circ-SOX5在肝细胞癌恶性进展中的作用及机制

Hepatocellular carcinoma (HCC) is one of the most prevalent manlignancies with high morbidity and mortality. However, the nature of HCC progression remains elusive. Previous studies suggest that circular RNA play an important role in human cancer progression. Previously, we found that circular RNA circ-SOX5 was down-regulated and significantly associated with malignant phenotype and poor prognosis of HCC. Our preliminary study showed that (a) knockdown circ-SOX5 markly increased the expression of miR-590-3p and promoted cell proliferation and migration; (b) miR-590-3p inhibited the expression of TRAF3; (c) TRAF3 expression was inversely correlated with the expresion of SOX5 in clinical HCC samples. Based on these findings, we assume that circ-SOX5 inhibits tumor invasion and metastasis via miR-590-3p and TRAF3 modulating SOX5. In this study, we aim to detemine the expression of circ-SOX5 and its clinical significance in HCC, to reveal the role and mechanism of circ-SOX5/miR-590-3p/TRAF3/SOX5 in cell proliferation, and invasion and metastasis in HCC. Our study is likely to provide not only solid evidence that circ-SOX5 is involved in HCC progression, but also a potential biomarker for HCC clinical management.

肝细胞癌(HCC)恶性度高，预后差，研究表明环状RNA在肿瘤进展发挥重要作用，但其在HCC的作用及机制均尚未清楚。我们前期发现环状RNA circ-SOX5 在HCC组织低表达，且与肿瘤恶性表型及预后差相关；预实验显示：(a) 沉默 circ-SOX5 后 miR-590-3p 表达增多并促进HCC增殖、迁移；(b) miR-590-3p抑制TRAF3表达；(c) 临床HCC样本中，TRAF3 与 SOX5 表达呈负相关。因此，我们提出circ-SOX5 通过 miR-590-3p 与 TRAF3 调控SOX5抑制HCC浸润转移的假说。本项目拟采用一系列免疫学及细胞生物学实验，明确 circ-SOX5在HCC中的表达与意义，阐述circ-SOX5/miR-590-3p/TRAF3/SOX5 通路在HCC细胞增殖、浸润转移中的作用及其机制，为诠释肝癌进展的分子机制和寻找靶向治疗提供科学依据。

肝细胞癌(HCC)恶性度高，预后差，研究表明环状RNA在肿瘤进展发挥重要作用，但其在HCC的作用及机制均尚未清楚。本研究通过对6对肝癌组织与癌旁组织进行CircRNA-seq高通量二代测序，获得人类circRNA 在6对肝癌组织及癌旁组织中的表达差异情况，其中以circ-SOX5（has_circ_0098181）在癌组织中下调最为明显。circ-SOX5为闭合环状RNA 分子，定位于细胞核内，是一种肿瘤抑制因子，在癌组织及肝癌细胞系中表达明显下调，参与抑制肝癌恶性进展，环状RNA circ-SOX5分子或可作为肝癌早期诊断的分子标记物。过表达环状RNA circ-SOX5可抑制肝癌细胞增殖及侵袭迁移，circ-SOX5显著抑制小鼠体内皮下肿瘤的增殖。circ-SOX5低表达与患者预后不良相关。机制探究发现环状RNA circ-SOX5序列中存在开放阅读框，可编码约25kd大小的短肽，通过对比circ-SOX5 ATGmut环状与环状翻译短肽的功能，我们发现真正发挥抑癌功能的为circ-SOX5翻译的短肽。翻译的短肽可以与SOX5结合，影响SOX5的转录活性，通过对这些基因进行通路富集，我们发现自噬信号通路有显著改变。通过RT-qPCR和WB验证，我们发现ATG5在过表达环状或短肽质粒时水平明显下降，从而抑制自噬的发生，影响肝癌的恶性进展。本研究为诠释肝癌进展的分子机制和寻找靶向治疗提供科学依据。