锌指蛋白ZNF322A是一个致癌转录因子。ZNF322A的过度表达激活了与肺癌进展相关的前转移、癌干细胞特性和新生血管生成相关基因。然而，ZNF322A的上游调节因子尚未明确。microRNA(miRNA)的失调可以介导癌细胞的生长、迁移和侵袭，促进肿瘤发生。在这里，我们揭示了miRNA介导的转录调控机制在ZNF322A驱动的致癌事件中的作用。ZNF322A在其3'未翻译区(UTR)中含有几个可能的miRNA结合位点。我们验证了miR-326可以下调ZNF322A-3'UTR的荧光素酶活性和mRNA表达。此外，miR-326抑制了ZNF322A驱动的癌相关基因，如cyclin D1和alpha-adducin的表达。通过过表达ZNF322A的重建实验，我们发现miR-326抑制了癌细胞的增殖和迁移能力。此外，miR-326也减弱了ZNF322A诱导的肿瘤生长和肺转移。临床上，miR-326的表达与120例非小细胞肺癌(NSCLC)患者手术切除组织中的ZNF322A mRNA表达呈负相关。多变量Cox回归分析表明，miR-326表达低/ZNF322A表达高的NSCLC患者总生存率较差。我们的结果揭示了miR-326的失调表达导致ZNF322A驱动的致癌信号的过度激活。靶向miR-326/ZNF322A轴将为肺癌患者提供新的治疗策略。©2023国际生物化学与分子生物学联合会。

Zinc finger protein ZNF322A is an oncogenic transcription factor. Overexpression of ZNF322A activates pro-metastasis, cancer stemness, and neo-angiogenesis-related genes to enhance lung cancer progression. However, the upstream regulator of ZNF322A is not well defined. Dysregulation of microRNAs (miRNAs) can mediate cancer cell growth, migration, and invasion to promote tumorigenesis. Here, we uncover the mechanism of miRNA-mediated transcriptional regulation in ZNF322A-driven oncogenic events. ZNF322A harbors several putative miRNA-binding sites in the 3'-untranslated region (UTR). We validated that miR-326 downregulated ZNF322A-3'-UTR luciferase activity and mRNA expression. Furthermore, miR-326 suppressed the expression of ZNF322A-driven cancer-associated genes such as cyclin D1 and alpha-adducin. Reconstitution experiments by ectopic overexpression of ZNF322A abolished miR-326-suppressed cancer cell proliferation and cell migration capacity. Moreover, miR-326 attenuated ZNF322A-induced tumor growth and lung tumor metastasis in vivo. Clinically, the expression of miR-326 negatively correlated with ZNF322A mRNA expression in surgically resected tissues from 120 non-small cell lung cancer (NSCLC) patients. Multivariate Cox regression analysis demonstrated that NSCLC patients with low miR-326/high ZNF322A profile showed poor overall survival. Our results reveal that the deregulated expression of miR-326 leads to hyperactivation of ZNF322A-driven oncogenic signaling. Targeting the miR-326/ZNF322A axis would provide new therapeutic strategies for lung cancer patients.© 2023 International Union of Biochemistry and Molecular Biology.