PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma

Abstract

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.

Inside-Out of Complement in Cancer

“…This notion seems to be valid across several cancer mouse models and human cell lines. C3 secretion induced by Piwi Like RNA-Mediated Gene Silencing 1 protein (PIWIL1) in human hepatocellular carcinoma (HCC) cells leads to the activation of p38 and MAPK signalling in MDSCs, which, in turn, triggers the expression of immunosuppressive cytokine IL-10 in these cells ( 83 ). C3 secreted from liver metastatic breast cancer cells was also found to recruit, in C3aR-dependent manner, immature low-density prometastatic neutrophils to the liver ( 84 ).…”

Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges

“…Complement C3 stimulates HCC cell secretion via PIWIL1 and mediates the contact between HCC cells and MDSC via p38 MAPK activation in MD38, and then initiates the expression of immunosuppressive cytokine IL10. PIWIL1, which is expressed by tumor cells, could be a viable target for the development of new HCC treatments ( Wang et al, 2021a ). Tumor-infiltrating LY6G MDSCs from orthotopic liver tumors treated with sorafenib dramatically increased CD4 T cells expressing IL-10 and TGF-and decreased CD8 T cell cytotoxicity.…”

Elevated P-Element-Induced Wimpy-Testis-Like Protein 1 Expression Predicts Unfavorable Prognosis for Patients with Various Cancers

“…Specifically, in human HCC, PIWIL1 expression was significantly higher in HCC tissue [45], and PIWIL1 played a critical role in HCC proliferation and metastasis by being mediated by small hairpin RNA [46]. Recently, Wang et al reported the critical role of PIWIL1 in mediating the crosstalk of cancer cell metabolism and immune cell response of HCC, and they found that overexpression of PIWIL1 promoted the proliferation rate of human HCC; moreover, they revealed that PIWIL1 increased energy production and oxygen consumption through fatty acid metabolism without altering aerobic glycolysis, and PIWIL1 attracted myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment (TME) and activated p38-MAPK signaling, which in turn improved secretion of immunosuppressive cytokine IL10 [47]. Similarly, the mature transcripts were associated with the PIWIL1-piRNA complex code critical regulatory proteins involved in controlling cell proliferation, differentiation, and survival in CRC cells, which actively contributes to the establishment and maintenance of clinicopathological characteristics of CRC [48].…”