Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells

Vikrant Rai,Devendra K Agrawal

doi:10.3390/reports4020017

Abstract

Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.

Highlights

Liver cancer is the sixth most common cancer diagnosis and the third most common cause of cancer-related death worldwide [1]
We have investigated the effect of calcitriol on triggering receptors expressed on myeloid cell (TREM)-1 and TREM-2 in epithelial cells transformed with SV40 large T antigen (THLE-2) and Hepatocellular carcinoma (HCC) cell line (HepG2) cells with the hypothesis that calcitriol attenuates TREM-1 expression
NF-κB is a downstream signaling transcription factor in the High mobility group box-1 (HMGB-1) pathway and regulates TREM-1 expression, so we investigated the effect of calcitriol, IL-6, tumor necrosis factor (TNF)-α, and LPS on the expression of NF-κB

Summary

Introduction

Liver cancer is the sixth most common cancer diagnosis and the third most common cause of cancer-related death worldwide [1]. High mobility group box-1 (HMGB-1) released from necrotic cells or dying hepatocytes mediate the activation of surface receptors such as triggering receptors expressed on myeloid cell (TREM)-1 and toll-like receptors (TLRs) activating the downstream signaling pathways and secretion of pro-inflammatory cytokines [8]. Deregulation between innate and adaptive immunity due to chronic inflammation results in the loss of hepatocyte and regenerative process This leads to the over secretion of pro-inflammatory cytokines involving signaling pathways and transcription factors mediating excessive tissue remodeling, loss of tissue architecture, apoptosis, and necrosis, thereby increasing the risk of carcinogenesis and development of HCC [9,10]. There is a need to understand the inflammatory pathophysiology in-depth to investigate the noble therapeutic targets

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