miR-222通过AKT诱导甲状腺癌增殖和侵袭转移的机制研究

Thyroid cancer is the most common endocrine-related cancer, of which death risk factors include lymph node or distant metastasis. Previous studies have shown that genetics disorders such as gene mutation, gene fusion are associated with invasiveness and metastasis of thyroid cancer, yet, existing in only some patients. In our previous study, expression of miR-222 was found significantly elevated in patients with papillary thyroid cancer (PTC), which declined dramatically post-operatively; In addition, miR-222 expression positively correlates lymph node metastasis and TNM stage, indicating that miR-222 is associated with proliferation, invasion and metastasis of PTC. AKT is considered a carcinogenic kinase and activated in thyroid cancer. FOXO3 and mTOR, downstream molecules of AKT, were found to relate to thyroid cancer as well. Interestingly, PTEN and PPP2R2A, target genes of miR-222, play a role in regulating AKT activation. Hence, we speculate that miR-222 induce proliferation, invasion and metastasis of thyroid cancer through AKT signaling pathway. To prove this speculation, in vitro and in vivo studies involving cell proliferation assay, invasion and migration assay and signaling pathway experiments will be performed to verify that i) the role of miR-222 in proliferation, invasion and metastasis of thyroid cancer; ii) miR-222 regulates thyroid cancer through PTEN/PPP2R2A-AKT-FOXO3/mTOR signal pathway, and the correlation between miR-222-AKT-FOXO3/mTOR signal pathway and tumor stage, invasion and metastasis of thyroid cancer in clinical practice; iii) the mechanism underlying differential expression of miR-222, and the role of serum miR-222 in predicting the prognosis and recurrence of thyroid cancer. The completion of this study will for the first time clarify the important role of miR-222 in thyroid cancer and hopefully provide a new therapeutic target.

甲状腺癌(TC)是最常见的内分泌恶性肿瘤，死亡危险因素包括淋巴结及远处转移。我们的前期研究发现PTC患者术前miR-222表达明显升高而术后下降，其表达与淋巴结转移及TNM分期呈正相关，提示miR-222与PTC增殖、侵袭转移相关。我们推测miR-222可能通过作用于PTEN、PPP2R2靶基因，调控AKT活性，影响下游分子FOXO3及mTOR，从而诱导TC增殖及侵袭转移。本课题拟通过体内外细胞增殖、侵袭转移和信号通路上下游调控实验，获得miR-222调控TC增殖及侵袭转移的证据；阐明PTEN/PPP2R2A-AKT-FOXO3/mTOR信号通路在miR-222调控TC中的作用，以及该通路与肿瘤分级及侵袭转移相关性；探索miR-222差异表达的机制和血清miR-222在预测甲状腺肿瘤预后及复发中的作用。本研究将首次阐明miR-222在TC发生发展中的重要作用，为TC的防治提供治疗新靶点。

MicroRNA(MiRNA)的异常表达在甲状腺乳头状癌（PTC）的发生发展中起重要调控作用。本项目探讨miR-222和miR-20b在PTC中的差异表达及其作用机制。我们的研究发现miR-222在PTC患者甲状腺癌组织中表达显著升高，且与淋巴结转移及肿瘤TNM分期相关。同时，我们发现miR-222通过靶向下调PPP2R2A蛋白的表达，进而促进AKT蛋白的磷酸化，促进PTC的侵袭及转移。随着我们对miRNA与PTC研究的深入，我们进一步揭示了miR-20b在PTC中的作用机制。研究结果发现miR-20b在PTC中呈低表达水平，且与肿瘤TNM分期相关，miR-20b在III/IV期中的表达水平明显低于I/II期。miR-20b通过作用于靶基因SOS1和ERK2，抑制MAPK通路的活性，从而抑制PTC细胞的增殖、转移和侵袭，促进细胞凋亡。该项目研究结果为甲状腺癌早期诊断及治疗提供新的理论基础。.基于糖尿病的高发病率，近年来胰高血糖素样肽1（Glucagon-like Peptide-1，GLP-1）作为新型的降血糖药物，受到广大医生及患者的青睐，但其长期应用的安全性，特别是与肿瘤相关性也备受关注。明确 GLP-1受体激动剂exendin-4对卵巢癌和结肠癌细胞生物学行为的影响，从体外和体内分别探讨exendin-4对卵巢癌、结肠癌细胞发生发展及可能的分子作用机制。研究结果发现exendin-4对卵巢癌生长和转移有抑制作用，抑瘤作用是受体依赖性并且可能通过下调PI3K/Akt信号通路发挥作用。同时也发现结肠癌组织标本和细胞系均不表达GLP-1R，exendin-4并不促进结肠癌细胞增殖和抑制细胞凋亡。该项目结果提示exendin-4不促进卵巢癌或结肠癌的发生发展，而且可能对卵巢癌发展具有一定的保护作用，为exendin-4安全用药提供理论依据，具有重要的临床意义。