PTCSC3通过miR-574及相关调节因子抑制甲状腺癌侵袭转移的作用和机制

Thyroid cancer is the most common malignant tumor of the endocrine organs and molecular mutations represent different invasion ability and high frequency of local lymph metastasis. It is being increasingly recognized that altered expression of lncRNAs is specifically associated with tumorigenesis, tumor progression and metastasis of thyroid cancer. Our previous studies showed that significantly decreased expression of lncRNA PTCSC3 in thyroid cancer cells and up-regulation of PTCSC3 demonstrated significant growth inhibition, cell cycle arrest, decreased cell migration and increased apoptosis probably through binding miR-574-5p competitively. Meanwhile, IQGAP1 expression is negatively related to PTCSC3 expression. The present project will firstly analyze the alteration of PTCSC3 expression affects the biological behavior of thyroid cancer cells. Secondly, PTCSC3 modulates thyroid cancer invasion and metastasis through binding miR-574-5p competitively using bioinformatics method and biologic function analysis. Isolate and identify the PTCSC3-asscioated key regulator and related molecular mechanism also will be analyzed. Lastly, relationship of PTCSC3 and its targeted molecules expression and the clinicopathologic features will be studies and their expression in circulation will be investigated as potential biomarkers of thyroid cancer. The project will provide new clues to diagnosis, treatment and prognosis of thyroid cancer.

甲状腺癌是内分泌器官来源最常见的恶性肿瘤，由于分子遗传背景不同而具有不同的侵袭和转移能力。LncRNA表达异常在甲状腺癌的侵袭转移中起重要作用。我们的前期研究发现PTCSC3在甲状腺癌细胞中表达水平明显下调，PTCSC3可能通过调节miR-574-5p靶基因抑制甲状腺癌细胞生长、迁移和促进凋亡；同时也发现甲状腺癌细胞和组织中PTCSC3与IQGAP1的表达呈负相关。研究拟首先利用功能获得与缺失实验，确定PTCSC3在甲状腺癌细胞中的生物学功能；其次通过生物信息学、生物功能分析等方法证实PTCSC3通过竞争性结合miR-574-5p调节其靶基因的表达；利用表达谱芯片筛选和验证与PTCSC3生物学功能相关的关键性调控分子和相关机制；最后研究分析PTCSC3及其靶分子在甲状腺癌原发灶、转移灶和血液中的表达与临床病理特征之间的关系。项目研究有助于为甲状腺癌的早期诊断、治疗和预后监测提供新的思路。

长链非编码RNA（LncRNA）在肿瘤发生发展中扮演重要角色。有氧糖酵解是肿瘤重要标志，是诊断和治疗极具前景的靶位点。目前也有较多证据表明lncRNA在肿瘤细胞有氧糖酵解中发挥重要作用。然而，甲状腺癌细胞中lncRNA与糖酵解的相关性尚不清楚。在本研究中，我们发现lncRNA甲状腺乳头状癌易感候选基因3（PTCSC3）在甲状腺癌中表达明显下调。体内外实验证实过表达PTCSC3显著抑制甲状腺癌细胞增殖和有氧糖酵解作用。机制上我们发现，PTCSC3与PGK1直接结合，促进其泛素化降解，从未抑制肿瘤细胞增殖和有氧糖酵解作用。因此PTCSC3可通过直接靶向调控PGK1发挥肿瘤相关生物学作用，从而参与肿瘤发生发展。我们推测PTCSC3/PGK1可能作为甲状腺癌诊断和治疗的潜在靶点。