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    [45] Pluda JM. Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies. Semin Oncol 1997;24(2):203e18. Cellular Signalling 62 (2019) 109350
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    Adipose derived stem FF-MAS promote tumor metastasis in breast Cancer cells T by stem cell factor inhibition of miR20b
    Haiqian Xua, Wenjie Lib, Sai Luoa, Jian Yuana, Lijun Haoa,
    a Plastic and Aesthetic surgery Center, The First Affiliated Hospital of Harbin Medical University, No.143 Yiman Road, Nangang District, Harbin, PR China
    b Department of Oncological Surgery, Heilongjiang Provincial Hospital, No.82 Zhongshan Road, Xiangfang District, Harbin, PR China
    Adipose-derived stem cell
    Breast Cancer
    Breast cancer (BC) metastasis after surgery is associated with the tumor microenvironment and especially with adipose tissue-derived mesenchymal stem cells (ASCs) that have been shown to promote the BC progression. To better understand the role of ASCs in tumor metastasis, our study explored a novel mechanism that mediates the negative regulation of miR20b during ASC-induced tumor metastasis of BC cells. In this study, we found that the migration and invasion abilities of BC cells are markedly increased coculture with ASCs. By studying the reg-ulatory mechanism, we found that miR20b biogenesis in BC cells can be attenuated by ASC-released stem cell factor (SCF) through the downstream c-Kit/MAPK-p38/E2F1 signaling cascade and that miR-20b acts as a tumor suppressor miRNA in the inhibition of BC migration and invasion. HIF-1α and VEGFA are the target genes of miR20b and miR20b downregulation activated HIF-1α-mediated VEGFA transcription and ASC-induced BC migration and invasion. The upregulation of miR20b abrogated the activation of EMT and lung metastasis of breast cancer cells cocultured with ASCs by the inhibition of N-cadherin, vimentin and Twist expression in vitro and in vivo. Collectively, our findings indicate that downregulation of miR20b by ASCs/SCF activates HIF-1α/ VEGFA and induces BC cell EMT and metastasis, suggesting that this process is activated by the p-c-Kit/MAPK-p38/E2F1 pathway.
    1. Introduction
    Breast cancer (BC) is a common malignant tumor and a leading cause of death among women [1]. Although great achievement has been made, the high incidence of postsurgical recurrence and metas-tasis remain serious problems. Accumulating evidence suggests that ASCs may favor tumor progression by autocrine and paracrine signaling in different transplanted and metastatic tumor models [2]. However, the mechanism of interaction between ASCs and breast cancer in the tumor microenvironment remains to be determined.
    The c-Kit signaling network is well studied in the tumor micro-environment [3]. SCF binds to the tyrosine kinase receptor c-kit (SCF/c-kit) and triggers the subsequent activation of the mitogen activated protein kinase (MAPK) pathways [4], inducing translocation of phos-phorylated protein kinases to the nucleus and to stimulate transcrip-tional factor activities, including that of the E2F transcription factor 1 (E2F1), which is generally involved in cell proliferation, apoptosis and differentiation [5]. Abnormalities in E2F1 are frequently associated with tumor progression or metastasis and anticancer drug resistance [6]. E2F1-dependent progression can be mediated by the upregulation
    Corresponding author.
    E-mail addresses: [email protected], [email protected] (L. Hao). 
    of EGFR and the activation of the cytoplasmic Ras/MAPK/ERK and PI3K/AKT signaling cascades [7]. Furthermore, E2F1 export from the nucleus and subsequent degradation are triggered by the stimulation of protein kinase C (PKC) and MAPK-P38 [8]. The phosphorylation of E2F1 at Ser403 and Thr433 by p38 is critical for the modulation of E2F1 stability and subcellular localization and for cell differentiation [8]. However, only a few studies have investigated whether E2F1 is regulated by the MAPK-p38 pathway to mediate the ASC-induced progression of breast cancer cells.
    Tumor cell metastasis requires a coordinated sequence of multiple events, including tumor-host interactions and prometastatic molecular regulators. Many activated transcriptional factors can modulate the expression of posttranscriptional regulators in tumor cells to regulate tumor metastasis. For example, E2F transcription factor 1 (E2F1), modulates the expression of small non-coding RNAs in the tumor [9]. MicroRNAs(miRNAs), are endogenous non-coding small RNAs and miRNA involvement has been reported to be involved in numerous cancer cell processes, including proliferation, apoptosis, metabolism and angiogenesis [10]. Among the miRs, miR20b is encoded by the miR-106a-363 cluster located on human chromosome X and grouped