Abstract
Metastasis is the predominant reason for high mortality of hepatocellular carcinoma (HCC) patients. It is critical to explore the molecular mechanism underlying HCC metastasis. Here, we reported that transcription factor One Cut homeobox 2 (ONECUT2) functioned as an oncogene to facilitate HCC metastasis. Elevated ONECUT2 expression was positively correlated with increased tumor number, tumor encapsulation loss, microvascular invasion, poor tumor differentiation, and advanced TNM stage. Mechanistically, ONECUT2 directly bound to the promoters of fibroblast growth factor 2 (FGF2) and ATP citrate lyase (ACLY) and transcriptionally upregulated their expression. Knockdown of FGF2 and ACLY inhibited ONECUT2-mediated HCC metastasis, whereas upregulation of FGF2 and ACLY rescued ONECUT2 knockdown-induced suppression of HCC metastasis. ONECUT2 expression was positively correlated with FGF2 and ACLY expression in human HCC tissues. HCC patients with positive coexpression of ONECUT2/FGF2 or ONECUT2/ACLY exhibited the worst prognosis. In addition, FGF2 upregulated ONECUT2 expression through the FGFR1/ERK/ELK1 pathway, which formed an FGF2-FGFR1-ONECUT2 positive feedback loop. Knockdown of ONECUT2 inhibited FGF2-induced HCC metastasis. Furthermore, the combination of FGFR1 inhibitor PD173074 with ACLY inhibitor ETC-1002 markedly suppressed ONECUT2-mediated HCC metastasis. In summary, ONECUT2 was a potential prognostic biomarker in HCC and targeting this oncogenic signaling pathway may provide an efficient therapeutic strategy against HCC metastasis.
Highlights
Hepatocellular carcinoma (HCC) is a highly prevalent malignant disease worldwide, with the sixth highest diagnostic rate and the third highest mortality rate among cancers [1]
fibroblast growth factor 2 (FGF2) or ATP citrate lyase (ACLY) overexpression markedly enhanced pulmonary metastasis and decreased overall survival in MHCC97H-shONECUT2 xenograft mice (Fig. 4C–H). These findings indicated that One Cut homeobox 2 (ONECUT2) facilitated HCC metastasis by upregulating FGF2 and ACLY
PD173074 in combination with ETC-1002 significantly suppresses ONECUT2-mediated HCC metastasis Based on the finding that FGF2 and ACLY collaboratively mediated the carcinogenic effect of ONECUT2, we investigated the efficacy of a combined intervention targeting FGF2 and ACLY against ONECUT2-mediated HCC metastasis
Summary
Hepatocellular carcinoma (HCC) is a highly prevalent malignant disease worldwide, with the sixth highest diagnostic rate and the third highest mortality rate among cancers [1]. The aberrant activation of fibroblast growth factor (FGF)/FGFreceptor (FGFR) signaling accelerates HCC development through regulating angiogenesis, metabolism, and metastasis [12]. Upregulated in several types of cancer including liver cancer [20], and ONECUT2 expression was examined in human normal liver facilitates the proliferation and metastasis of cancer cells [21, 22]. Primary HCC tissues tional levels, including transactivation [23], phosphorylation by AKT had the highest mRNA levels of ONECUT2, followed by adjacent [24], acetylation by P300/calcium-binding protein-associated factor nontumor tissues, and normal liver tissues. FGF2, in turn, higher ONECUT2 expression was detected in upregulated ONECUT2 expression through the FGFR1-extracellular metastatic HCC tissues than in primary HCC tissues and adjacent signal-regulated protein kinase (ERK)-ELK1 signaling pathway, nontumor tissues (Fig. 1B). A strong positive staining pattern for ONECUT2 was observed in HCC
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