The anti-metastatic effect of elemene in human hepatocellular carcinoma is potentially mediated by inhibiting a novel driver-circBPTF.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metastasis being one of the primary characteristics. Elemene, a natural product derived from Curcuma wenyujin, has been approved for treating advanced and metastasis HCC patients. However, the molecular mechanism of elemene in HCC is still unclear.

Purpose: Dysregulation circular RNA (circRNA) plays a critical role in the progression of HCC. This study aimed to evaluate the anti-HCC mechanism of elemene from circRNA point.

Methods: Transwell and wound-healing assays were employed to evaluate the function of circBPTF and elemene in vitro. Orthotopic xenograft tumor mouse models were used to explore the metastatic impact of circBPTF in vivo and were evaluated by haematoxylin and eosin (H&E) and immunohistochemistry (IHC). To investigate the effects of elemene on circBPTF, RNA pulldown, western blotting, qPCR, transwell and RNA-seq assays were employed.

Results: In this study, we demonstrated circBPTF (hsa_circ_0045431) was a previously uncharacterized pro-metastatic regulator in HCC, and elemene could significantly inhibit circBPTF expression and reduced lung metastasis. Mechanistically, circBPTF acted as a molecular sponge for miR-548m, thereby consequently upregulated the expression of RNA polymerase III subunit G (POLR3G) and zinc finger and BTB domain containing 41 (ZBTB41) in HCC cells. Additionally, the biosynthesis of circBPTF was further governed by RNA-binding proteins HNRNPC and HNRNPU. Furthermore, elemene suppressed circBPTF/miR-548m, leading to the downregulation of POLR3G via inhibition of HNRNPC.

Conclusion: This study elucidated that circBPTF could promote HCC lung metastasis and indicated that the downregulation of circBPTF was an important mechanism underlying the anti-HCC effects of elemene.