Alpha-fetoprotein: Past, present, and future

Abstract

Alpha-fetoprotein (AFP) is a glycoprotein that plays an important role in immune regulation with critical involvement in early human development and maintaining the immune balance during pregnancy. Postfetal development, the regulatory mechanisms controlling AFP undergo a shift and AFP gene transcription is suppressed. Instead, these enhancers refocus their activity to maintain albumin gene transcription throughout adulthood. During the postnatal period, AFP expression can increase in the setting of hepatocyte injury, regeneration, and malignant transformation. It is the first oncoprotein discovered and is routinely used as part of a screening strategy for HCC. AFP has been shown to be a powerful prognostic biomarker, and multiple HCC prognosis models confirmed the independent prognostic utility of AFP. AFP is also a useful predictive biomarker for monitoring the treatment response of HCC. In addition to its role as a biomarker, AFP plays important roles in immune modulation to promote tumorigenesis and thus has been investigated as a therapeutic target in HCC. In this review article, we aim to provide an overview of AFP, encompassing the discovery, biological role, and utility as an HCC biomarker in combination with other biomarkers and how it impacts clinical practice and future direction.

FIGURE 1

Biological pathways of AFP involvement in the inhibition of HCC cell apoptosis, promotion of HCC cell proliferation, and promotion of HCC migration, invasion, and metastasis. Abbreviations: Ac, acetylation; AFP, alpha-fetoprotein; AFPR, AFP receptor; ATRA, all-trans retinoic acid; CBP, CREB binding protein; CXCR4, CXC chemokine receptor 4; DR5, death receptor 5; FADD, Fas-associated death domain; FasL, Fas ligand; HBx, hepatitis B virus X protein; HIF-1α, hypoxia-inducible factor-1α; HuR, human antigen R; MMP, matrix metalloproteinase; PA, palmitic acid; RAR, retinoic acid receptor; SIRT1, sirtuin type 1; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand; Ub, ubiquitin; UTR, untranslated region.