miR-22在皮肤鳞状细胞癌发生发展中的功能研究

Cutaneous squamous cell carcinoma (cSCC) is one of the common malignant tumors and its potential to recurrence and metastasis makes it accounts for the majority of deaths from the non-melanoma skin cancers. But the pathogenesis of cSCC is not clear. miR-22 is a cancer related gene and its aberrant expression has been identified in multiple human cancers not including cSCC. Our previous results showed that miR-22 is a key regulator of skin and hair follicle development and may be an important negative regulator of skin stress damage repair mechanism. Overexpression of miR-22 in mouse skin can induce excessive proliferation of skin cell and thickening of the epidermis. It suggested that miR-22 may be an oncogene of skin. Additionally, our results also showed that the expression of miR-22 is significantly upregulated in cSCC cell line and miR-22 has a function of promoting proliferation and migration of cSCC cell line. These results suggested that miR-22 may induce the development of cSCC. In order to confirm this assumption, we will deeply study the role of miR-22 in the development of cSCC using miR-22 knockout mouse and miR-22 transgenic mouse with the DMBA/TPA induced cSCC mouse model. This research is highly significant to provide scientific evidences for the diagnosis and therapy of cSCC, and to develop new targets for drug design as well.

皮肤鳞状细胞癌（cSCC）是一种常见的恶性肿瘤，易发生转移和复发，是导致非黑色素瘤皮肤癌患者死亡的主要原因，但cSCC的发病机制不清楚。miR-22是一个癌症密切相关的基因，广泛参与各种癌症的形成，但未见cSCC中的报道。在前期工作中，我们首次报道了miR-22还是皮肤毛囊发育的关键调控因子，并可能是皮肤应激损伤修复机制的负调控因子，且过表达miR-22能导致小鼠表皮细胞过度增殖、表皮增厚，显示出其对皮肤细胞的致癌性。我们还发现miR-22在cSCC细胞中异常高表达，且具有促进cSCC细胞增殖和迁移的功能。这些结果预示miR-22具有促进cSCC形成的功能。为了证实这一假设，本项目将以miR-22过表达和敲除小鼠为基础，以DMBA/TPA诱导的小鼠cSCC为模型，进行体内外的功能分析，深入揭示miR-22在cSCC发生发展中的分子机制，为临床上诊断和治疗cSCC提供新的靶点和科学依据。

大量证据表明，癌干细胞是导致癌细胞转移和耐药的关键原因。因此揭示调控癌干细胞功能及关键的信号通路具有重要的理论和临床意义。本项目的研究发现miR-22随着人和小鼠皮肤鳞癌的病理进程的恶化，其表达水平都显著升高。体外及体内基因敲除小鼠模型研究结果进一步揭示，miR-22通过直接抑制瓜氨酸酶PAD2水平从而降低β-catenin的降解，同时通过靶向FosB-DDK1转录轴抑制DKK1介导的Wnt/β-catenin信号的抑制，从而在两个层面维持Wnt/β-catenin信号通路的激活状态，以及促进LGR5癌干细胞的自我更新与转移能力，从而促进皮肤鳞癌的起始、进程和转移。此外，在体外和异种移植小鼠中抑制miR-22可显著抑制皮肤鳞癌的进程并提高其化疗敏感性。总之，我们的结果在皮肤鳞癌中揭示了一种新的miR-22-WNT-CSCs调控机制，并发现miR-22可作为Wnt/β-catenin信号通路和CSCs的共同靶向治疗分子，显示出miR-22在癌症分子分型及治疗干预方面具有重要的应用前景。