Abstract
Hepatitis B X-interacting protein (HBXIP, also termed as LAMTOR5) plays a crucial role in regulation of cancer progression, while the mechanism is still unclear. Here we found that HBXIP increased the expression of PPARδ (peroxisome proliferator-activated receptor-δ) in gene and protein levels of SW480 or HT-29 colonic cancer cells. Chromatin immunoprecipitation and luciferase reporter assays showed that HBXIP occupied the core promoter (−1079/−239 nt) regions of PPARδ and that HBXIP activated the transcription activity of PPARδ in an NF-κB (p65)-dependent manner. Moreover, Co-immunoprecipitation and immunofluorescence analysis showed that HBXIP bound to NF-κB/p65 in the cells. Interestingly, we found that PPARδ could conversely increase the expression of NF-κB/p65 through activating its transcription activity. In addition, the clinical observations showed that both HBXIP and PPARδ were highly expressed in colonic carcinoma, and HBXIP expression was positively associated with that of PPARδ in the clinical specimen. Importantly, HBXIP expression levels were positively correlated with the clinical pathological parameters including lymph node metastasis and advanced TNM stage. These findings suggest that HBXIP served as a co-activator to activate the positive feedback regulations of NF-κB/PPARδ, which promoted the fast proliferation of the colonic cancer cells. Therapeutically, HBXIP may serve as a potential drug target of colonic cancer cells.
Highlights
Colonic cancer is the third death-related cancer in the worldwide, accounting for more than 1,300,000 new cases annually and its incidence has sharply increased over the past two decades [1]
Research reported that Hepatitis B X-interacting protein (HBXIP) showed a high www.impactjournals.com/oncotarget expression in the colonic cancer cells and we found the different expression levels of HBXIP in the colonic cancer cells by RT-PCR assays (Supplementary Figure 1A)
Previous report indicated that HBXIP functioned in the cytoplasm [25], which is consistent with our immunofluorescent results indicated that HBXIP mainly localized in the cytoplasm, while a small amount of HBXIP proteins located in the nuclues (Figure 4H), suggesting HBXIP may have some functions in the nucleus, which is consistent with our previous studies [4, 6]
Summary
Colonic cancer is the third death-related cancer in the worldwide, accounting for more than 1,300,000 new cases annually and its incidence has sharply increased over the past two decades [1]. Previous studies have reported that HBXIP functions as a coactivator of multiple oncogenic transcription factors, such as TF-IID, SP1, STAT3 on the promotion of proliferation and metastasis of breast cancer cells [4,5,6]. The mechanism by which HBXIP enhances the growth of colonic cancer remains poorly documented. Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three isoforms: PPARα, δ and γ, which are expressed in all cell types of the brain [7, 8]. PPARδ enhances the expression of VEGF, an angiogenic factor, in colonic carcinoma cells [18]. PPARδ deficiency disrupts hypoxia-mediated tumorigenic potential of colonic cancer cells [20]. PPARδ is required for chronic colonic inflammation and colitisassociated carcinogenesis [21]
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