lncRNA KRAL reverses 5-fluorouracil resistance in hepatocellular carcinoma cells by acting as a ceRNA against miR-141

Abstract

Background5-Fluorouracil (5-FU) has been widely applied to treat various types of cancers, including hepatocellular carcinoma (HCC). However, primary or acquired 5-FU resistance prevents the clinical application of this drug in cancer therapy. Herein, our study is the first to demonstrate that lower expression of KRAL, a long non-coding RNA (lncRNA), mediates 5-FU resistance in HCC via the miR-141/Keap1 axis.MethodsCell proliferation assays, western blot analysis, qRT-PCR, the dual-luciferase reporter assay and RNA immunoprecipitation were performed to investigate the mechanisms by which KRAL mediates 5-fluorouracil resistance in HCC cell lines.ResultsThe quantitative analysis indicated that KRAL and Keap1 were significantly decreased and that Nrf2 was increased in HepG2/5-FU and SMMC-7721/5-FU cells compared with the corresponding expression levels in the respective parental cells. Overexpression of KRAL increased Keap1 expression, and inactivating the Nrf2-dependent antioxidant pathway could reverse the resistance of HepG2/5-FU and SMMC-7721/5-FU cells to 5-FU. Moreover, KRAL functioned as a competitive endogenous RNA (ceRNA) by effectively binding to the common miR-141 and then restoring Keap1 expression. These findings demonstrated that KRAL is an important regulator of Keap1; furthermore, the ceRNA network involving KRAL may serve as a treatment strategy against 5-FU resistance in hepatocellular carcinoma cells.ConclusionsKRAL/miR-141/Keap1 axis mediates 5-fluorouracil resistance in HCC cell lines.

Risk scoring based on expression of long non‑coding RNAs can effectively predict survival in hepatocellular carcinoma patients with or without fibrosis

“…Long non-coding RNAs (lncRNAs), located in the nucleus and cytoplasm of eukaryotic cells, are non-coding transcripts >200 nucleotides in length (5). Studies suggest that lncRNAs serve crucial roles in the occurrence and progression of malignant tumors (6)(7)(8). For example, one study found that lncRNA-KRTAP5-AS1 and lncRNA-TUBB2A acted as competing endogenous RNAs to influence the function of claudin-4 and thereby affect the prognosis of patients with gastric cancer (9).…”

Long non‐coding RNA F11‐AS1 inhibits HBV‐related hepatocellular carcinoma progression by regulating NR1I3 via binding to microRNA‐211‐5p

“…8,9 For example, lncRNA F11-AS1 is reported to bind to miR-3146 to affect the HCC progression. 8,9 For example, lncRNA F11-AS1 is reported to bind to miR-3146 to affect the HCC progression.…”

“…More recently, emerging evidence has demonstrated that ln-cRNAs can function as a competing endogenous RNA (ceRNA) for specific miRNAs and regulate their function and downstream targets of miRNA to influence the development of HCC. 8,9 For example, lncRNA F11-AS1 is reported to bind to miR-3146 to affect the HCC progression. 10 microRNA-211 (miR-211) is closely related to the progression and development of human cancers, and lncRNA SNHG15 promotes the occurrence and progression of lung cancer by enhancing the proliferative and migration capacity of lung cancer cells through binding to miR-211-3p.…”

Competing endogenous RNA network and prognostic nomograms for hepatocellular carcinoma patients who underwent R0 resection

“…Salmena, Poliseno, Tay, Kats, and Pandolfi, () presented the competing endogenous RNA (ceRNA) hypothesis in 2011. lncRNAs may compete with miRNAs to regulate the transcriptome by interacting with miRNA response elements. Some lncRNAs have been confirmed as ceRNAs that participate in the development of HCC (Bai et al, ; Wu et al, ). A few studies have constructed ceRNA network based on differentially expressed RNAs (DERNAs) between tumor and normal tissues (Hou et al, ; Lin et al, ; Zhang, Fan, Jian, Chen, & Lai, ).…”