American Association for Cancer Research
00085472can150977-sup-148133_1_supp_3155212_nv2h7g.doc (38 kB)

Supplementary Table and Figure Legends from Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis

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journal contribution
posted on 2023-03-30, 23:52 authored by Long-Yun Ye, Wei Chen, Xue-Li Bai, Xing-Yuan Xu, Qi Zhang, Xue-Feng Xia, Xu Sun, Guo-Gang Li, Qi-Da Hu, Qi-Han Fu, Ting-Bo Liang

Legends for Supplementary Tables S1-S2 and Supplementary Figures S1-S6.


National High Technology Research and Development Program 863 of China

National Natural Science Foundation of China



Portal vein tumor thrombosis (PVTT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and is therefore associated with poor prognosis. The presence of PVTT frequently accompanies substantial hypoxia within the tumor microenvironment, which is suggested to accelerate tumor metastasis, but it is unclear how this occurs. Recent evidence has shown that the hypoxia-inducible factor HIF-1α induces epithelial-to-mesenchymal transition (EMT) in tumor cells to facilitate metastasis. In this study, we investigated whether hypoxia-induced EMT in cancer cells also affects immune cells in the tumor microenvironment to promote immunosuppression. We found that hypoxia-induced EMT increased the expression of the CCL20 cytokine in hepatoma cells. Furthermore, coculture of monocyte-derived macrophages with hypoxic hepatoma cells revealed that the expression of indoleamine 2, 3-dioxygenase (IDO) was induced in monocyte-derived macrophages in a CCL20-dependent manner. In turn, these IDO-expressing monocyte-derived macrophages suppressed T-cell proliferation and promoted the expansion of immunosuppressive regulatory T cells. Moreover, high CCL20 expression in HCC specimens was associated with PVTT and poor patient survival. Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network. Cancer Res; 76(4); 818–30. ©2016 AACR.

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