HBXIP activates the PPARδ/NF-κB feedback loop resulting in cell proliferation

// Qian Liu 1, * , Wenbin Lu 1, * , Chunxia Yang 1 , Yue Wang 1 , Wenjing Li 1 , Ying Chu 1 , Jianzhong Deng 1 , Yongzhong Hou 2 and Jianhua Jin 1 1 Department of Oncology, The Changzhou Wujin People’s Hospital, Jiangsu Province, 213017, China 2 Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China * These authors contributed equally to this work Correspondence to: Jianhua Jin, email: jianhuajin88@sina.com Yongzhong Hou, email: houyz@ujs.edu.cn Keywords: HBXIP; PPARδ; NF-κB; proliferation; colonic cancer Received: July 10, 2017      Accepted: November 14, 2017      Published: December 08, 2017 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.