A Mammalian Conserved Circular RNA CircLARP1B Regulates Hepatocellular Carcinoma Metastasis and Lipid Metabolism

Abstract

Circular RNAs (circRNAs) have emerged as crucial regulators in physiology and human diseases. However, evolutionarily conserved circRNAs with potent functions in cancers are rarely reported. In this study, a mammalian conserved circRNA circLARP1B is identified to play critical roles in hepatocellular carcinoma (HCC). Patients with high circLARP1B levels have advanced prognostic stage and poor overall survival. CircLARP1B facilitates cellular metastatic properties and lipid accumulation through promoting fatty acid synthesis in HCC. CircLARP1B deficient mice exhibit reduced metastasis and less lipid accumulation in an induced HCC model. Multiple lines of evidence demonstrate that circLARP1B binds to heterogeneous nuclear ribonucleoprotein D (HNRNPD) in the cytoplasm, and thus affects the binding of HNRNPD to sensitive transcripts including liver kinase B1 (LKB1) mRNA. This regulation causes decreased LKB1 mRNA stability and lower LKB1 protein levels. Antisense oligodeoxynucleotide complementary to theHNRNPD binding sites in circLARP1B increases the HNRNPD binding to LKB1 mRNA. Through the HNRNPD–LKB1–AMPK pathway, circLARP1B promotes HCC metastasis and lipid accumulation. Results from AAV8‐mediated hepatocyte‐directed knockdown of circLARP1B or Lkb1 in mouse models also demonstrate critical roles of hepatocytic circLARP1B regulatory pathway in HCC metastasis and lipid accumulation, and indicate that circLARP1B may be potential target of HCC treatment.

The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma

“…CircLARP1B interacts with heterogeneous nuclear ribonucleoprotein D to destabilize the mRNA of liver kinase B1, which induces the lipid metabolic reprogramming to mediate the pro-metastatic effect and lipid surplus resulting from increased lipid synthesis via regulating the AMP-activated protein kinase (AMPK) pathway. [55] SREBPs are a family of proteins that control diverse lipid metabolic pathways. DExD-box helicase 39B is a helicase participating in pre-mRNA splicin and maintenance of genomic stability.…”

“…CircLARP1B interacts with heterogeneous nuclear ribonucleoprotein D to destabilize the mRNA of liver kinase B1, which induces the lipid metabolic reprogramming to mediate the pro-metastatic effect and lipid surplus resulting from increased lipid synthesis via regulating the AMP-activated protein kinase (AMPK) pathway. [ 55 ]…”