RETRACTED ARTICLE: LNCAROD enhances hepatocellular carcinoma malignancy by activating glycolysis through induction of pyruvate kinase isoform PKM2

Abstract

Background Mounting evidence has suggested the essential role of long non-coding RNAs (lncRNAs) in a plethora of malignant tumors, including hepatocellular carcinoma. However, the underlyling mechanisms of lncRNAs remain unidentified in HCC. The present work was aimed to explore the regulatory functions and mechanisms of LncRNA LNCAROD in HCC progression and chemotherapeutic response. Methods The expression of LNCAROD in HCC tissues and cell lines were detected by quantitative reverse transcription PCR (qPCR). Cancer cell proliferation, migration, invasion, and chemoresistance were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and chemosensitivity assays. Methylated RNA immunoprecipitation qRCR (MeRIP-qPCR) was used to determine N6-methyladenosine (m6A) modification level. RNA immunoprecipitation (RIP) and RNA pull down were applied to identify the molecular sponge role of LNCAROD for modulation of miR-145-5p via the competing endogenous RNA (ceRNA) mechanism, as well as the interaction between LNCAROD and serine-and arginine-rich splicing factor 3 (SRSF3). The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and LNCAROD was also identified by RIP assay. Gain- or-loss-of-function assays were used to identify the function and underlying mechanisms of LNCAROD in HCC. Results We found that LNCAROD was significantly upregulated and predicted a poorer prognosis in HCC patients. LNCAROD upregulation was maintained by increased m6A methylation-mediated RNA stability. LNCAROD significantly promoted HCC cell proliferation, migration, invasion, and chemoresistance both in vitro and in vivo. Furthermore, mechanistic studies revealed that pyruvate kinase isoform M2 (PKM2)-mediated glycolysis enhancement is critical for the role of LNACROD in HCC. According to bioinformatics prediction and our experimental data, LNCAROD directly binds to SRSF3 to induce PKM switching towards PKM2 and maintains PKM2 levels in HCC by acting as a ceRNA against miR-145-5p. The oncogenic effects of LNCAROD in HCC were more prominent under hypoxia than normoxia due to the upregulation of hypoxia-triggered hypoxia-inducible factor 1α. Conclusions In summary, our present study suggests that LNCAROD induces PKM2 upregulation via simultaneously enhancing SRSF3-mediated PKM switching to PKM2 and sponging miR-145-5p to increase PKM2 level, eventually increasing cancer cell aerobic glycolysis to participate in tumor malignancy and chemoresistance, especially under hypoxic microenvironment. This study provides a promising diagnostic marker and therapeutic target for HCC patients.

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

“… 9 , 27 , 28 Jia et al reported that activation of glycolysis improves tumor malignancy and chemoresistance of hepatocellular carcinoma. 29 And the study of Lin et al found that POU2F1 directly bound to the ALDOA promoter and then decreased the sensitivity to oxaliplatin in colon cancer cells by enhancing glycolysis. 30 Furthermore, targeting metabolism reprogramming was an efficient method to overcome the chemoresistance of pancreatic ductal adenocarcinoma.…”

Glycolysis-Related LINC02432/Hsa-miR-98–5p/HK2 Axis Inhibits Ferroptosis and Predicts Immune Infiltration, Tumor Mutation Burden, and Drug Sensitivity in Pancreatic Adenocarcinoma

“…Mounting evidence has shown that lncRNAs, functioning as a ceRNA by competitively binding to miRNAs, affect aerobic glycolysis and participate in cancer progression and treatment resistance. For example, Jia et al demonstrated that the lncRNA LNCAROD induced pyruvate kinase isoenzyme M2 (PKM2) upregulation via sponging miR-145–5p, increased aerobic glycolysis in hepatocellular carcinoma cells, and was eventually involved in tumor malignancy and chemoresistance ( Jia et al, 2021 ). Xu et al had reported that LINC01448 promoted cell proliferation, cell invasion, and glucose consumption by modulating the miR-505/HK2 pathway in PAAD ( Xu Z. et al, 2020 ).…”

Regulation of Gamma-Aminobutyric Acid Transaminase Expression and Its Clinical Significance in Hepatocellular Carcinoma

“…The two isoforms of PKM, PKM1 and PKM2, are produced by the splicing of PKM. The long non-coding RNA LNCAROD could induce the upregulation of PKM2, eventually increasing cancer cell aerobic glycolysis, which is related to poor prognosis in HCC ( 10 ). PGK1 is an important glycolysis-related enzyme.…”

“…One cause of the “Warburg effect” is the overexpression of glycolysis-related enzymes ( 8 ). The expression of the glycolysis-related enzymes hexokinase 2 (HK2) ( 8 ), 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3 (PFKFB3) ( 9 ), pyruvate kinase M (PKM) ( 10 ), phosphoglycerate kinase 1 (PGK1) ( 11 ), and lactate dehydrogenase A (LDHA) ( 12 ) in HCC were evaluated using TCGA expression profile data. The correlation between ABAT and glycolysis-related enzymes was also determined.…”