Xinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan Province, People's Republic of China.
Molecular Biology Laboratory, First People's Hospital of Shangqiu, Shangqiu, City, 476000, Henan Province, People's Republic of China.
J Exp Clin Cancer Res. 2022 Dec 29;41(1):364. doi: 10.1186/s13046-022-02576-y.
Recently genome-based studies revealed that the abnormality of Hippo signaling is pervasive in TNBC and played important role in cancer progression. RING finger protein 31 (RNF31) comes to RING family E3 ubiquitin ligase. Our previously published studies have revealed RNF31 is elevated in ER positive breast cancer via activating estrogen signaling and suppressing P53 pathway.
We used several TNBC cell lines and xenograft models and performed immuno-blots, QPCR, in vivo studies to investigate the function of RNF31 in TNBC progression.
Here, we demonstrate that RNF31 plays tumor suppressive function in triple negative breast cancer (TNBC). RNF31 depletion increased TNBC cell proliferation and migration in vitro and in vitro. RNF31 depletion in TNBC coupled with global genomic expression profiling indicated Hippo signaling could be the potential target for RNF31 to exert its function. Further data showed that RNF31 depletion could increase the level of YAP protein, and Hippo signaling target genes expression in several TNBC cell lines, while clinical data illustrated that RNF31 expression correlated with longer relapse-free survival in TNBC patients and reversely correlated with YAP protein level. The molecular biology assays implicated that RNF31 could associate with YAP protein, facilitate YAP poly-ubiquitination and degradation at YAP K76 sites. Interestingly, RNF31 could also repress PDL1 expression and sensitive TNBC immunotherapy via inhibiting Hippo/YAP/PDL1 axis.
Our study revealed the multi-faced function of RNF31 in different subtypes of breast malignancies, while activation RNF31 could be a plausible strategy for TNBC therapeutics.
最近基于基因组的研究表明，Hippo 信号异常在三阴性乳腺癌（TNBC）中普遍存在，并在癌症进展中发挥重要作用。RING 指蛋白 31（RNF31）属于 RING 家族 E3 泛素连接酶。我们之前的研究表明，RNF31 通过激活雌激素信号和抑制 P53 通路在 ER 阳性乳腺癌中上调。
我们使用了几种 TNBC 细胞系和异种移植模型，并进行了免疫印迹、QPCR 和体内研究，以研究 RNF31 在 TNBC 进展中的作用。
在这里，我们证明 RNF31 在三阴性乳腺癌（TNBC）中发挥肿瘤抑制作用。RNF31 耗竭增加了 TNBC 细胞的体外和体内增殖和迁移。TNBC 中 RNF31 的耗竭与全基因组表达谱分析表明，Hippo 信号可能是 RNF31 发挥其功能的潜在靶点。进一步的数据表明，RNF31 耗竭可以增加几个 TNBC 细胞系中 YAP 蛋白和 Hippo 信号靶基因的表达，而临床数据表明 RNF31 表达与 TNBC 患者无复发生存期延长相关，与 YAP 蛋白水平呈负相关。分子生物学检测表明，RNF31 可以与 YAP 蛋白结合，促进 YAP 在 YAP K76 位点的多泛素化和降解。有趣的是，RNF31 还可以通过抑制 Hippo/YAP/PDL1 轴来抑制 PDL1 的表达，从而提高 TNBC 免疫治疗的敏感性。
我们的研究揭示了 RNF31 在不同亚型乳腺癌中的多方面功能，而激活 RNF31 可能是 TNBC 治疗的一种可行策略。
