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. 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. 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. 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.

中文翻译：

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长的非编码RNA GSTM3TV2通过竞争性地使let-7增强胰腺癌的吉西他滨耐药性，从而上调LAT2和OLR1。

化学抵抗是胰腺癌患者预后不良的主要原因之一。了解与胰腺癌的化学抗性有关的机制对于改善患者预后至关重要。最近的证据表明，长的非编码RNA（lncRNA）参与胰腺癌的化学耐药性。然而，lncRNA的机制有助于胰腺癌的耐药性，并且在很大程度上尚不清楚。这项研究的目的是建立与胰腺癌的化学抗性相关的lncRNA相关竞争内源性RNA（ceRNA）网络，并确定调节该网络化学抗性的关键lncRNA。首先，对耐吉西他滨的胰腺癌细胞进行lncRNA表达谱分析，以通过芯片分析鉴定与化学抗性相关的lncRNA。其次，深入了解ceRNA的机制后，我们使用了生物信息学方法来构建与化学抗性相关的lncRNA关联的ceRNA网络。然后，我们在分子生物学方法中鉴定了ceRNA网络中的拓扑关键lncRNA，并证明了其在胰腺癌化学耐药性中的功能或机制。进一步的研究评估了其表达，以评估其与胰腺癌患者生存率的潜在关联。首先，我们证明了在耐吉西他滨的胰腺癌细胞中lncRNAs失调。然后，我们构建了与化学抗性相关的lncRNA相关的ceRNA网络，并提出了lncRNA智人谷胱甘肽S-转移酶mu 3，转录本变体2和非编码RNA（GSTM3TV2； NCBI参考序列：NR_024537）。1）可能是通过上调L型氨基酸转运蛋白2（LAT2）和氧化型低密度脂蛋白受体1（OLR1）来增强胰腺癌化学抵抗的关键ceRNA。进一步的研究表明，在吉西他滨耐药细胞中过表达的GSTM3TV2在体外和体内均可增强胰腺癌细胞对吉西他滨的耐药性。从机制上讲，我们确定GSTM3TV2通过竞争性地让let-7增强吉西他滨耐药性来上调LAT2和OLR1。此外，我们发现胰腺癌组织中GSTM3TV2的表达水平显着增加，并且与不良预后相关。我们的结果表明，GSTM3TV2是参与化学耐药性的重要致癌调节剂，并且可能是胰腺癌的新治疗靶标或预后标志物。