Department of Cancer Biology and Urology, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2012 Nov 15;72(22):5757-66. doi: 10.1158/0008-5472.CAN-12-2424. Epub 2012 Sep 17.
Melanoma is the deadliest form of skin cancer in which patients with metastatic disease have a 5-year survival rate of less than 10%. Recently, the overexpression of a β-galactoside binding protein, galectin-3 (LGALS3), has been correlated with metastatic melanoma in patients. We have previously shown that silencing galectin-3 in metastatic melanoma cells reduces tumor growth and metastasis. Gene expression profiling identified the protumorigenic gene autotaxin (ENPP2) to be downregulated after silencing galectin-3. Here we report that galectin-3 regulates autotaxin expression at the transcriptional level by modulating the expression of the transcription factor NFAT1 (NFATC2). Silencing galectin-3 reduced NFAT1 protein expression, which resulted in decreased autotaxin expression and activity. Reexpression of autotaxin in galectin-3 silenced melanoma cells rescues angiogenesis, tumor growth, and metastasis in vivo. Silencing NFAT1 expression in metastatic melanoma cells inhibited tumor growth and metastatic capabilities in vivo. Our data elucidate a previously unidentified mechanism by which galectin-3 regulates autotaxin and assign a novel role for NFAT1 during melanoma progression.
黑色素瘤是皮肤癌中最致命的一种，转移性疾病患者的 5 年生存率低于 10%。最近，β-半乳糖苷结合蛋白半乳糖凝集素-3（LGALS3）的过度表达与转移性黑色素瘤患者相关。我们之前已经表明，沉默转移性黑色素瘤细胞中的半乳糖凝集素-3可减少肿瘤生长和转移。基因表达谱分析确定促肿瘤基因自分泌酶（ENPP2）在沉默半乳糖凝集素-3后下调。在这里，我们报告半乳糖凝集素-3通过调节转录因子 NFAT1（NFATC2）的表达来调节自分泌酶的表达，从而在转录水平上调节自分泌酶的表达。沉默半乳糖凝集素-3会降低 NFAT1 蛋白表达，从而导致自分泌酶表达和活性降低。在沉默半乳糖凝集素-3的黑色素瘤细胞中重新表达自分泌酶可挽救体内血管生成、肿瘤生长和转移。沉默转移性黑色素瘤细胞中的 NFAT1 表达可抑制体内肿瘤生长和转移能力。我们的数据阐明了半乳糖凝集素-3调节自分泌酶的一个以前未被识别的机制，并在黑色素瘤进展过程中为 NFAT1 赋予了新的作用。
