中国学者在乳腺癌干细胞特性及靶向治疗领域取得新成果

　　目前，乳腺癌的临床治疗效果虽然大大改善，但耐药和复发转移现象日益严重。越来越多的证据表明，肿瘤干细胞与肿瘤治疗过程中的药物抵抗、疾病复发和转移高度相关。但由于肿瘤干细胞的动态演进及高度异质性，针对肿瘤干细胞的治疗仍然缺乏有效的靶点和干预机制。

　　2017年1月19日，英国《自然》旗下《癌基因》正式发表大连医科大学附属第二医院、肿瘤干细胞研究院、中山大学华南肿瘤学国家重点实验室、肿瘤医学协同创新中心、广东药科大学附属第一医院、中山大学附属第六医院、大连医科大学附属第一医院、英国伦敦帝国学院的研究报告，在乳腺癌干细胞特性及靶向治疗领域取得新成果，首次阐述了p62/SQSTM1-let-7a/b-MYC信号通路对乳腺癌肿瘤干细胞特性的关键调控效应，提示信号枢纽蛋白p62/SQSTM1可以作为干预的有效靶点，为攻克乳腺癌的复发转移和耐药提供了新思路。

　　p62/SQSTM1蛋白作为细胞内的“信号枢纽”，通过自身一系列功能结构域，与多种信号分子相互结合，参与调节多种信号通路。

　　该研究以乳腺癌为例，通过体外细胞系实验及裸鼠体内动物实验，首次揭示信号蛋白p62/SQSTM1在肿瘤干细胞富集群体中高表达，并且对肿瘤干细胞的“干性”特征起正向调节作用，干预该基因的表达可显著降低肿瘤干细胞的“干性”能力。

　　该研究还发现，信号蛋白p62/SQSTM1可通过下调一种微小RNA（let-7a/b）的表达，促进致癌基因MYC转录后的mRNA稳定性，从而介导维持肿瘤干细胞的“干性”表型。后续的临床样本分析进一步验证了信号蛋白p62/SQSTM1的高表达与乳腺癌患者的PFS和OS呈负相关。

Oncogene. 2017 Jan 19;36(3):304-317.

p62/SQSTM1 enhances breast cancer stem-like properties by stabilizing MYC mRNA.

Xu LZ, Li SS, Zhou W, Kang ZJ, Zhang QX, Kamran M, Xu J, Liang DP, Wang CL, Hou ZJ, Wan XB, Wang HJ, Lam EW, Zhao ZW, Liu Q.

The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China; The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China; The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; The First Affiliated Hospital, Dalian Medical University, Dalian, China; Imperial College London, London, UK.

Aberrant p62 overexpression has been implicated in breast cancer development. Here, we found that p62 expression was elevated in breast cancer stem cells (BCSCs), including CD44+CD24- fractions, mammospheres, ALDH1+ populations and side population cells. Indeed, short-hairpin RNA (shRNA)-mediated knockdown of p62 impaired breast cancer cells from self-renewing under anchorage-independent conditions, whereas ectopic overexpression of p62 enhanced the self-renewal ability of breast cancer cells in vitro. Genetic depletion of p62 robustly inhibited tumor-initiating frequencies, as well as growth rates of BCSC-derived tumor xenografts in immunodeficient mice. Consistently, immunohistochemical analysis of clinical breast tumor tissues showed that high p62 expression levels were linked to poorer clinical outcome. Further gene expression profiling analysis revealed that p62 was positively correlated with MYC expression level, which mediated the function of p62 in promoting breast cancer stem-like properties. MYC mRNA level was reduced upon p62 deletion by siRNA and increased with p62 overexpression in breast cancer cells, suggesting that p62 positively regulated MYC mRNA. Interestingly, p62 did not transactivate MYC promoter. Instead, p62 delayed the degradation of MYC mRNA by repressing the expression of let-7a and let-7b, thus promoting MYC mRNA stabilization at the post-transcriptional level. Consistently, let-7a and let-7b mimics attenuated p62-mediated MYC mRNA stabilization. Together, these findings unveiled a previously unappreciated role of p62 in the regulation of BCSCs, assigning p62 as a promising therapeutic target for breast cancer treatments.

PMID: 27345399

DOI: 10.1038/onc.2016.202