Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer

Abstract

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.

LncRNA FAM83A-AS1 Dives ESCC Progression by Regulating miR-214/CDC25B Axis

“…in the cell cytoplasm, lncRNA GSTM3TV2 served as ceRNA to up-regulate LAT2 and OLR1 expression, promoting gemcitabine resistance in pancreatic cancer. In the current study, we found that miR-214 was a direct target miRNA of FAM83A-AS1 in ESCC [33]. It was reported that miR-214 inhibited cell proliferation, migration, and invasion process in ESCC [20].…”

Screening prognosis-related lncRNAs based on WGCNA to establish a new risk score for predicting prognosis in patients with hepatocellular carcinoma

“…Therefore, these results may also be regulation [33]. Moreover, lncRNAs play a role through the competitive binding of miRNAs to regulate their target mRNAs [34].…”

Long non-coding RNAs regulate drug resistance in cancer

“…In addition, HOTAIR promotes the invasion of breast cancer cells by affecting the expression of cell surface glycosaminoglycans [13]. The lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2) levels are significantly increased in pancreatic tumor tissues and it upregulates the L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) by competitively sequestering let-7 (a mRNA targeting c-Myc, HMGA2 and Ras) to induce gemcitabine resistance in pancreatic cancer [15].…”