Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer
Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer
复制标题
长非编码RNA GSTM3TV2通过竞争性海绵let-7上调LAT2和OLR1以促进胰腺癌中的吉西他滨耐药
DOI：
10.1186/s13045-019-0777-7
复制
发表时间：
2019-09-12
影响因子：
28.5
通讯作者：
Zhao, Yupei
中科院分区：
文献类型：
--
作者：
Xiong, Guangbing;Liu, Chang;Zhao, Yupei
背景化疗耐药是胰腺癌患者预后不良的主要原因之一。了解胰腺癌化疗耐药的机制对改善患者预后至关重要。最近的研究表明，长链非编码RNA（lncRNA）参与了胰腺癌的化疗耐药。然而，lncRNA的机制有助于胰腺癌的耐药性，并且在很大程度上仍然未知。本研究的目的是构建胰腺癌耐药相关lncRNA相关竞争性内源性RNA（ceRNA）网络，并鉴定调控该网络耐药的关键lncRNA。方法首先采用基因芯片技术检测胰腺癌吉西他滨耐药细胞的lncRNA表达谱，筛选与吉西他滨耐药相关的lncRNA。其次，在深入了解ceRNA作用机制的基础上，我们利用生物信息学方法构建了一个与化疗耐药相关的lncRNA相关的ceRNA网络。然后我们鉴定了ceRNA网络中的拓扑关键lncRNA，并使用分子生物学方法证明了其在胰腺癌化疗耐药中的功能或机制。进一步的研究评估了其表达，以评估其与胰腺癌患者生存的潜在相关性。结果首先，我们证明了lncRNA在吉西他滨耐药的胰腺癌细胞中表达失调。然后，我们构建了一个与化疗耐药相关的lncRNA相关的ceRNA网络，并提出lncRNA智人谷胱甘肽S-转移酶μ 3，转录变体2和非编码RNA（GSTM 3 TV 2; NCBI参考序列：NR_024537.1）可能通过上调L型氨基酸转运蛋白2（LAT 2）和氧化低密度脂蛋白受体1（OLR 1）作为增强化疗耐药性的关键ceRNA。在胰腺癌中。进一步的研究表明，在吉西他滨耐药细胞中过表达的GSTM 3 TV 2在体外和体内增强胰腺癌细胞的吉西他滨耐药性。从机制上讲，我们确定GSTM 3 TV 2通过竞争性地海绵化let-7来上调LAT 2和OLR 1以促进吉西他滨抗性。此外，我们发现GSTM 3 TV 2的表达水平在胰腺癌组织中显著升高，并且与不良预后相关。结论GSTM 3 TV 2是胰腺癌化疗耐药的重要调控因子，可能成为胰腺癌治疗的新靶点或预后指标。
Background Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. Methods Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. Results Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. Conclusion Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.