膜联蛋白为一类与酸性膜磷脂反应的钙结合蛋白家族，其氨基端区不同、羧基端区高度同源，参与膜转运、膜表面依赖钙调蛋白的活动等。膜联蛋白A3（ANXA3）为膜联蛋白家族非常重要成员，既往研究证实ANXA3参与细胞增殖、分化与凋亡、细胞信号转导和胞吞胞吐等一系列重要生理过程，其异常表达可能与多种癌症的侵袭、进展或转移密切相关，其高表达可能促进乳腺癌、肺腺癌、胆囊癌等的侵袭或转移，其低表达可能促进乳头状甲状腺癌、前列腺癌等的转移；此外，ANXA3可能通过促进结肠癌血管生成促使肿瘤细胞的转移。抑制或促进ANXA3表达可能为癌症治疗提供新的方向。

       2018年1月26日，英国《自然》旗下《细胞死亡与疾病》在线发表中国科学技术大学生命科学学院、复旦大学肿瘤研究所、复旦大学生物医学研究院、细胞信号网络协同创新中心、复旦大学附属肿瘤医院、安徽医科大学第一附属医院、安徽省立医院、安徽医科大学附属省立医院、中国科学技术大学附属第一医院、安徽省脑功能与脑疾病重点实验室的柳素玲团队研究报告，发现下调ANXA3可以抑制肿瘤转移并减少乳腺癌耐药。

　　该研究发现，乳腺癌组织的ANXA3表达水平显著上调。减少ANXA3表达能够抑制癌细胞侵犯和破坏周围正常组织，却促进癌细胞分裂增殖，无论体外还是体内。此外，减少ANXA3表达能够上调IκBα而抑制NFκB通路，引起间质-上皮转化和乳腺癌干细胞异质性改变。此外，该研究证实减少ANXA3表达能够增加乳腺癌细胞对化疗药物多柔比星的摄取和敏感性。减少ANXA3表达联合多柔比星可以同时抑制肿瘤生长和体内转移。

　　因此，该研究描述了ANXA3对调控乳腺癌干细胞和乳腺癌生长转移的作用及其机制，表明减少ANXA3表达联合化疗可能成为治疗乳腺癌的新方法。

Cell Death Dis. 2018 Jan 26;9(2):126.

Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer.

Ruikai Du, Bingjie Liu, Lei Zhou, Dong Wang, Xueyan He, Xiaojun Xu, Lixing Zhang, Chaoshi Niu, Suling Liu.

University of Science & Technology of China, Hefei, Anhui, China; Key Laboratory of Breast Cancer in Shanghai, Cancer Institute; Institutes of Biomedical Sciences; Innovation Center for Cell Signaling Network; Fudan University Shanghai Cancer Center, Shanghai, China; The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China; Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui, China; AnHui Province Key Laboratory of Brain Function and Brain Disease, Hefei, Anhui, China.

Annexin A3 (ANXA3) is dysregulated and plays an important role in various cancers. However, the role of ANXA3 in breast cancer is still unclear. Here, we observed that the expression level of ANXA3 was significantly upregulated in breast cancer tissues. ANXA3 knockdown inhibited cell invasion but promoted cell proliferation in both in vitro and in vivo assays. Furthermore, we found that ANXA3 knockdown inhibited the NFκB pathway via upregulating IκBα, resulting in mesenchymal-epithelial transition (MET) and a heterogeneity change of breast cancer stem cells (BCSCs). In addition, we demonstrated that ANXA3 knockdown increased the sensitivity of breast cancer cells to doxorubicin by increasing the drug uptake. The combination of ANXA3 knockdown and doxorubicin treatment simultaneously inhibited tumor growth and metastasis in vivo. This study described the role and mechanisms of ANXA3 in regulating BCSCs and breast cancer growth and metastasis, indicating that downregulating ANXA3 together with chemotherapy might be a novel therapeutic strategy for treating breast cancer.

DOI: 10.1038/s41419-017-0143-z