Zhao Chenglong, Cai Xiaopan, Wang Yao, Wang Dongsheng, Wang Ting, Gong Haiyi, Sun Haitao, Jia Qi, Zhou Wang, Wu Zhipeng, Li Zhenxi, Xiao Jianru
Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Navy Medical University (Second Military Medical University) Shanghai, China.
Am J Cancer Res. 2020 Aug 1;10(8):2464-2479. eCollection 2020.
Breast cancer is a molecularly heterogeneous disease that can be subdivided into different subtypes. Compared with the other subtypes, luminal breast cancer (LBC) is considered more susceptible to bone metastasis. However, the intrinsic mechanisms remain elusive. Bioinformatics analysis of the preset study showed that N-acetyltransferase 1 (NAT1) was specifically expressed in LBC and closely correlated with bone metastasis. In addition, NAT1 could promote LBC cell migration and clonal formation, induce osteoclast differentiation and raise the Rankl/Opg ratio in osteoblasts. Our in vivo experiment demonstrated that NAT1 promoted LBC bone metastasis and bone destruction, which could be reversed by NAT1 inhibitor treatment. The result of cytokine array showed that NAT1 could significantly over activate the NF-κB signaling pathway and up-regulate the expression of IL-1B, which further worked as downstream factors in these processes. All these results demonstrated NAT1 was up-regulated in LBC and promoted the formation of bone metastatic niche and osteolytic bone metastasis through the NAT1/NF-κB/IL-1B axis. This finding may provide a new pathway to help understand the mechanisms of LBC bone metastasis and suggest a novel therapeutic and diagnostic target for its treatment.
乳腺癌是一种分子异质性疾病，可细分为不同亚型。与其他亚型相比，管腔型乳腺癌（LBC）被认为更容易发生骨转移。然而，其内在机制仍不清楚。本研究的生物信息学分析表明，N-乙酰基转移酶1（NAT1）在LBC中特异性表达，且与骨转移密切相关。此外，NAT1可促进LBC细胞迁移和克隆形成，诱导破骨细胞分化，并提高成骨细胞中的Rankl/Opg比值。我们的体内实验表明，NAT1促进LBC骨转移和骨破坏，而NAT1抑制剂治疗可逆转这种情况。细胞因子阵列结果显示，NAT1可显著过度激活NF-κB信号通路并上调IL-1B的表达，IL-1B在这些过程中作为下游因子发挥作用。所有这些结果表明，NAT1在LBC中上调，并通过NAT1/NF-κB/IL-1B轴促进骨转移微环境的形成和溶骨性骨转移。这一发现可能为帮助理解LBC骨转移机制提供一条新途径，并为其治疗提出一个新的治疗和诊断靶点。
