Yin Zhuming, Chen Wenlin, Yin Jian, Sun Jingyan, Xie Qianrong, Wu Min, Zeng Fanxin, Ren Huiwen
Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer; Sino-Russian Joint Research Center for Oncoplastic Breast Surgery, Tianjin, China.
Department of Breast Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
NPJ Breast Cancer. 2021 May 12;7(1):53. doi: 10.1038/s41523-021-00261-5.
The triple-negative breast carcinoma (TNBC) is the most aggressive subtype of breast cancer. In TNBC, Aquaporin 1 (AQP1), a water-transporting transmembrane protein, is aberrantly enriched in cytoplasm and causes tumor cell death evasion. However, the carcinogenetic bioactivities of cytoplasmic AQP1 cannot be attributed to the canonical "osmotic engine model". In the present study, the receptor-interacting protein kinase 1 (RIPK1), a cell death regulator, was identified to negatively mediate AQP1-driven TNBC progression and metastasis. AQP1 overabundance and RIPK1 depletion occurred in TNBC, which were correlated with aggressive oncological features and poor prognosis. AQP1 bound with RIPK1, resulting in the inhibition of RIPK1/RIPK3/MLKL-mediated necroptosis and RIPK1/caspase-8/caspase-3-mediated apoptosis. Genetic inhibition of RIPK1 significantly exacerbated the pro-tumor effect of AQP1, while ectopic expression of RIPK1 notably blunted AQP1 signaling. Mechanistically, AQP1 binds to the D324 site of RIPK1, and facilitates RIPK1 cleavage and inactivation by excessively activating the caspase-8/RIPK1 negative feedback loop. RIPK1 overexpression significantly prevented RIPK1 cleavage and weakened the aggressiveness of AQP1-enriched TNBC cells. Overall, our findings clarify the underlying mechanism of cytoplasmic AQP1-driven TNBC progression and metastasis, in which RIPK1 exerts an essential role as a negative mediator and exhibits the potential as a therapeutic target for TNBC.
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型。在TNBC中，水通道蛋白1（AQP1）是一种水转运跨膜蛋白，在细胞质中异常富集并导致肿瘤细胞逃避死亡。然而，细胞质AQP1的致癌生物活性不能归因于经典的“渗透引擎模型”。在本研究中，细胞死亡调节因子受体相互作用蛋白激酶1（RIPK1）被确定为负向介导AQP1驱动的TNBC进展和转移。TNBC中出现AQP1过量和RIPK1缺失，这与侵袭性肿瘤特征和不良预后相关。AQP1与RIPK1结合，导致RIPK1/RIPK3/MLKL介导的坏死性凋亡和RIPK1/半胱天冬酶-8/半胱天冬酶-3介导的凋亡受到抑制。RIPK1的基因抑制显著加剧了AQP1的促肿瘤作用，而RIPK1的异位表达显著减弱了AQP1信号。机制上，AQP1与RIPK1的D324位点结合，并通过过度激活半胱天冬酶-8/RIPK1负反馈环促进RIPK1的切割和失活。RIPK1过表达显著阻止了RIPK1的切割，并减弱了富含AQP1的TNBC细胞的侵袭性。总体而言，我们的研究结果阐明了细胞质AQP1驱动TNBC进展和转移的潜在机制，其中RIPK1作为负向调节因子发挥重要作用，并展现出作为TNBC治疗靶点的潜力。
