Tsai Chun-Hao, Tsai Hsiao-Chi, Huang Ho-Ning, Hung Chih-Hung, Hsu Chin-Jung, Fong Yi-Chin, Hsu Horng-Chaung, Huang Yuan-Li, Tang Chih-Hsin
Department of Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Oncotarget. 2015 Jan 1;6(1):258-70. doi: 10.18632/oncotarget.2724.
Resistin is a recently discovered adipocyte-secreting adipokine, which may play a critical role in modulating cancer pathogenesis. Chondrosarcoma is a highly malignant tumor known to frequently metastasize; however, the role of resistin in the metastasis of human chondrosarcoma is largely unknown. Here, we found that the expression of resistin was higher in chondrosarcoma biopsy tissues than in normal cartilage. Moreover, treatment with resistin increased matrix metalloproteinase (MMP)-2 expression and promoted cell migration in human chondrosarcoma cells. Co-transfection with microRNA (miR)-519d mimic resulted in reversed resistin-mediated cell migration and MMP-2 expression. Additionally, AMP-activated protein kinase (AMPK) and p38 inhibitors or siRNAs reduced the resistin-increased cell migration and miR-519d suppression, and inhibition of resistin expression resulted in suppression of MMP-2 expression and lung metastasis in vivo. Taken together, our results indicate that resistin promotes chondrosarcoma metastasis and MMP-2 expression through activation of the AMPK/p38 signaling pathway and down-regulation of miR-519d expression. Therefore, resistin may represent a potential novel molecular therapeutic target in chondrosarcoma metastasis.
抵抗素是一种最近发现的由脂肪细胞分泌的脂肪因子，它可能在调节癌症发病机制中起关键作用。软骨肉瘤是一种已知极易发生转移的高度恶性肿瘤；然而，抵抗素在人类软骨肉瘤转移中的作用在很大程度上尚不清楚。在此，我们发现抵抗素在软骨肉瘤活检组织中的表达高于正常软骨。此外，用抵抗素处理可增加基质金属蛋白酶（MMP）-2的表达，并促进人类软骨肉瘤细胞的迁移。与微小RNA（miR）-519d模拟物共转染导致抵抗素介导的细胞迁移和MMP-2表达逆转。此外，AMP激活的蛋白激酶（AMPK）和p38抑制剂或小干扰RNA（siRNA）可降低抵抗素增加的细胞迁移和miR-519d抑制，并且抑制抵抗素表达可导致体内MMP-2表达和肺转移受到抑制。综上所述，我们的结果表明，抵抗素通过激活AMPK/p38信号通路和下调miR-519d表达来促进软骨肉瘤转移和MMP-2表达。因此，抵抗素可能是软骨肉瘤转移中一个潜在的新型分子治疗靶点。
