Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Abstract

Obesity and related metabolic abnormalities, including adipocytokine dysbalance, are risk factors for hepatocellular carcinoma (HCC). Visfatin, an adipocytokine that is highly expressed in visceral fat, is suggested to play a role in the progression of human malignancies. Branched-chain amino acids (BCAA) reduce the incidence of HCC in obese patients with liver cirrhosis and prevent obesity-related liver carcinogenesis in mice. In this study, we investigated the possible role of visfatin on HCC progression and the effects of BCAA on visfatin-induced proliferation of HCC cells. In patients with HCCs, serum visfatin levels were significantly correlated with stage progression and tumor enlargement. Visfatin preferentially stimulated the proliferation of HepG2, Hep3B, and HuH7 human HCC cells compared with Hc normal hepatocytes. Visfatin phosphorylated extracellular signal-regulated kinase (ERK), Akt, and GSK-3b proteins in HepG2 cells. LY294002 [a phosphoinositide-3-kinase (PI3K) inhibitor], PD98059 [a MAP/ERK 1 kinase (MEK1) inhibitor], CHIR99021 (a GSK-3b inhibitor), and BCAA significantly inhibited visfatin-induced proliferation in HepG2 cells. BCAA also inhibited phosphorylation of GSK-3b, increased cellular levels of p21 CIP1 , caused cell-cycle arrest in G 0 /G 1 phase, and induced apoptosis in HCC cells in the presence of visfatin. These findings suggest that visfatin plays a critical role in the proliferation of HCC cells and may be associated with the progression of this malignancy. In addition, BCAA might inhibit obesity-related liver carcinogenesis by targeting and, possibly, by overcoming the stimulatory effects of visfatin.

Nicotinamide Phosphoribosyltransferase in Malignancy: A Review

“…Increased iNampt expression also occurs in malignant lymphomas, including diffuse large B-cell lymphoma, follicular B-cell lymphoma, Hodgkin's lymphoma, and peripheral T-cell lymphoma (Table 1). [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] eNampt also increases the growth fraction of the hepatocellular carcinoma HepG2 cell line in vitro, suggesting a role for it in hepatocellular carcinoma. 53 Many of these studies have found interesting aspects of Nampt expression in cancer.…”

“…Plasma eNampt is elevated in a variety of human malignancies, including astrocytomas, myeloma, and male oral squamous cell; gastric, endometrial, hepatocellular, and colorectal carcinomas; and invasive breast cancer. [47][48][49]52,53,[90][91][92][93] Interestingly, plasma eNampt increases with increased astrocytoma grade and has been hypothesized to be a prognostic marker. 52 Similarly, eNampt is elevated at tumor higher stages in male oral squamous cell, hepatocellular, endometrial, and invasive breast carcinomas.…”

“…52 Similarly, eNampt is elevated at tumor higher stages in male oral squamous cell, hepatocellular, endometrial, and invasive breast carcinomas. 47,53,93 Higher eNampt levels correlate with myometrial invasion and shorter patient survival in women with endometrial carcinoma. 44 Last, higher eNampt levels in invasive breast cancer correlated with lymph node metastases and the absence of estrogen and progesterone receptors.…”

107 a Randomised Controlled Trial of Meloxicam, a Cox-2 Inhibitor, to Prevent Hepatocellular Carcinoma Recurrence After Initial Curative Treatment

“…Various agents such as acyclic retinoids, branched-chain amino acids [11,18], antihypertensives such as angiotensin-converting-enzyme inhibitors [19], and Cox-2 inhibitors have been clinically introduced. Chemical stimuli including cytokines and growth factors upregulate the expression of Cox-2, and inflammation induces Cox-2 to mediate increased synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2) [13].…”

“…Anti-viral treatments, such as interferons and nucleoside analogues, have been commonly used for the management of hepatitis B or C virus infections [8,9], respectively. Subsequently, acyclic retinoids [10], branched-chain amino acids, antihypertensives [11], and cyclooxygenase 2 (Cox-2) inhibitors [12] have been clinically introduced.…”