长链非编码 RNA PTTG3P 通过上调 PTTG1 和激活 PI3K/AKT 信号通路促进肝癌细胞生长和转移。

BACKGROUND: Dysfunctions of long non-coding RNA (lncRNAs) have been associated with the initiation and progression of hepatocellular carcinoma (HCC), but the clinicopathologic significance and potential role of lncRNA PTTG3P (pituitary tumor-transforming 3, pseudogene) in HCC remains largely unknown. METHODS: We compared the expression profiles of lncRNAs in 3 HCC tumor tissues and adjacent non-tumor tissues by microarrays. In situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to assess the level of PTTG3P and prognostic values of PTTG3P were assayed in two HCC cohorts (n = 46 and 90). Artificial modulation of PTTG3P (down- and over-expression) was performed to explore the role of PTTG3P in tumor growth and metastasis in vitro and in vivo. Involvement of PTTG1 (pituitary tumor-transforming 1), PI3K/AKT signaling and its downstream signals were validated by qRT-PCR and western blot. RESULTS: We found that PTTG3P was frequently up-regulated in HCC and its level was positively correlated to tumor size, TNM stage and poor survival of patients with HCC. Enforced expression of PTTG3P significantly promoted cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, PTTG3P knockdown had opposite effects. Mechanistically, over-expression of PTTG3P up-regulated PTTG1, activated PI3K/AKT signaling and its downstream signals including cell cycle progression, cell apoptosis and epithelial-mesenchymal transition (EMT)-associated genes. CONCLUSIONS: Our findings suggest that PTTG3P, a valuable marker of HCC prognosis, promotes tumor growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in HCC and might represent a potential target for gene-based therapy.

背景：长链非编码 RNA（lncRNA）的功能障碍与肝细胞癌（HCC）的发生和发展有关，但 lncRNA PTTG3P（垂体肿瘤转化基因 3，假基因）在 HCC 中的临床病理意义和潜在作用在很大程度上仍然未知。

方法：我们通过微阵列比较了 3 例 HCC 肿瘤组织和相邻非肿瘤组织中 lncRNA 的表达谱。应用原位杂交（ISH）和实时定量聚合酶链反应（qRT-PCR）检测 PTTG3P 的水平，并在两个 HCC 队列（n=46 和 90）中检测 PTTG3P 的预后价值。通过下调和过表达人工调节 PTTG3P，探讨 PTTG3P 在体外和体内肿瘤生长和转移中的作用。通过 qRT-PCR 和 Western blot 验证 PTTG1（垂体肿瘤转化基因 1）、PI3K/AKT 信号及其下游信号的参与。

结果：我们发现 PTTG3P 在 HCC 中经常上调，其水平与肿瘤大小、TNM 分期和 HCC 患者的不良生存呈正相关。过表达 PTTG3P 显著促进了细胞的增殖、迁移和侵袭，以及体内的肿瘤发生和转移。相反，PTTG3P 敲低则产生相反的效果。机制上，PTTG3P 的过表达上调了 PTTG1，激活了 PI3K/AKT 信号及其下游信号，包括细胞周期进程、细胞凋亡和上皮间质转化（EMT）相关基因。

结论：我们的研究结果表明，PTTG3P 是 HCC 预后的一个有价值的标志物，通过上调 PTTG1 和激活 PI3K/AKT 信号通路促进 HCC 肿瘤的生长和转移，可能代表了基因治疗的潜在靶点。