Ting,Zhang Qin,Chen Hui-Fen
BackgroundEndometriosis (EM) is a benign gynecological disease that shares some characteristics with malignancy, such as proliferation and invasion. So far, the pathogenesis of EM is still unclear. In this study, we investigated whether TRIM65 can play a role in the development of EM.MethodsTRIM65 expression levels in eutopic, ectopic, and normal endometrium were detected by quantitative real-time PCR and Western blot. Cell proliferation and invasion of primary endometrial stromal (EMS) cells were detected by CCK-8 and Transwell analysis. The interaction between TRIM65 and DUSP6 or C-myc was measured by coimmunoprecipitation, ubiquitylation, dual luciferase, and chromatin immunoprecipitation analysis.ResultsWe found that TRIM65 was identified as an up-regulated gene in ectopic endometrial tissues and EMS cells compared with control groups without EM. TRIM65 expression was positively correlated with the levels of p-ERK1/2, C-myc, matrix metalloproteinase-2, and integrin β1 in ectopic endometrial tissues in patients and mice. TRIM65 promoted the cell proliferation and invasion of EMS cells via the ERK1/2/C-myc pathway through ubiquitination of DUSP6. C-myc promoted TRIM65 expression through inducing TRIM65 promoter activity. Additionally, the increased expression of TRIM65, C-myc, matrix metalloproteinase-2, integrin β1, and p-ERK1/2 and the decreased expression of DUSP6 in ectopic endometrial tissues were significantly suppressed by inhibition of ERK1/2 signaling pathway in ectopic endometrial tissues in experimental mice model.ConclusionIn conclusion, TRIM65 promotes invasion of ectopic EMS cells by activating a feedback loop with the ERK1/2/C-myc signaling pathway and may be a potential therapeutic target for EM.
研究领域:
妇科学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Huan Liu,Longsheng Wang,Xiaokai Shi,Lei Yin,Wei Zhai,Shenglin Gao,Yonghui Chen,Tao Zhang
Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Reproductive Sciences
·
2025
·
IF 2.5
Qiu Yingying,Wei Xinjun,Cao Jian,Wang Jindan,Dou Qianru,Zhou Fangfang,Chen Xi,Liu Yongli,Wan Guiping,Huang Meihua,Li Zhenli,Gui Tao
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial–mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Graphical
研究领域:
妇科学
·
干细胞生物学
·
分子生物学
·
细胞信号传导
·
癌症生物学
·
免疫学
·
microRNA研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）