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CircRNA_001275 upregulates Wnt7a expression by competitively sponging miR‑370‑3p to promote cisplatin resistance in esophageal cancer.

ABSTRACT: Circular RNAs (circRNAs) are aberrantly expressed in various tumors and are associated with tumorigenesis. The present study aimed to determine the role of circRNA_001275 in cisplatin‑resistant esophageal cancer. Three pairs of cisplatin‑resistant tissues and corresponding adjacent tissues were collected and subjected to circRNA chip analysis. Additionally, the effect of circRNA_001275 on cisplatin‑resistant cells was investigated. The relationship between circRNA_001275, microRNAs (miRs) and target genes were analyzed using luciferase assays, and validated via reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. The results showed that circRNA_001275 was significantly upregulated in cisplatin‑resistant esophageal cancer tissues and cells (P<0.05). Overexpression of circRNA_001275 promoted the proliferation and invasion, and decreased the apoptosis of cisplatin‑resistant cells. On the other hand, circRNA_001275 silencing inhibited cell proliferation and invasion, and promoted cell apoptosis (P<0.05). Dual‑luciferase reporter assays revealed that circRNA_001275 directly binds to miR‑370‑3p, and that Wnt family member 7A (Wnt7a) is targeted by miR‑370‑3p. RT‑qPCR and western blotting further demonstrated that circRNA_001275 serves as an miR‑370‑3p sponge to upregulate Wnt7a expression. In conclusion, the present study revealed that circRNA_001275 was upregulated in cisplatin‑resistant esophageal cancer and promoted cisplatin resistance by sponging miR‑370‑3p to upregulate Wnt7a expression. Therefore, circRNA_001275 may serve as a potential diagnostic biomarker and therapeutic target for patients with cisplatin‑resistant esophageal cancer.

SUBMITTER: Zou FW

PROVIDER: S-EPMC7252462 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleCircular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis.MethodsFunctions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq.ResultsCircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI.ConclusionOur research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.

Project description:BackgroundChemoresistance 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.MethodsFirstly, 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.ResultsFirstly, 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.ConclusionOur 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.

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CircRNA_001275 upregulates Wnt7a expression by competitively sponging miR‑370‑3p to promote cisplatin resistance in esophageal cancer.

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