State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China.
Department of Pathology, Guangdong Provincial People's Hospital, Guangzhou, China.
Int J Cancer. 2020 Jul 15;147(2):505-518. doi: 10.1002/ijc.32922. Epub 2020 Feb 25.
Although early detection and systemic therapies have improved the diagnosis and clinical cure rate of breast cancer, breast cancer remains the most frequently occurring malignant cancer in women due to a lack of sufficiently effective treatments. Thus, to develop potential targeted therapies and thus benefit more patients, it is helpful to understand how cancer cells work. ZIC family members have been shown to play important roles in neural development and carcinogenesis. In our study, we found that ZIC2 is downregulated in breast cancer tissues at both the mRNA and protein levels. Low expression of ZIC2 was correlated with poor outcome in breast cancer patients and serves as an independent prognostic marker. Furthermore, overexpression of ZIC2 repressed, whereas knockdown of ZIC2 promoted, cell proliferation and colony formation ability in vitro and tumor growth in vivo. Using ChIP-seq and RNA-seq analysis, we screened and identified STAT3 as a potential target for ZIC2. ZIC2 bound to the STAT3 promoter and repressed the promoter activities of STAT3. ZIC2 knockdown induced the expression of STAT3, increasing the level of phosphorylated STAT3. These results suggest that ZIC2 regulates the transcription of STAT3 by directly binding to the STAT3 promoter. Additionally, interfering STAT3 with siRNAs or inhibitors abrogated the oncogenic effects induced by decreased ZIC2. Taken together, our results indicate that ZIC2 serves as a useful prognostic marker in breast cancer and acts as a tumor suppressor by regulating STAT3, implying that STAT3 inhibitors might provide an alternative treatment option for breast cancer patients with ZIC2 downregulation.
尽管早期检测和系统治疗已经提高了乳腺癌的诊断和临床治愈率，但由于缺乏足够有效的治疗方法，乳腺癌仍然是女性中最常见的恶性肿瘤。因此，为了开发潜在的靶向治疗方法，从而使更多的患者受益，了解癌细胞的工作方式是有帮助的。ZIC 家族成员已被证明在神经发育和致癌作用中发挥重要作用。在我们的研究中，我们发现 ZIC2 在乳腺癌组织中的 mRNA 和蛋白水平均下调。ZIC2 的低表达与乳腺癌患者的不良预后相关，并可作为独立的预后标志物。此外，ZIC2 的过表达抑制，而敲低 ZIC2 则促进体外细胞增殖和集落形成能力以及体内肿瘤生长。通过 ChIP-seq 和 RNA-seq 分析，我们筛选并鉴定 STAT3 是 ZIC2 的潜在靶标。ZIC2 结合到 STAT3 启动子上，抑制 STAT3 启动子活性。ZIC2 敲低诱导 STAT3 的表达，增加磷酸化 STAT3 的水平。这些结果表明 ZIC2 通过直接结合 STAT3 启动子来调节 STAT3 的转录。此外，用 siRNAs 或抑制剂干扰 STAT3 可消除由 ZIC2 下调引起的致癌作用。总之，我们的研究结果表明 ZIC2 可作为乳腺癌的有用预后标志物，并通过调节 STAT3 发挥肿瘤抑制作用，这意味着 STAT3 抑制剂可能为 ZIC2 下调的乳腺癌患者提供一种替代治疗选择。
