The TNF-α/ROS/HIF-1-induced Upregulation of FoxMI Expression Promotes HCC Proliferation and Resistance to Apoptosis

Abstract

The proliferation-specific transcription factor Forkhead box M1 (FoxM1) acts as a master regulator of cancer cell growth and survival and plays an important role in the development of hepatocellular carcinoma. However, the molecular mechanisms that regulate FoxM1 expression remain largely unknown. In the current study, we demonstrated that tumor necrosis factor (TNF)-αα induced FoxM1 expression and transactivated its promoter activity in hepatoma cells. Serial 5" deletion and site-directed mutagenesis revealed that the induction of FoxM1 expression by TNF-α was dependent upon the hypoxia-inducible factor 1 (HIF1)-1 and HIF1-3/4 binding sites within the FoxM1 promoter. Furthermore, at the transcriptional level, the stabilization of HIF-1α via reactive oxygen species generation led to the binding of HIF-1α to the FoxM1 promoter and resulted in increased FoxM1 expression. The inhibition of both HIF-1α expression and reactive oxygen species generation significantly decreased TNF-α-induced FoxM1 overexpression. Consequently, the upregulation of FoxM1 promoted the proliferation of hepatoma cells and enhanced their resistance to TNF-α-induced apoptosis. Consistently, there was a positive correlation between HIF-1α and FoxM1 expression in 406 human hepatocellular carcinoma tissues, and the combination of these two parameters was a powerful predictor of poor prognosis in hepatocellular carcinoma patients after curative resection. Here, we report a new molecular mechanism by which FoxM1 expression is regulated by the TNF-α/reactive oxygen species/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis.

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

“…In addition, ELK3 is known as a regulator of HIF-1α expression by modulating HIF-1α stability (21)(22)(23)30,31). HIF-1α plays a key role in the induction of cancer invasion, metastasis and angiogenesis, as well as in cancer growth, glucose metabolism, and other metastasis-associated signaling pathways (32)(33)(34)(35)(36). notably, HIF-1α is a key regulator of cancer metastasis and invasion in HCC (35,36).…”

“…HIF-1α is a transcription factor that plays a well-established role in cancer development, progression and metastasis. HIF-1α is associated with the regulation of genes associated with cancer metastasis, invasion, angiogenesis, cellular proliferation, apoptosis and glucose metabolism (32)(33)(34)(35)(36). Vascular endothelial growth factor (VEgF) and metalloproteinase-2 (MMP-2), which are target molecules of HIF-1α, are also linked to the development, invasion and metastasis of HCC (35)(36)(37)(38).…”

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

“…Conversely, experiments in macrophages from Foxm1 -/-mice and FOXM1-deficient primary amnion cells showed increased levels of IL-6 (Lim et al, 2014;Balli et al, 2012). Another adipokine TNF-a decreases the expression of FOXO3 at the transcript level (Sente et al, 2016) and increases FOXM1 expression to promote cell proliferation and the resistance to apoptosis (Xia et al, 2012) (Fig. 3 B).…”

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

“…TNF-a has pleiotropic functions in inflammatory progression depending on cell type or biological context 7 . In certain conditions, TNF-a induces apoptosis; however, recent studies have indicated that TNF-a may promote hepatocellular carcinogenesis by activating a variety of signal pathways related to cell proliferation, differentiation and survival [8][9][10] . The mechanism of inflammation linked to TNF-a and involved in hepatocellular carcinogenesis still needs to be fully elucidated.…”