长链非编码 RNA AK023391 通过激活 PI3K/Akt 信号通路促进胃癌的发生和侵袭。
LncRNA AK023391 promotes tumorigenesis and invasion of gastric cancer through activation of the PI3K/Akt signaling pathway.
机构信息
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China.
Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
J Exp Clin Cancer Res. 2017 Dec 28;36(1):194. doi: 10.1186/s13046-017-0666-2.
BACKGROUND
Patients with gastric cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Recent studies have confirmed the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including gastric cancer. However, little is known about the molecular mechanism by which lncRNA AK023391 contributes to gastric cancer.
METHODS
A lncRNA microarray was used to identify the differentially expressed lncRNA AK023391 in gastric cancer and adjacent normal tissues. In addition, RNA fluorescence in situ hybridization (FISH) was used to investigate the association between AK023391 expression and the clinicopathological characteristics and prognosis of patients with gastric cancer. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA AK023391 in gastric cancer cells. A cancer pathway microarray, bioinformatic analysis, western blotting, and immunochemistry were carried out to verify the regulation of AK023391 and its downstream PI3K/Akt signaling pathway.
RESULTS
Expression of lncRNA AK023391 was significantly upregulated in gastric cancer samples and cell lines in comparison to adjacent normal tissues, and was positively correlated with poor survival in patients with gastric cancer. The multivariate Cox regression model revealed that AK023391 expression acted as an independent prognostic factor for survival in patients with gastric cancer. Knockdown of AK023391 inhibited cell growth and invasion both in vitro and in vivo, and induced apoptosis and cell cycle arrest in gastric cancer cells, whereas its overexpression reversed these effects. Mechanistically, PI3K/Akt signaling mediated the NF-κB, FOXO3a, and p53 pathways. Moreover, downstream transcription factors, such as c-myb, cyclinB1/G2, and BCL-6 might be involved in AK023391-induced tumorigenesis in gastric cancer.
CONCLUSIONS
The novel oncogenic lncRNA AK023391 in gastric cancer exerts its effects through activation of the PI3K/Akt signaling pathway, and may act as a potential biomarker for survival in patients with gastric cancer.
背景
由于胃癌的侵袭性和远处转移，患者预后通常较差。最近的研究证实，长非编码 RNA（lncRNA）在肿瘤发生和恶性肿瘤的进展中起着关键作用，包括胃癌。然而，lncRNA AK023391 如何促进胃癌的分子机制知之甚少。
方法
使用 lncRNA 微阵列鉴定胃癌和相邻正常组织中差异表达的 lncRNA AK023391。此外，采用 RNA 荧光原位杂交（FISH）检测 AK023391 表达与胃癌患者临床病理特征和预后的关系。随后，通过一系列体外实验和异种移植肿瘤模型观察 lncRNA AK023391 在胃癌细胞中的功能。进行癌症途径微阵列分析、生物信息学分析、Western blot 和免疫组化，以验证 AK023391 及其下游 PI3K/Akt 信号通路的调节作用。
结果
与相邻正常组织相比，lncRNA AK023391 在胃癌样本和细胞系中的表达明显上调，与胃癌患者的不良生存相关。多变量 Cox 回归模型显示，AK023391 表达是胃癌患者生存的独立预后因素。AK023391 敲低不仅在体外而且在体内均抑制胃癌细胞的生长和侵袭，并诱导胃癌细胞凋亡和细胞周期停滞，而过表达则逆转了这些作用。机制上，PI3K/Akt 信号转导介导 NF-κB、FOXO3a 和 p53 通路。此外，下游转录因子，如 c-myb、cyclinB1/G2 和 BCL-6 可能参与 AK023391 诱导的胃癌发生。
结论
胃癌中新型致癌 lncRNA AK023391 通过激活 PI3K/Akt 信号通路发挥作用，可能成为预测胃癌患者生存的潜在标志物。
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