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  • Our present data together with other studies have shown that


    Our present data together with other studies have shown that the communication of stroma and cancer cells via ECM-cell interaction led to the primary activation of FAK [41]. Here we propose a model depicting an important role of ADAM12-L in the regulation of ESCC invasion and metastasis. ADAM12-L overexpression in ESCC cells triggers a positive feedback loop, which initiates from ECM-cancer cell interaction and activates FAK/c-Jun axis to enhance ADAM12-L expression, leading to the further activation of FAK (Fig. 4K). When ESCC cells encounter the stroma at invasive edge, this loop continuously amplifies the tumor cell-stroma signal transduction, leading to the hyper aggressive phenotype of the esophageal carcinomas and early metastasis. In this study, we demonstrate that c-Jun is the transcription factor (TF) of ADAM12 upon FAK activation. It is possible that ADAM12 may be regulated by multiple TFs. However, in the scenario of FAK activation, our data suggest that c-Jun is a specific TF for ADAM12 in ESCC cells. Matrigel-induced FAK activation and enforced FAK expression both increased the binding of c-Jun to ADAM12 promoter, whereas FAK RNAi reduced the binding of c-Jun to ADAM12 promoter and deceased ADAM12 transcription. We further revealed that activated FAK enhanced JNK activation and c-Jun phosphorylation (Fig. 4). Of note, Twist1 was reported to induce ADAM12 in the EMT of breast cancer [65], but we didn't find predicted Glycopyrrolate of EMT-inducing TF (Twist1, Slug, Snail) on the promoter of ADAM12 using JASPAR or ChIPBase [48,66]. Although c-Jun may not be the strongest TF of ADAM12-L, the positive feedback loop amplifies the stimulation, and accumulatively enhances the regulatory effect of c-Jun on ADAM12-L. Our in vivo study also showed that down-regulation of ADAM12-L expression was able to suppress FAK phosphorylation in vivo, and hence inhibited esophageal tumor metastasis, suggesting that disturbing the function of AMAM12-L is effective to suspend this positive feedback loop and is an attractive therapeutic strategy for ESCC metastasis. In addition, reducing ADAM12-L expression decreased tumor growth in vivo. We think this is because that ADAM12-L promotes ESCC tumor growth via increasing tumor cell invasion as well as directly driving tumor cell proliferation. The metalloproteinases activity of ADAM12 is involved in “ectodomain shedding” of diverse growth factors [36,37], which endows the growth advantage to ADAM12-overexpressing tumors. Besides this FAK-independent mechanism, ADAM12-L may promote cell proliferation in a FAK-dependent manner, as FAK can trigger AKT activation [67,68]. Thus ADAM12-L may increase tumor growth through FAK-dependent AKT activation. Consistently, we did observe a trend that EC9706-P4 tumors had relatively higher Ki67 levels comparing with the ADAM12 RNAi tumors (Supplementary Fig. 5B), although it failed to reach statistical significance.
    Conflict-of-interest statement
    Acknowledgements This work was supported by grants from the Natural Science Foundation of China (81572890 to M-L.L., 81772837 to Y.Y., and 81672738 to H.H.), from the Science and Technology Foundation of the Guangdong Province (2014A050503029), from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology (Grant [2013]163), from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes (KLB09001), and from Guangdong Science and Technology Department (2015B050501004).
    Introduction Human adipose tissue contains a sub-type of cells with potential to differentiate into multiple lineages. These cells are described as adipose derived stem cells (ADSCs) [1,2]. ADSCs were considered similar to mesenchymal stem cells (MSCs). Under proper stimulation, ADSCs could exert osteogenic differentiation and promote bone regeneration [1]. Thus studying osteogenic regulation of ADSCs is important.