Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is often associated with poor outcomes due to lung metastasis. ICAM-1+ circulating tumor cells, termed circulating cancer stem cells (CCSCs), possess stem cell–like characteristics. However, it is still unexplored how their presence indicates lung metastasis tendency, and particularly, what mechanism drives their lung metastasis. Here, we demonstrated that a preoperative CCSC count in 5 mL of blood (CCSC5) of >3 was a risk factor for lung metastasis in clinical HCC patients. The CSCs overexpressed with circ-CDYL entered the bloodstream and developed lung metastases in mice. Mechanistically, circ-CDYL promoted COL14A1 expression and thus ERK signaling to facilitate epithelial-mesenchymal transition. Furthermore, we uncovered that an RNA-binding protein, EEF1A2, acted as a novel transcriptional (co-) factor to cooperate with circ-CDYL and initiate COL14A1 transcription. A high circ-CDYL level is caused by HIF-1⍺-mediated transcriptional upregulation of its parental gene CDYL and splicing factor EIF4A3 under a hypoxia microenvironment. Hence, the hypoxia microenvironment enables the high-tendency lung metastasis of ICAM-1+ CCSCs through the HIF-1⍺/circ-CDYL-EEF1A2/COL14A1 axis, potentially allowing clinicians to preoperatively detect ICAM-1+ CCSCs as a real-time biomarker for precisely deciding HCC treatment strategies.