SOX2 promotes autocrine Semenogelins1 signaling to regulate proliferation and doxorubicin resistance in A673 human Ewing sarcoma cell

Sex-determining region Y-box 2 (SOX2) has been demonstrated to promote the malignancy in various types of cancer, but the detail regulatory mechanisms remain to be completely understood. Here we show that Semenogelin 1 (SEMG1) is one of the tumor-specific SOX2 target genes and directly regulates the malignancy of Ewing sarcoma (EwS) cells. SOX2 was overexpressed in human EwS cell line A673 or human immortal mesenchymal stem cell line UE7T-13. Their RNA expression profiles were compared by bulkRNAseq analysis to find tumor-specific SOX2 target genes that encode secretory proteins. Interestingly, SEMG1 was expressed only in A673 and its mRNA level was increased by SOX2 overexpression. When A673 was infected with lentivirus encoding shRNA against SOX2 (shSOX2) or SEMG1 (shSEMG1), the proliferation and the expression of SEMG1 were decreased. Importantly, the inhibitory effect of shSOX2 or shSEMG1 on cell proliferation was rescued by conditioned medium that was prepared from UE7T-13 overexpressing SEMG1. In addition, SOX2 or SEMG1 knockdown increased the sensitivity to doxorubicin. These results demonstrate that SOX2 positively regulates the proliferation or doxorubicin resistance of A673 by activating autocrine SEMG1 signaling.