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

Ning Wang,Hor-Yue Tan,Feiyu Chen,Yibin Feng,Yuanjun Lu,Yu Xu,Yau-Tuen Chan,Guoyi Tang,Di Wang,Cheng Zhang,Wei Guo

doi:10.1038/s41392-021-00485-8

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.

Highlights

Hepatocellular carcinoma (HCC) is one of the most malignant human cancers that has ranked as the third leading cause of cancer-related death all over the world.[1]
SP600125.42,43 In our study, we found that SB203580 exhibited stronger inhibition than SP600125 on the increased production of IL10 in myeloid-derived suppressor cells (MDSCs) cultured with conditioned medium from Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1)-overexpressing HCC cells
To sum up, in this study, we reported that PIWIL1 plays a vital role in regulating the crosstalk of the metabolic and immune systems of HCC

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most malignant human cancers that has ranked as the third leading cause of cancer-related death all over the world.[1] The morbidity and mortality of HCC are recently increasing in Western countries in contrast to the decreasing trend in Asia.[2] Early diagnosis is difficult due to the late appearance of clinical manifestation and insignificant pathognomonic symptoms or signs,[3] and treatment allocation is complex, and HCC often arises with other comorbidities.[4] The prognosis of HCC patients remains very poor though a variety of treatments has been developed This is because that HCC development is closely related to the presence of chronic liver diseases arisen from various risk factors,[2] and due to the complex nature of the liver as a significant metabolic and immunological organ that may foster a complicated hepatic microenvironment favoring tumor growth. Some previous studies have revealed that metabolites from cancer cells could shape the pro-tumoral microenvironment through regulating functional phenotypes of different immune populations.[5,6] In particular, metabolic switch towards Warburg effects during the oncogenic changes of cancer cells was found to instigate the immunosuppressive network that favors cancer progression.[7]

Methods

Findings

Discussion

Conclusion