Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts 02114, USA.
J Clin Invest. 2011 Feb;121(2):809-20. doi: 10.1172/JCI43897.
The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, a central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct functions—p73 mediates chemosensitivity while p63 promotes proliferation and cell survival—and are both overexpressed in squamous cell carcinomas (SCCs). However, how p63 and p73 interact functionally and govern the balance between prosurvival and proapoptotic programs in SCC remains elusive. Here, we identify a microRNA-dependent mechanism of p63/p73 crosstalk that regulates p53-independent survival of both human and murine SCC. We first discovered that a subset of p63-regulated microRNAs target p73 for inhibition. One of these, miR-193a-5p, expression of which was repressed by p63, was activated by proapoptotic p73 isoforms in both normal cells and tumor cells in vivo. Chemotherapy caused p63/p73-dependent induction of this microRNA, thereby limiting chemosensitivity due to microRNA-mediated feedback inhibition of p73. Importantly, inhibiting miR-193a interrupted this feedback and thereby suppressed tumor cell viability and induced dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, microRNA-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition may provide a new therapeutic opportunity in p53-deficient tumors.
抑癌基因 p53 是正常细胞中化学敏感性的核心介质，在许多人类癌症中其功能失活。因此，人类癌症治疗的一个核心挑战是确定在缺乏功能性 p53 的情况下控制肿瘤细胞存活和化学敏感性的途径。p53 相关转录因子 p63 和 p73 具有不同的功能——p73 介导化学敏感性，而 p63 促进增殖和细胞存活——并且在鳞状细胞癌 (SCC) 中均过度表达。然而，p63 和 p73 如何在功能上相互作用并控制 SCC 中促生存和促凋亡程序之间的平衡仍然难以捉摸。在这里，我们确定了一种依赖 microRNA 的 p63/p73 串扰机制，该机制调节 SCC 中 p53 非依赖性存活。我们首先发现一组 p63 调节的 microRNAs 靶向 p73 进行抑制。其中之一，miR-193a-5p，其表达受 p63 抑制，在体内正常细胞和肿瘤细胞中被促凋亡 p73 同工型激活。化疗导致 p63/p73 依赖性诱导这种 microRNA，从而由于 microRNA 介导的 p73 反馈抑制导致化学敏感性降低。重要的是，抑制 miR-193a 打断了这种反馈，从而抑制了体外和体内肿瘤细胞的活力，并显著增强了化学敏感性。因此，我们已经确定了一种直接的、依赖 microRNA 的调节回路，介导诱导性耐药，其抑制可能为 p53 缺陷型肿瘤提供新的治疗机会。
