Qiu Jun-Jun, Lin Ying-Ying, Ding Jing-Xin, Feng Wei-Wei, Jin Hong-Yan, Hua Ke-Qin
Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai 200127, P.R. China.
Int J Oncol. 2015;46(6):2497-505. doi: 10.3892/ijo.2015.2943. Epub 2015 Mar 31.
Recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in carcinogenesis and have suggested that genes of this class might be used as biomarkers in cancer. However, whether lncRNAs are involved in serous ovarian cancer (SOC) remains largely unknown. In the present study, we focused on lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) and investigated its expression pattern, clinical significance, and biological function in SOC. We found that ANRIL levels were elevated in SOC tissues compared with normal controls and were highly correlated with advanced FIGO stage, high histological grade, lymph node metastasis, and poor prognosis. Multivariate analysis further revealed that ANRIL is an independent prognostic factor for predicting overall survival of SOC patients. In vitro, we compared differential ANRIL levels between SOC parental cell lines (SK-OV-3, HO8910) and highly metastatic sublines (SK-OV-3.ip1, HO8910-PM). Notably, ANRIL was highly expressed in both SK-OV-3.ip1 cells and HO8910-PM cells. SiRNA-mediated ANRIL silencing in these cells impaired cell migration and invasion. Based on the metastasis-related mRNA microarray analysis and subsequent western blotting confirmation, we found that MET and MMP3 are key downstream genes of ANRIL involved in SOC cell migration/invasion. Together, our data suggest that lncRNA ANRIL plays an important role in SOC invasion/metastasis and could represent a novel biomarker for predicting poor survival as well a promising therapeutic target.
近期研究突显了长链非编码RNA（lncRNA）在肿瘤发生中的作用，并表明这类基因可能用作癌症的生物标志物。然而，lncRNA是否参与浆液性卵巢癌（SOC）仍 largely未知。在本研究中，我们聚焦于INK4基因座中的lncRNA反义非编码RNA（ANRIL），并研究了其在SOC中的表达模式、临床意义及生物学功能。我们发现，与正常对照相比，SOC组织中ANRIL水平升高，且与国际妇产科联盟（FIGO）晚期、高组织学分级、淋巴结转移及预后不良高度相关。多变量分析进一步显示，ANRIL是预测SOC患者总生存期的独立预后因素。在体外，我们比较了SOC亲本细胞系（SK-OV-3、HO8910）与高转移性亚系（SK-OV-3.ip1、HO8910-PM）之间ANRIL水平的差异。值得注意的是，ANRIL在SK-OV-3.ip1细胞和HO8910-PM细胞中均高表达。在这些细胞中，小干扰RNA（siRNA）介导的ANRIL沉默会损害细胞迁移和侵袭。基于与转移相关的mRNA微阵列分析及随后的蛋白质印迹确认，我们发现MET和MMP3是ANRIL参与SOC细胞迁移/侵袭的关键下游基因。总之，我们的数据表明lncRNA ANRIL在SOC侵袭/转移中起重要作用，可能代表一种预测不良生存的新型生物标志物以及一个有前景的治疗靶点。
