The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China.
Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China.
Hepatol Commun. 2022 Dec;6(12):3578-3591. doi: 10.1002/hep4.2074. Epub 2022 Nov 8.
CircRNAs have been reported to play crucial roles in tumor progression and recurrence, showing potential as biomarkers in cancer. However, the global abundance of circRNA and their involvement in hepatocellular carcinoma (HCC) development have not been fully explored. Whole transcriptome sequencing was performed on tumor and peritumor from 60 patients with HCC to quantify the expression of circRNAs, and the global circRNA abundance was calculated by circRNA index (CRI). Gene-set enrichment analysis and weighted gene co-expression network analysis were used to reveal the biological signaling pathways associated with the global circRNA abundance. The correlation between the global circRNA abundance and the infiltration level of CD8 T cells was explored by immunohistochemical assays. Small interfering RNA was used to knock down the pre-messenger RNA spliceosome in HCC cell lines to verify the regulation of spliceosome in global circRNA abundance. We found that dysregulation of global circRNA abundance in both tumor and peritumor could lead to worse prognosis. The immunohistochemical assay further revealed that the dysregulation of global circRNA abundance in both tumor and peritumor would obstruct the CD8 T cells from invading into the tumor, which might explain its correlation with HCC prognosis. We also demonstrated that the spliceosome genes were the main factors to regulate the global circRNA abundance in HCC, and these results were also confirmed by knockdown experiments. Conclusion: This study revealed the association between the global circRNA abundance and patients' prognosis and its underlying mechanism.
CircRNAs 已被报道在肿瘤进展和复发中发挥关键作用，显示出作为癌症生物标志物的潜力。然而，circRNA 的全球丰度及其在肝细胞癌 (HCC) 发展中的作用尚未得到充分探索。对 60 例 HCC 患者的肿瘤和肿瘤周围组织进行全转录组测序，以定量检测 circRNAs 的表达，并通过 circRNA 指数 (CRI) 计算全球 circRNA 的丰度。采用基因集富集分析和加权基因共表达网络分析揭示与全球 circRNA 丰度相关的生物学信号通路。通过免疫组织化学检测探索全球 circRNA 丰度与 CD8 T 细胞浸润水平的相关性。使用小干扰 RNA 敲低 HCC 细胞系中的前信使 RNA 剪接体，以验证剪接体对全球 circRNA 丰度的调节作用。我们发现肿瘤和肿瘤周围组织中全球 circRNA 丰度的失调可导致预后更差。免疫组织化学检测进一步表明，肿瘤和肿瘤周围组织中全球 circRNA 丰度的失调会阻碍 CD8 T 细胞浸润肿瘤，这可能解释了其与 HCC 预后的相关性。我们还证明了剪接体基因是调节 HCC 中全球 circRNA 丰度的主要因素，这些结果也通过敲低实验得到了证实。结论：本研究揭示了全球 circRNA 丰度与患者预后之间的关联及其潜在机制。
