KCTD1 Downregulation Suppresses Hepatocellular Carcinoma by Regulating Angiogenesis and Influencing the HIF-1α/VEGF Pathway

Abstract Background: Potassium channel tetramerization domain-containing 1 (KCTD1) plays a critical role in transcriptional regulation and adipogenesis, but the significance of KCTD1 in hepatocellular cancer (HCC) has not been reported. Methods: KCTD1 expression was detected by immunohistochemistry, Western blotting, and quantitative RT-PCR. Malignant behaviors of cells were analyzed by MTT assays, liquid colony formation, scratch, transwell assays and FACS analysis. The in vivo functional assays were examined by mouse models using subcutaneous, tail vein, intrahepatic injection combined with sorafenib or exosome treatment. The angiogenesis was analyzed by tube formation and Matrigel plug model. The protein-protein interaction was demonstrated by Co-immunoprecipitation. The protein-DNA binding was confirmed by luciferase assays and chromatin immunoprecipitation. Results: KCTD1 expression is increased in human HCC tissues and closely associated with advanced tumor stages. KCTD1 overexpression enhances HCC growth, migration, and invasion both in vitro and in vivo , while KCTD1 knockdown reverses these effects. Moreover, KCTD1 overexpression promotes the in vitro growth, migration, and tube formation of human umbilical-vein endothelial cells (HUVECs) and induces in vivo angiogenesis. Mechanistically, KCTD1 interacts with HIF-1α to activate the VEGF pathway in HCC cells, which is concurrent with increased M2 macrophage infiltration. Sorafenib blocks the expression of KCTD1 protein and synergistically inhibits subcutaneous and intrahepatic tumor growth. miR-129-5p downregulates KCTD1 expression by binding with KCTD1 3′ UTR and abrogates the oncogenic role of KCTD1 in vitro . Finally, exosomes derived from miR-129-5p-overexpressing HCC cells combine with sorafenib to decrease HCC tumor size. Conclusions: These results suggest that KCTD1 expression activates the VEGF signaling cascade to enhance HCC progression, and angiogenesis. Therefore, KCTD1 may serve as a novel target of sorafenib and pave the way for an efficient therapy for advanced human HCC.