Clear cell sarcoma (CCS) is a rare but chemotherapy-resistant and often fatal high-grade soft-tissue sarcoma (STS) characterized by melanocytic differentiation under control of microphthalmia-associated transcription factor (MITF). Eribulin mesilate (eribulin) is a mechanistically unique microtubule inhibitor commonly used for STS treatment, particularly liposarcoma and leiomyosarcoma. In this study, we examined the antitumor efficacy of eribulin on four human CCS cell lines and two mouse xenograft models. Eribulin inhibited CCS cell proliferation by inducing cell-cycle arrest and apoptosis, shrunk CCS xenograft tumors, and increased tumor vessel density. Eribulin induced MITF protein upregulation and stimulated tumor cell melanocytic differentiation through ERK1/2 inactivation (a MITF negative regulator) in vitro and in vivo. Moreover, tumor reoxygenation, probably caused by eribulin-induced vascular remodeling, attenuated cell growth and inhibited ERK1/2 activity, thereby upregulating MITF expression and promoting melanocytic differentiation. Finally, downregulation of MITF protein levels modestly debilitated the antiproliferative effect of eribulin on CCS cells. Taken together, eribulin suppresses CCS through inhibition of cell proliferation and promotion of tumor differentiation by acting both directly on tumor cells and indirectly through tumor reoxygenation.

中文翻译：

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艾日布林通过直接和通过血管重塑抑制细胞增殖和诱导黑素细胞分化来抑制透明细胞肉瘤的生长

透明细胞肉瘤 (CCS) 是一种罕见但对化疗耐药且通常致命的高级软组织肉瘤 (STS)，其特征在于小眼相关转录因子 (MITF) 控制下的黑素细胞分化。甲磺酸艾日布林（艾日布林）是一种机械上独特的微管抑制剂，常用于 STS 治疗，尤其是脂肪肉瘤和平滑肌肉瘤。在这项研究中，我们检查了艾日布林对四种人类 CCS 细胞系和两种小鼠异种移植模型的抗肿瘤功效。艾日布林通过诱导细胞周期停滞和凋亡、缩小 CCS 异种移植肿瘤和增加肿瘤血管密度来抑制 CCS 细胞增殖。在体外和体内，艾日布林通过 ERK1/2 失活（一种 MITF 负调节因子）诱导 MITF 蛋白上调并刺激肿瘤细胞黑素细胞分化。而且，肿瘤再氧合，可能由艾日布林诱导的血管重塑引起，减弱细胞生长并抑制 ERK1/2 活性，从而上调 MITF 表达并促进黑素细胞分化。最后，MITF 蛋白水平的下调适度削弱了艾日布林对 CCS 细胞的抗增殖作用。总之，艾日布林通过直接作用于肿瘤细胞和间接通过肿瘤再氧合来抑制细胞增殖和促进肿瘤分化来抑制 CCS。MITF 蛋白水平的下调适度削弱了艾日布林对 CCS 细胞的抗增殖作用。总之，艾日布林通过直接作用于肿瘤细胞和间接通过肿瘤再氧合来抑制细胞增殖和促进肿瘤分化来抑制 CCS。MITF 蛋白水平的下调适度削弱了艾日布林对 CCS 细胞的抗增殖作用。总之，艾日布林通过直接作用于肿瘤细胞和间接通过肿瘤再氧合来抑制细胞增殖和促进肿瘤分化来抑制 CCS。