School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People's Republic of China.
School of Life Sciences, Jilin University, Changchun City, Jilin Province, People's Republic of China.
Signal Transduct Target Ther. 2021 Feb 26;6(1):86. doi: 10.1038/s41392-021-00485-8.
Altered energy metabolism of cancer cells shapes the immune cell response in the tumor microenvironment that facilitates tumor progression. Herein, we reported the novel of tumor cell-expressed Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1) in mediating the crosstalk of fatty acid metabolism and immune response of human hepatocellular carcinoma (HCC). PIWIL1 expression in HCC was increased compared to normal hepatic tissues and was positively correlated with the proliferation rate of HCC cell lines. PIWIL1 overexpression accelerated in vitro proliferation and in vivo growth of HCC tumors, while PIWIL1 knockdown showed opposite effects. PIWIL1 increased oxygen consumption and energy production via fatty acid metabolism without altering aerobic glycolysis. Inhibition of fatty acid metabolism abolished PIWIL1-induced HCC proliferation and growth. RNA-seq analysis revealed that immune system regulation might be involved, which was echoed by the experimental observation that PIWIL1-overexpressing HCC cells attracted myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. MDSCs depletion reduced the proliferation and growth of PIWIL1-overexpressing HCC tumors. Complement C3, whose secretion was induced by PIWIL1 in HCC cells, mediates the interaction of HCC cells with MDSCs by activated p38 MAPK signaling in MDSCs, which in turn initiated expression of immunosuppressive cytokine IL10. Neutralizing IL10 secretion reduced the immunosuppressive activity of MDSCs in the microenvironment of PIWIL1-overexpressing HCC. Taken together, our study unraveled the critical role of PIWIL1 in initiating the interaction of cancer cell metabolism and immune cell response in HCC. Tumor cells-expressed PIWIL1 may be a potential target for the development of novel HCC treatment.
癌细胞能量代谢的改变塑造了肿瘤微环境中免疫细胞的反应，从而促进了肿瘤的进展。在此，我们报道了肿瘤细胞表达的 Piwi 样 RNA 介导基因沉默 1（PIWIL1）在介导脂肪酸代谢和人肝细胞癌（HCC）免疫反应的串扰中的新作用。与正常肝组织相比，PIWIL1 在 HCC 中的表达增加，并且与 HCC 细胞系的增殖率呈正相关。PIWIL1 过表达加速了 HCC 肿瘤的体外增殖和体内生长，而 PIWIL1 敲低则显示出相反的效果。PIWIL1 通过脂肪酸代谢增加氧消耗和能量产生，而不改变有氧糖酵解。抑制脂肪酸代谢消除了 PIWIL1 诱导的 HCC 增殖和生长。RNA-seq 分析显示免疫系统调节可能涉及其中，这与实验观察结果相呼应，即 PIWIL1 过表达的 HCC 细胞吸引髓源性抑制细胞（MDSC）进入肿瘤微环境。MDSC 耗竭减少了 PIWIL1 过表达 HCC 肿瘤的增殖和生长。补体 C3 的分泌被 HCC 细胞中的 PIWIL1 诱导，通过 MDSC 中激活的 p38 MAPK 信号介导 HCC 细胞与 MDSC 的相互作用，进而引发免疫抑制细胞因子 IL10 的表达。中和 IL10 的分泌减少了 PIWIL1 过表达 HCC 微环境中 MDSC 的免疫抑制活性。总之，我们的研究揭示了 PIWIL1 在启动 HCC 中癌细胞代谢和免疫细胞反应相互作用中的关键作用。肿瘤细胞表达的 PIWIL1 可能是开发新型 HCC 治疗方法的潜在靶点。
