The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China.
Cell Death Dis. 2018 Jan 24;9(2):91. doi: 10.1038/s41419-017-0128-y.
The identification of specific drug targets guides the development of precise cancer treatments. Compared with oncogenes, tumor suppressor genes have been poorly studied in the treatment of breast cancer. We integrate the microRNA expression array from GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) databases in clinical breast cancer tissues, and find that miR-27a is significantly upregulated and correlated with poor survival outcome and tumor progression. Transmembrane protein 170B (TMEM170B), a new functional target of miR-27a, is identified via target prediction and experimental validation, suppressing breast cancer proliferation, metastasis, and tumorigenesis. Furthermore, TMEM170B overexpression promotes cytoplasmic β-catenin phosphorylation, resulting in the inhibition of β-catenin stabilization, reduction of nuclear β-catenin levels and downstream targets expression. Clinically, TMEM170B or β-catenin expression is significantly correlated with overall survival ratio in breast cancer patients. Thus, these results highlight TMEM170B as a novel tumor suppressor target in association with the β-catenin pathway, which may provide a new therapeutic approach for human breast cancer therapy.
特定药物靶点的鉴定指导着精准癌症治疗的发展。与癌基因相比，肿瘤抑制基因在乳腺癌治疗中的研究还很不充分。我们整合了 GEO（基因表达综合数据库）和 TCGA（癌症基因组图谱）数据库中临床乳腺癌组织中的 microRNA 表达谱，发现 miR-27a 显著上调，并与不良生存结局和肿瘤进展相关。跨膜蛋白 170B（TMEM170B）是 miR-27a 的一个新的功能靶标，通过靶标预测和实验验证确定，可抑制乳腺癌的增殖、转移和肿瘤发生。此外，TMEM170B 的过表达促进细胞质 β-连环蛋白磷酸化，导致β-连环蛋白稳定、核内β-连环蛋白水平和下游靶基因表达减少。临床上，TMEM170B 或 β-连环蛋白的表达与乳腺癌患者的总生存率显著相关。因此，这些结果强调了 TMEM170B 作为与β-连环蛋白通路相关的新型肿瘤抑制靶标，可能为人类乳腺癌治疗提供新的治疗方法。
