Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China; School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Clinical Research Institute and Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China.
Cancer Lett. 2023 Dec 1;578:216442. doi: 10.1016/j.canlet.2023.216442. Epub 2023 Oct 16.
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 (CCSC) 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.
肝细胞癌 (HCC) 常伴有肺转移，预后不良。ICAM-1 循环肿瘤细胞，称为循环肿瘤干细胞 (CCSCs)，具有干细胞样特征。然而，它们的存在如何预示肺转移倾向，特别是哪些机制驱动其肺转移，目前仍不清楚。在这里，我们证明了临床 HCC 患者术前 5ml 血液中的 CCSC（CCSC）计数>3 是肺转移的危险因素。过表达 circ-CDYL 的 CSCs 进入血液，并在小鼠中发展为肺转移。从机制上讲，circ-CDYL 促进 COL14A1 的表达，从而激活 ERK 信号通路，促进上皮间质转化。此外，我们发现一种 RNA 结合蛋白 EEF1A2 作为一种新型转录（共）因子，与 circ-CDYL 合作并启动 COL14A1 的转录。在低氧微环境下，HIF-1 ⍺ 通过转录上调其亲本基因 CDYL 和剪接因子 EIF4A3 来介导 circ-CDYL 的高水平表达。因此，缺氧微环境通过 HIF-1 ⍺/circ-CDYL-EEF1A2/COL14A1 轴使 ICAM-1 CCSCs 具有高转移倾向的肺转移，这可能使临床医生能够在术前检测到 ICAM-1 CCSCs，作为实时生物标志物，准确决定 HCC 治疗策略。
