CircRPN2 Inhibits Aerobic Glycolysis and Metastasis in Hepatocellular Carcinoma

Abstract

Although circular RNAs (circRNA) are known to modulate tumor initiation and progression, their role in hepatocellular carcinoma (HCC) metastasis remains poorly understood. Here, three metastasis-associated circRNAs identified in a previous circRNA-sequencing study were screened and validated in two HCC cohorts. CircRPN2 was downregulated in highly metastatic HCC cell lines and HCC tissues with metastasis. Patients with HCC with lower circRPN2 levels displayed shorter overall survival and higher rates of cumulative recurrence. Mechanistic studies in vitro and in vivo revealed that circRPN2 binds to enolase 1 (ENO1) and accelerates its degradation to promote glycolytic reprogramming through the AKT/mTOR pathway, thereby inhibiting HCC metastasis. CircRPN2 also acted as a competing endogenous RNA for miR-183–5p, which increases forkhead box protein O1 (FOXO1) expression to suppress glucose metabolism and tumor progression. In clinical samples, circRPN2 expression negatively correlated with ENO1 and positively correlated with FOXO1, and expression of circRPN2, either alone or in combination with ENO1 and FOXO1, was a novel indicator of HCC prognosis. These data support a model wherein circRPN2 inhibits HCC aerobic glycolysis and metastasis via acceleration of ENO1 degradation and regulation of the miR-183–5p/FOXO1 axis, suggesting that circRPN2 represents a possible therapeutic target in HCC. Significance: The circRNA circRPN2 is a potential prognostic biomarker and therapeutic target in hepatocellular carcinoma that suppresses aerobic glycolysis and metastasis.

A novel protein encoded by ZCRB1-induced circHEATR5B suppresses aerobic glycolysis of GBM through phosphorylation of JMJD5

“…In GBM, circHEATR5B was expressed at low levels and could suppress glycolysis, whereas HEATR5B mRNA levels showed no significant differences and could not be regulated by ZCRB1, indicating that it is circHEATR5B but not HEATR5B mRNA that exerts glycolytic inhibition in GBM cells under the regulation of ZCRB1. Similarly, circRPN2 inhibits aerobic glycolysis in hepatocellular carcinoma and represents a therapeutic target in hepatocellular carcinoma [ 41 ].…”

Long noncoding RNA LINC01426 promotes the progression of lung adenocarcinoma via regulating miRNA-125a-5p/ casein kinase 2 alpha 1 axis

“…GAPDH and U6 were used as internal references. The relative mRNA levels were calculated using the 2 −ΔΔCT method [ 25 ]. Primer sequences were as follows:…”

The role and mechanism of noncoding RNAs in regulation of metabolic reprogramming in hepatocellular carcinoma

“…49,50,53,54 It was found that circCDR1as, circSMARCA5, circ-ZEB1.33, circSETD3, circMTO1, circSMAD2, circFBLIM1 and circHIPK3 played oncogenic or suppressive roles in the progression of HCC. 22,[55][56][57][58][59][60][61] Furthermore, a series of cir-cRNAs were found to be closely related to metabolic reprogramming in HCC, 62 such as circMAT2B, circSPECC1, circC3P1 and circRPN2 [63][64][65][66] (Table S2).…”

“…64 A recently published study demonstrated that circRPN2 inhibited HCC aerobic glycolysis and metastasis via accelerating enolase 1 (ENO1) degradation and modulating the miR-183-5p/FOXO1 axis. 66 Not only that, Law et al 120 found that a new piRNA (piR-Hep1) was upregulated in HCC in a small RNA transcriptome sequencing analysis. Further studies indicated that silencing piR-Hep1 could decrease AKT phosphorylation and inhibit the growth and aggressiveness of HCC.…”

“…Furthermore, circSPECC1 was significantly downregulated under H 2 O 2 treatment, and knockdown of it inhibited HCC cell proliferation and promoted apoptosis 64 . A recently published study demonstrated that circRPN2 inhibited HCC aerobic glycolysis and metastasis via accelerating enolase 1 (ENO1) degradation and modulating the miR‐183‐5p/FOXO1 axis 66 …”