Abstract
Endometrial carcinogenesis is involved in several signaling pathways and it comprises multiple steps. The four major signaling pathways—PI3K/AKT, Ras/Raf/MEK/ERK, WNT/β-catenin, and vascular endothelial growth factor (VEGF)—are involved in tumor cell metabolism, growth, proliferation, survival, and angiogenesis. The genetic mutation and germline mitochondrial DNA mutations also impair cell proliferation, anti-apoptosis signaling, and epithelial–mesenchymal transition by several transcription factors, leading to endometrial carcinogenesis and distant metastasis. The PI3K/AKT pathway activates the ransforming growth factor beta (TGF-β)-mediated endothelial-to-mesenchymal transition (EMT) and it interacts with downstream signals to upregulate EMT-associated factors. Estrogen and progesterone signaling in EMT also play key roles in the prognosis of endometrial carcinogenesis. In this review article, we summarize the current clinical and basic research efforts regarding the detailed molecular regulation in endometrial carcinogenesis, especially in EMT, to provide novel targets for further anti-carcinogenesis treatment.
Highlights
Endometrial cancer is the most common neoplasm of the female genital tract
Estrogen overstimulation was associated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway and the downstream mammalian target of rapamycin signaling to promote epithelial-mesenchymal transition (EMT), which occurs due to the inhibition of E-cadherin [4]
The mammalian target of rapamycin (mTOR) signaling was reported in cancer-associated fibroblasts (CAF)-mediated cell proliferation and it was confirmed by the use of the mTOR inhibitor rapamycin [106,108]
Summary
Endometrial cancer is the most common neoplasm of the female genital tract. Its incidence and mortality rates are increasing. As summarized by Sanderson et al [3], the factors that contribute to endometrial carcinogenesis during estrogen stimulation include polycystic ovary syndrome (PCOS), obesity, perimenopause, functional tumor, and iatrogenic events. These conditions induce continuous estrogen stimulation that is unopposed by progesterone. Many studies have focused on the molecular and cell biology on endometrial cancer, including the immune escape, local inflammation, mitochondria dysfunction, tumor cell proliferation, and cell death. These studies have informed novel approaches for the therapeutic strategies of endometrial cancer [8]. Our aim is to provide a strong foundation for the development of further therapeutic interventions
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