SOSTDC1通过Wnt/β-catenin通路调控甲状腺未分化癌干细胞特性

Cancer stem cells (CSCs) have self-renewal and multilineage differentiation potential, which contribute to tumor initiation and therapeutic resistance. It has been reported that constitutive activation of Wnt/β-catenin signaling plays an important role in regulating CSCs. Our previous studies showed that SOSTDC1 was significantly down-regulated in anaplastic thyroid cancer (ATC). Moreover, our preliminary studies illustrated that: 1) SOSTDC1 could inhibit the stemness of ATC cells; 2) Overexpression of SOSTDC1 could suppress the activity of Wnt/β-catenin signaling. Based on the above results, our aim in current proposal is to systematically investigate mechanism involved in SOSTDC1 regulating the self-renew activity of ATC CSCs via inhibition of Wnt/β-catenin signaling, which may provide new insights of the therapeutic strategies for ATC.

肿瘤干细胞（cancer stem cell, CSCs）是肿瘤中具有自我更新能力和多向分化潜能的细胞，放、化疗后残留的CSCs是肿瘤复发的重要原因。研究表明Wnt/β-catenin信号通路的持续激活在调控CSCs中发挥重要作用，但具体分子机制尚不明确。本课题组前期的研究结果表明SOSTDC1在包括甲状腺未分化癌（ATC）在内的三种甲状腺癌中的表达均明显下调。前期预实验我们发现外源性稳定过表达SOSTDC1可以抑制ATC干细胞特性。我们还发现稳定过表达SOSTDC1可抑制Wnt/β-catenin通路的活性。以上述实验结果为基础，本项目将系统性的研究SOSTDC1调控Wnt/β-catenin通路在调控ATC干细胞特性中的作用，以及深入探讨SOSTDC1调控Wnt/β-catenin通路的分子机制，为ATC的治疗寻找新的靶点。

甲状腺癌是内分泌系统中最常见的恶性肿瘤，其发病率逐年升高。分子遗传学研究结果表明甲状腺癌的形成是一系列的遗传的和后天获得性的变化的逐步累积过程，这些变化导致原癌基因获得功能和抑癌基因丧失功能。因此，探讨参与甲状腺癌启动和进展的原癌基因和抑癌基因的调控机制对于提高我们对甲状腺癌发生发展的认识以及寻找有效的治疗手段很有必要。本研究发现Trop2通过活化ERK及JNK通路促进MMP2表达从而促进甲状腺肿瘤侵袭性；INAVA通过上调MMP9的表达从而促进甲状腺乳头状癌细胞侵袭；CITED1通过调控p21和p27的表达进而促进甲状腺乳头状癌细胞增殖。