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  • EMT is characterized by changes in

    2019-09-02

    EMT is characterized by changes in specific molecules, such as CDH1, SNAI1, SNAI2, and VIM, followed by the loss of cell–cell junctions, cell–matrix adhesion, or modulation of polarity, resulting in increasing migration and invasion ability [38,39]. TGF-β1 signaling plays a pivotal role in regulating EMT [22]. There are some reports regarding the interaction of DCN and BGN with TGF-β1. TGF-β1 inhibits transcription of DCN and induces transcription of BGN [40]. Moreover, TGF-β1 was increased in DCN knockout fetal mice and decreased in BGN knockout fetal mice [41]. Recent investigations demonstrated that the invasion ability of DCN-overexpressing trophoblast BCI-121 was significantly lower than controls [25]. On the other hand, the invasion ability of BGN knockdown endometrial cancer cells was significantly lower than controls [42]. Although there are still many unclear points regarding the interaction of DCN and BGN with TGF-β1, it is quite possible that the interaction of DCN and BGN with TGF-β1 regulates EMT. We found that TSK overexpression in a lung ADC cell line inhibited expression of SNAI1, SNAI2, and VIM, and TSK knockout in the cell line induced the expression of SNAI2 and VIM. According to these molecular modifications, TSK led to the inhibition of EMT. Little was known previously about the effect of TSK on EMT in lung cancer. Previously, we reported that TGF-β1 was significantly more highly expressed in TSK knockout mice in comparison with wild-type mice [8]. In the present study, TGF-β1 was significantly more highly expressed in TSK-KO cells, and expression was reduced in TSK-OE cells in comparison to each in mock transfected cells. In addition, expression of PODXL showed similar results. Because PODXL also plays a pivotal role in regulating EMT [30], it is possible that the interaction of TSK regulates EMT through controlling TGF-β1 and PODXL. Although little was known previously about the role of TSK in the proliferation of human neoplasms, we found that TSK expression promotes cell proliferation of lung cancer cells. In the present study, xenotransplanted tumors from TSK-OE cells were significantly larger than those from mock transfected cells, and cell growth of TSK-OE cells was also significantly faster than mock transfected cells in vitro. It has been reported that DCN overexpression inhibited cell proliferation [43], whereas BGN overexpression enhanced cell proliferation [44]. DCN interacts with EGFR and induces p21-mediated cell cycle arrest and apoptosis [11,45]. Then, DCN interacts with Met and attenuates of β-catenin and Myc signaling, which inhibits tumor growth [11,46]. BGN interacts with TLR2 and 4, and activates the NF-κB and MAPK pathways, which leads to cancer progression due to increased tumor cell proliferation, resistance to apoptosis, and increased production of growth factors [11,19,47]. It has also been reported that TGF-β1 not only regulates EMT but also suppresses proliferation [48,49]. It is possible that the reduction in TGF-β1 promotes proliferation in TSK-OE cells. TSK is considered to interact with several pathways, but the mechanism by which TSK induces proliferation activity has not been clarified. A limitation of our study was that we focused on only the H1975 cell line. For further studies, we consider that we should evaluate the possible association of EMT and proliferation in other cell lines. Then, we need to clarify how TSK interacts with the WNT, Notch, BMP4, and TGF-β1 signaling pathways.
    Conclusion
    Conflict of interest
    Acknowledgments We thank Ms. Motoko Kagayama and Ms. Takako Maeda for technical assistance; and Mr. Shingo Usuki, Mr. Naoki Tani, and the staff of the LILA for technical support; the Institute of Molecular Embryology and Genetics, Kumamoto University, for help with RNA sequencing and Proteomics analyses. This study was supported in part by the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University.