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由于三阴性乳腺癌缺乏靶向治疗药物，而且转移和复发的比例较高，故对相当一部分患者的生活质量和生存结局都产生了不利影响。近年来，科学家发现不同的三阴性乳腺癌存在不同的靶点，需要不同的靶向治疗方法。 2019年12月20日，英国《自然》旗下《自然通讯》在线发表韩国首尔大学、基督人文医科大学、延世大学、日本筑波大学、国立癌症中心研究所的研究报告，发现了抑制三阴性乳腺癌细胞转移的新靶点。 该研究发现，锌指蛋白RNF208通过连接多个泛素分子的蛋白酶复合体分解作用，可以破坏波形微丝蛋白的稳定性，从而抑制三阴性乳腺癌细胞的转移。波形微丝蛋白存在于间叶细胞和非表皮细胞，其一端与细胞核膜相连，另一端与细胞表面的桥粒或半桥粒相连，将细胞核和细胞器维持于特定空间，细胞分裂时，其磷酸化程度和可溶性提高。三阴性乳腺癌与激素受体阳性乳腺癌相比，RNF208表达水平显著较低，而RNF208低表达与临床结局不良密切相关。 此外，17β雌二醇可以通过雌激素受体α诱导RNF208过表达，而RNF208过表达可以抑制三阴性乳腺癌细胞形成肿瘤并转移至肺。 机制分析表明，RNF208通过与可溶磷酸化波形微丝蛋白第39个丝氨酸残基发生相互作用，从而将波形微丝蛋白头部结构区第97个赖氨酸残基与多个泛素分子结合，最终促进波形微丝蛋白被蛋白酶复合体分解。 因此，该研究结果表明，RNF208作为可溶波形微丝蛋白抑制靶点，有望成为三阴性乳腺癌的预后生物标志和治疗靶点。
RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers. Kyoungwha Pang, Jinah Park, Sung Gwe Ahn, Jihee Lee, Yuna Park, Akira Ooshima, Seiya Mizuno, Satoshi Yamashita, Kyung-Soon Park, So-Young Lee, Joon Jeong, Toshikazu Ushijima, Kyung-Min Yang, Seong-Jin Kim. Seoul National University, Suwon, Korea; CHA University, Seongnam City, Korea; Yonsei University Medical College, Seoul, Korea; University of Tsukuba, Tsukuba, Ibaraki, Japan; National Cancer Center Research Institute, Tokyo, Japan; TheragenEtex Co, Suwon, Korea. The development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ERα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells. DOI: 10.1038/s41467-019-13852-5
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