Molecular mechanism of activating protein-4 regulated growth of hepatocellular carcinoma

Abstract

The molecular regulation of growth of hepatocellular carcinoma (HCC) is yet to be fully clarified. Here we found a significantly higher ratio of phosphorylated β-catenin (phos-β-cat) to β-catenin (β-cat) as an indicator of an activated Wnt signaling, with significantly higher levels of c-myc and transcription factor activating protein-4 (AP-4) and a significantly lower level of p21 in the resected HCC, compared to the paired adjacent healthy hepatic tissue from the patients. Moreover, strong correlations were detected between phos-β-cat/β-cat ratio and c-myc level, between c-myc and AP-4 levels, and between AP-4 and p21 levels. These data support the presence of a Wnt/c-myc/AP-4/p21 regulation cascade in HCC as has been reported in colorectal cancer. To prove it, we overexpressed c-myc in two HCC lines, which significantly increased AP-4 level, inhibited p21 level, and then increased cell growth. Meanwhile, c-myc inhibition in these two HCC lines significantly decreased AP-4 level, increased p21 level, and then decreased cell growth. Moreover, AP-4 inhibition in c-myc-overexpressing HCC lines abolished the inhibitory effect on p21 and abolished the increase in cell growth. In line with these findings, overexpression of AP-4 in these two HCC lines significantly decreased p21 level, and then increased cell growth, while AP-4 inhibition significantly increased p21 level, and then decreased cell growth. Our results on HCC are thus consistent with the model detected in colorectal carcinoma, suggesting that Wnt signaling activated c-myc may increase HCC growth through direct inhibitory effect of AP-4 on p21. Our study thus highlights AP-4 as a novel therapeutic target for HCC.

The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating LAPTM4B Expression

“…It indicates that AP4 may play a dual role in cell proliferation via different pathways. Similar to our results, AP4 has been reported to promote cell growth in HCC [41], colorectal carcinoma [42] and gastric cancer [43]. Moreover, it has been proposed that AP4 could activate cell migration and EMT mediated by p53 in MDA-MB-231 cells [44] and mediate a c-MYC-induced EMT in colorectal cancer [45].…”

“…Interestingly, it has been shown that c-MYC could directly regulate AP4 expression and c-MYC-AP4-p21 cascade plays an important role in maintaining cells in a proliferative, progenitor-like state of HCC and colorectal carcinoma [41,42]. Taken together, these results suggest that c-MYC-AP4-LAPTM4B-c-MYC axis may form a feedback loop to participate in cell growth and metastasis.…”

Silencing of AP-4 inhibits proliferation, induces cell cycle arrest and promotes apoptosis in human lung cancer cells

“…These observations suggest that AP-4 may have a significant role in the tumorigenesis or progression of a number of types of cancer (11,12,21,22).…”

“…In addition, AP-4 binds the recognition motifs located in the vicinity of the p21 promoter and is able to mediate the transcriptional repression of p21, which is a key cell cycle inhibitor (27). Ge et al (22) reported that c-Myc activated by the Wnt signaling pathway may promote hepatocellular carcinoma progression, through a direct inhibitory effect of AP-4 on p21. The present study identified that silencing of AP-4 was able to inhibit the proliferation of human lung cancer cells and induce cell cycle arrest at the G0/G1 phase.…”

Expression of Activating Protein 4 and Its Relationships with Prognosis in Gastric Cancer

“…In recent years, AP-4 has been widely studied as a popular molecular marker in a variety of tumors, including non-small cell lung cancer, prostate cancer, and such digestive system tumors as liver cancer, colorectal cancer, and GC [12,13,14,15]. However, current research into the relationships between AP-4 and the prognosis of GC is limited, prompting this study of the lesion tissues and normal tissues of 54 GC patients using immunohistochemistry.…”