Cell Cycle and Cancer Laboratory, School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, UP-221005, India.
BMC Cancer. 2022 Jul 15;22(1):777. doi: 10.1186/s12885-022-09879-5.
MicroRNAs have emerged as an important regulator of cell cycle and various other cellular processes. Aberration in microRNAs has been linked with development of several cancers and other diseases but still very little is known about the mechanism by which they regulate these cellular events. High risk human papilloma virus (HR HPV) is the causative agent of 99% of cervical cancer cases which attenuates multiple tumor suppressors and checkpoint factors of the host cell. The viral proteins also stabilize many oncogenic factors, including an essential cell cycle regulator Cdt2/DTL which in turn promotes cell transformation and proliferation. In this study, we report that a micro-RNA, miR-34a by suppressing HPV E6 protein, destabilizes Cdt2/DTL protein level in HPV infected cervical cancer cell lines. Destabilization of Cdt2 stabilizes pro-apoptotic and onco-suppressor proteins like p21 and Set8 and suppresses cell proliferation, invasion and migration capabilities of the HPV positive cervical cancer cells. Overexpression of either HPV E6 or Cdt2 genes along with miR-34a restored back the suppressed proliferation rate. This study is the first-ever report to show that miR-34a regulates cell cycle factor Cdt2 by suppressing viral E6 protein level, thus opening up the possibility of exploring miR-34a as a specific therapy for cervical cancer treatment.
微小 RNA 已成为细胞周期和各种其他细胞过程的重要调节因子。微小 RNA 的异常与多种癌症和其他疾病的发生有关，但人们对它们调节这些细胞事件的机制仍知之甚少。高危型人乳头瘤病毒（HR HPV）是 99%宫颈癌病例的致病因子，它可削弱宿主细胞的多个肿瘤抑制因子和检查点因子。病毒蛋白还稳定了许多致癌因子，包括一个必需的细胞周期调节剂 Cdt2/DTL，它反过来又促进细胞转化和增殖。在这项研究中，我们报告了一种微小 RNA，miR-34a 通过抑制 HPV E6 蛋白，使 HPV 感染的宫颈癌细胞系中 Cdt2/DTL 蛋白水平不稳定。Cdt2 的不稳定稳定了促凋亡和抑癌蛋白，如 p21 和 Set8，并抑制了 HPV 阳性宫颈癌细胞的增殖、侵袭和迁移能力。HPV E6 或 Cdt2 基因的过表达以及 miR-34a 的过表达恢复了受抑制的增殖率。这项研究首次表明，miR-34a 通过抑制病毒 E6 蛋白水平来调节细胞周期因子 Cdt2，从而为探索 miR-34a 作为宫颈癌治疗的特定疗法开辟了可能性。
