Over-expression of FSIP1 promotes breast cancer progression and confers resistance to docetaxel via MRP1 stabilization
Over-expression of FSIP1 promotes breast cancer progression and confers resistance to docetaxel via MRP1 stabilization
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FSIP1 过度表达促进乳腺癌进展并通过 MRP1 稳定作用赋予多西他赛耐药性
DOI：
10.1038/s41419-018-1248-8
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发表时间：
2019-02-27
影响因子：
9
通讯作者：
Li, Zhigao
中科院分区：
文献类型：
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作者：
Yan, Meisi;Wang, Jinsong;Li, Zhigao
纤维鞘相互作用蛋白1（FSIP 1）在乳腺癌的发生和发展中起着重要作用，但其确切作用仍有待澄清。因此，我们试图建立乳腺癌的临床病理特征与乳腺癌组织中FSIP 1表达之间的相关性，并验证其在肿瘤进展和化疗耐药性中的作用。我们通过免疫组化分析FSIP 1在乳腺癌和癌旁组织中的表达。我们采用MTT、Caspase-Glo 3/7检测、Annexin V染色、伤口愈合和trans-well检测来评估FSIP 1敲除和野生型乳腺癌细胞系中的细胞凋亡、增殖、迁移和侵袭。此外，我们研究了FSIP 1对多西他赛敏感性的影响，在裸鼠模型中移植对照或FSIP 1敲除乳腺癌细胞，并评估其在肿瘤转移中的作用。通过免疫共沉淀和质谱法测定FSIP 1和MRP 1的相互作用。我们发现乳腺癌细胞和组织始终表现出FSIP 1表达升高，这与总体生存率低相关。值得注意的是，接受多西他赛新辅助化疗的肿瘤中FSIP 1高表达的患者无病生存期较短。FSIP 1基因敲除乳腺癌细胞在体外和体内均显著增加其对多西他赛的敏感性。从机制上讲，FSIP 1结合多药耐药蛋白1（MRP 1）并稳定它，敲除FSIP 1可降低MRP 1表达并增加细胞多西他赛积累。总之，FSIP 1促进乳腺癌的发生并介导多西他赛耐药性，并可能在乳腺癌治疗的发展中作为一个新的靶点。
Fibrous sheath-interacting protein 1 (FSIP1) functions centrally in breast carcinogenesis and progression, although its exact role remains to be clarified. Therefore, we sought to establish a correlation between the clinico-pathological features of breast cancer and FSIP1 expression in breast cancer tissues, as well as to validate its role in tumor progression and chemo-resistance. We analyzed FSIP1 expression in the breast cancer and para-tumor tissues by immunohistochemistry. We performed MTT, Caspase-Glo 3/7 Assay, Annexin V staining, wound healing and trans-well assays to evaluate cellular apoptosis, proliferation, migration and invasion in FSIP1 knockout and wild-type breast cancer cell lines. Additionally, we examined the effects of FSIP1 on docetaxel sensitivity in a nude mice model transplanted with control or FSIP1 knockout breast cancer cells, and also evaluate its role in tumor metastasis. FSIP1 and MRP1 interaction was determined by co-immunoprecipitation and mass spectrometry. We found that breast cancer cells and tissues consistently demonstrated elevated FSIP1 expressions, which correlated with poor overall survival. Notably, patients with high FSIP1 expression in their tumors undergoing docetaxel neoadjuvant chemotherapy had shorter disease-free survival. FSIP1 knockout in breast cancer cells significantly increased their sensitivity to docetaxel both in vitro and in vivo. Mechanistically, FSIP1 bound to the multidrug resistance protein 1 (MRP1) and stabilized it, and knocking out FSIP1 decreased MRP1 expression and increased cellular docetaxel accumulation. In sum, FSIP1 promotes breast carcinogenesis and mediates docetaxel resistance, and may serve as a novel target in the development of breast cancer therapies.