| Epithelial-mesenchymal transition(EMT) is a biological phenomenon occurring in specific physiological or pathological conditions, in which cells of plasticity transform into the mesenchymal cells capable of migration. EMTs are classified into three different biological subtypes, i.e., Type 1, Type 2 and Type 3, based on the biological context in which they occur in the processes of embryonic development, organ fibrosis or tumorigenesis. The purpose of this study focuses on the tumor-associatied Type3 EMT. The existing studies have shown that EMT plays an important role in the process of invasion and metastasis in many kinds of cancers, including breast, prostate and lung cancer. The term EMT refers to a complex molecular and cellular program by which epithelial cells shed their differentiated characteristics, including cell–cell adhesion and lack of motility, and acquire the mesenchymal features, including motility and invasiveness. EMT can promote the cells to detach from the basement membrane and disperse through the extracellular matrix into the circulatory system, resulting in tumor metastasis.EMT is a process in which a variety of factors are involved, including many transcription factors and signaling pathways. A hallmark of EMT is a decline in the expression of E-cadherin and an increase of N-cadherin. The present study has confirmed that there are a lot of transcription factors involved in the occurrence of EMT program by regulating the expression of E-cadherin and N-cadherin. For example, Snail could combined to E-cadherin together with SIP1 in the form of overlap in E-cadherin promoter, resulting in a decline in the expression of the E-cadherin; Likewise, the zinc finger protein ZEB1 and ZEB2 also affect directly with E-cadherin promoter element, and inhibit the expression of E-cadherin; Similarly, there are some factors that can improve the expression of N-cadherin through acting directly on its promoter, including Twist, ZEB1 and MZF1.In addition, a variety of extracellular signals can also activate the EMT program, there is a very important "crosstalk" between transcription factors and the intracellular signaling pathways, such as the TGF-β, ERK, MAPK and Wnt. The crosstalk may induce a variety of positive and negative feedback loops. TGF-β is the main and the best characterized inducer of EMT. It functions through two pathways of Smad-dependent and Smad-independent. Some studies found that the activation of EMT could induce epigenetic changes gradually to maintain the state of mesenchymal cells, and generate stable change in the phenotype. The study also found that the epithelial cells could get stem cell characteristics through EMT events.SHON is identified as a novel secreted hominoid oncogene and expressed in most human cancer cell lines, and is oncogenic for human mammary carcinoma cells. But the mechanism through which SHON promotes the process of breast cancer is not clear.We report in this thesis that over-expression of SHON in immortalized human mammary epithelial cell MCF10 A and human mammary cancer cell MCF7 was competent for the obtainment of the enhanced ability of cell migration and invasion, and induced the occurrence of EMT, along with the change of the EMT markers E-cadherin and N-cadherin. We also found that ectopic over-expression of SHON in human mammary epithelial cells may induce an EMT program in epithelial cells and potentiate the stem-like properties, characterized by increased number of CD44high/CD24 low population and mammosphere forming ability. Furthermore, SHON has also been shown to upregulate many important regulators of EMT, such as Snail, TGF-β1 and Twist. Based on these previous data, we speculate that SHON may play a role in breast cancer progression through induction of an oncogenic EMT program.Our study also showed that SHON activated the TGF-β signaling, and SHON itself was induced by TGF-β signaling in mammary epithelial cells. Presumably, SHON may interact with TGF-β, resulting in self-autocrine feedback. These date suggest that SHON regulates the EMT via a SHON-TGFβ-SHON feedback loop in breast cancer progression. At the same time, we synthesized the functional monoclonal antibodies of SHON in inhibitory type, and we found that it can effectively inhibit the activation of TGF-β1 signaling pathways caused by SHON, and further affect the SHON-TGFβ-SHON feedback loop.In this report, we provide evidence that SHON is a novel inducer of EMT in breast cancer. SHON induces an EMT program in epithelial cells via TGF-β1 signaling pathways, and promotes cell migration and invasion, and plays an improtant role in breast cancer progression. These results indicate that the latent value of SHON as a new molecular diagnostic marker for clinical diagnosis in human breast cancer, also provide theoretical basis for the development of targeted drugs for breast cancer. |
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