Alpha‐fetoprotein: A new member of intracellular signal molecules in regulation of the PI3K/AKT signaling in human hepatoma cell lines

Abstract

Despite its well-defined role as a serum growth factor during fetal liver development and hepatic oncogenesis, the biological significance of cytoplasmic alpha-fetoprotein (AFP) remains incompletely understood. Here, we provide evidence to illustrate that cytoplasmic AFP may function as a regulator in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in human hepatocellular carcinoma cells. The results demonstrated colocalization and interaction of AFP and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the cytoplasm of AFP-producing Bel 7402 and HepG2 cells, with an interaction distance of 12.6 6 2.7 Å as determined with the fluorescence resonance energy transfer technique. Knockdown of AFP mRNA or inhibition of AFP expression by all trans-retinoic acid resulted in enhancement of the PTEN level with a synchronous decrease in phosphorylated AKT. Transfection of the afp gene into HLE cells (originally AFP negative) led to a significant activation of AKT signaling. The inhibition of PI3K signaling by LY 294002 was simultaneously reversed by transfection, accompanied by diminution of all trans-retinoic acid-induced upregulation of PTEN and enhancement of cell growth. In conclusion, these results demonstrate that cytoplasmic AFP is involved in regulation of hepatocellular growth and tumorigenesis.Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide with approximately 600,000 patients dying from this disease annually. 1 Alpha-fetoprotein (AFP) is frequently found in HCC (positive in more than 70% of tumors) and is considered to be a diagnostic and prognostic tumor marker for HCC. A vast biomedical literature has been amassed concerning the clinical use of AFP in adults with HCC. These studies have largely addressed the clinical monitoring of AFP levels in the sera of adult patients with HCC and other hepatic disorder, despite the fact that the physiological role of AFP is incompletely defined.In the last decade, great progress has been made in the field of AFP investigation. In addition to its application in diagnosis, AFP has been defined as a kind of growth regulator during ontogenic growth and tumor progression. 2 It has been demonstrated that AFP is involved in pleiotropic activities affecting the processes of cell differentiation, growth regulation and tumorigenesis. 3,4 As shown in previous studies, administration of AFP results in proliferation of both tumor and normal cells, which raises the possibility that overexpression of AFP may be of significance in the development of liver tumors. 5 We recently reported that regulation of AFP in development and growth of malignant hepatic tumor cells was achieved through escape of immune surveillance involving the Fas/FasL pathway. 6 We have also reported that the caspase-3 cascade is the main pathway in TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis, which is virtually abolished in the presence of AFP. 7 Despite its well-defined role in regulation of cell growth, less emphasis has been pl...

Alpha-fetoprotein acts as a novel signal molecule and mediates transcription of Fn14 in human hepatocellular carcinoma

“…AFP has served as a useful biomarker for diagnosis of HCC since the 1970s, and currently is widely used in the clinical diagnosis of liver cancer. However, recent findings on the signal molecule-like roles of AFP have led to a re-evaluation of this protein [4][5][6][7]. AFP therefore can no longer be regarded merely as a diagnostic marker for HCC, but may now be understood as an intracellular factor which is involved both in ontogenetic and oncogenic growth.…”

“…Subsequent studies showed that cytoplasmic AFP also blocks RA-RAR mediated expression of the growth arrest and DNA damage-inducible 153 gene (GADD153) and is responsible for the extent of cell survival [6]. In addition, cytoplasmic AFP was found to promote the PI3K/AKT pathway through interacting and interfering with PTEN protein which leads to aberrant growth of hepatocellular carcinoma cells [7]. These effects of cytoplasmic AFP were verified by knockdown of AFP mRNA with siRNA or overexpression of AFP by transfection of the afp gene in non-AFP producing cells.…”

Nonsecreted cytoplasmic alpha-fetoprotein: a newly discovered role in intracellular signaling and regulation. An update and commentary

“…The AKT/mTOR pathway is an intracellular signaling pathway important in regulating cell cycle, growth, and apoptosis. It had been previously shown that CyAFP initiated a signaling cascade that stimulated CXCR4 expression by activating the PI3K/AKT signaling pathway [48]. Zhu et al found that CyAFP colocalized and interacted with PTEN, thus inducing CXCR4 expression by activating AKT (Ser 473) phosphorylation.…”

“…In a second study, Li et al provided direct evidence that CyAFP functions as a regulator in the phosphatidylinositol-3-kinase (PI3K)/AKT pathway of Bel 7402 hepatoma cells [48,49]. PI3Ks are signal transducing enzymes capable of phosphorylating inositol involved in cell growth, proliferation, and cellular trafficking.…”

Tumor-Derived α-Fetoprotein Impairs the Differentiation and T Cell Stimulatory Activity of Human Dendritic Cells

“…With its structural similarity to albumin, it has been hypothesized to play a role in the transport of serum components, including fatty acids, steroids, and heavy metals, and may serve as an embryonic analogue of albumin (2). There have also been reports of AFP interfering with intracellular signaling, including both caspase 3 and PI3K/AKT pathways (5, 6). An immunoregulatory role for AFP has also been proposed.…”