环状RNA circ_000002在肾细胞癌侵袭转移中的作用及其分子机制研究

The metastatic renal cell carcinoma (RCC) resists to both radio- and chemo-therapy and has become a major obstacle in the treatment of RCC, thus its metastatic mechanism becomes a research focus of the present study. CicrRNA which has a unique structure could be promising molecular biomarkers and new targets based on the recent research. We identified a circRNA--- circ_000002 has a higher expression in RCC tissue from the patients with metastasis than that from the patients without metastasis through the circRNA miacroarray. Then we also found that circ_000002 could promote RCC cell invasion and function as a miRNA sponges with miR-19-3p and miR-29-3p which was found the negative role in RCC metastasis. Thus we hypothesize that circ_000002 may promote RCC metastasis via interacting with miR-19-3p and miR-29-3p. Our study aims to prove the hypothesis in vitro, in vivo and in clinical tissue and dissect its detailed mechanism. Insight in circ_000002 signaling in RCC metastasis may provide new therapeutic targets and biomakers.

转移性肾癌对放化疗均不敏感，是目前肾癌治疗中的难点，肾癌转移的机制已成为当下研究的焦点。环状RNA是近两年来肿瘤学研究领域的热点之一，它的特殊环状结构使其有望成为新的肿瘤标记物和治疗靶点。我们通过环状RNA芯片发现circ_000002在转移性肾癌患者组织标本中高表达，并证明其可促进肾癌细胞的侵袭能力，并可吸附miR-19-3p和miR-29-3p，而文献报道这两个miRNA可能抑制肾癌转移。因此，我们推测circ_000002可能通过竞争性吸附miRNA影响其下游基因的表达从而促进肾癌的转移。本课题拟通过一系列体内外实验，综合运用RNA-IP、RNA-pulldown、裸鼠原位肾癌移植瘤模型、锁核酸原位杂交等技术，从细胞、动物、临床多个层次研究circ_000002在肾癌转移中的作用，阐明其通过竞争性结合miRNA影响肾癌转移的具体分子机制，并评价其预测预后的价值。

转移性肾癌对放化疗均不敏感，是目前肾癌治疗中的难点，肾癌转移的机制已成为当下研究的焦点。环状RNA是近两年来肿瘤学研究领域的热点之一，它的特殊环状结构使其有望成为新的肿瘤标记物和治疗靶点。我们发现circ_000002可促进肾癌细胞的侵袭能力，并可吸附miR-19-3p和miR-29-3p。同时我们发现TR4可正向调控circ_000002的表达。我们通过一系列体内外实验，综合运用RNAIP、RNA-pulldown、裸鼠原位肾癌移植瘤模型，从细胞、动物多个层次研究circ_000002与肾癌转移之间的关系，TR4与circ_000002的关系以及circ_000002在TR4促进肾癌侵袭转移中的作用。最终证明证明TR4可以通过转录调控上调circ_000002的表达，而circ_000002可以和miR-19s-3p、miR-29s-3p结合，影响其分布进而促进其下游 IGF-1的表达，最终促进ccRCC侵袭转移。因此，circ_000002是ccRCC恶性程度的潜在标记物，并有望作为一种新的治疗手段更好地抑制ccRCC转移。