Abstract：
Secreted protein acidic and cysteine rich/osteonectin, cwcv and kazal-like domain proteoglycan 2 (SPOCK2) is a protein that regulates cell differentiation and growth. Recent studies have reported that SPOCK2 plays important roles in the progression of various human cancers; however, the role of SPOCK2 in melanoma remains unknown. Therefore, this study investigated the roles of SPOCK2 and the related mechanisms in melanoma progression. To evaluate the clinical significance of SPOCK2 expression in patients with melanoma, we analysed the association between SPOCK2 expression and its prognostic value for patients with melanoma using systematic multiomic analysis. Subsequently, to investigate the roles of Spock2 in melanoma progression in vitro and in vivo, we knocked down Spock2 in the B16F10 melanoma cell line. High SPOCK2 levels were positively associated with good prognosis and long survival rate of patients with melanoma. Spock2 knockdown promoted melanoma cell proliferation by inducing the cell cycle and inhibiting apoptosis. Moreover, Spock2 downregulation significantly increased cell migration and invasion by upregulating MMP2 and MT1-MMP. The increased cell proliferation and migration were inhibited by MAPK inhibitor, and ERK phosphorylation was considerably enhanced in Spock2 knockdown cells. Therefore, Spock2 could function as a tumour suppressor gene to regulate melanoma progression by regulating the MAPK/ERK signalling pathway. Additionally, Spock2 knockdown cell injection induced considerable tumour growth and lung metastasis in C57BL6 mice compared to that in the control group. Our findings suggest that SPOCK2 plays crucial roles in malignant progression of melanoma and functions as a novel therapeutic target of melanoma.
摘要：
分泌的蛋白质酸性和富含半胱氨酸/骨粘连蛋白，cwcv和kazal样结构域蛋白聚糖2（SPOCK2）是一种调节细胞分化和生长的蛋白质。最近的研究报道，SPOCK2在各种人类癌症的进展中起着重要作用；然而，SPOCK2在黑色素瘤中的作用尚不清楚.因此,本研究探讨了SPOCK2在黑色素瘤进展中的作用及相关机制.探讨SPOCK2在黑色素瘤患者中的表达及其临床意义。我们使用系统的多体分析,分析了SPOCK2表达与黑色素瘤患者预后价值之间的相关性.随后，为了研究Spock2在黑色素瘤的体外和体内进展中的作用，我们敲除了B16F10黑色素瘤细胞系中的Spock2。高SPOCK2水平与黑色素瘤患者的预后和长期生存率呈正相关。Spock2敲低通过诱导细胞周期和抑制凋亡促进黑色素瘤细胞增殖。此外，Spock2下调通过上调MMP2和MT1-MMP显著增加细胞迁移和侵袭。MAPK抑制剂抑制细胞增殖和迁移,ERK磷酸化在Spock2敲低细胞中显著增强。因此,Spock2可以作为肿瘤抑制基因，通过调节MAPK/ERK信号通路来调节黑色素瘤的进展。此外,与对照组相比，Spock2敲低细胞注射在C57BL6小鼠中诱导了相当大的肿瘤生长和肺转移。我们的发现表明，SPOCK2在黑色素瘤的恶性进展中起着至关重要的作用，并作为黑色素瘤的新治疗靶标发挥作用。
