Abstract
Fetuin-A is the protein product of the AHSG gene in humans. It is mainly synthesized by the liver in adult humans and is secreted into the blood where its concentration can vary from a low of ~0.2 mg/mL to a high of ~0.8 mg/mL. Presently, it is considered to be a multifunctional protein that plays important roles in diabetes, kidney disease, and cancer, as well as in inhibition of ectopic calcification. In this review we have focused on work that has been done regarding its potential role(s) in tumor progression and sequelae of diabetes. Recently a number of laboratories have demonstrated that a subset of tumor cells such as pancreatic, prostate and glioblastoma multiform synthesize ectopic fetuin-A, which drives their progression. Fetuin-A that is synthesized, modified, and secreted by tumor cells may be more relevant in understanding the pathophysiological role of this enigmatic protein in tumors, as opposed to the relatively high serum concentrations of the liver derived protein. Lastly, auto-antibodies to fetuin-A frequently appear in the sera of tumor patients that could be useful as biomarkers for early diagnosis. In diabetes, solid experimental evidence shows that fetuin-A binds the β-subunit of the insulin receptor to attenuate insulin signaling, thereby contributing to insulin resistance in type 2 diabetes mellitus (T2DM). Fetuin-A also may, together with free fatty acids, induce apoptotic signals in the beta islets cells of the pancreas, reducing the secretion of insulin and further exacerbating T2DM.
Highlights
Fetuin-A is a glycoprotein that is synthesized by a number of fetal tissues, while in adult animals including humans, it is synthesized mainly by the liver parenchyma cells [1]
The potential role of fetuin-A in tumor progression stemmed from earlier studies that suggested that it was the cell attachment factor in serum [9]
Further purification strategies starting with Pedersen fetuin-A yielded more homogenous fetuin-A preparations that lacked cell attachment and growth promoting properties [12]
Summary
Fetuin-A is a glycoprotein that is synthesized by a number of fetal tissues, while in adult animals including humans, it is synthesized mainly by the liver parenchyma cells [1]. The potential role of fetuin-A in tumor progression stemmed from earlier studies that suggested that it was the cell attachment factor in serum [9]. The Spiro method of purification employed zinc acetate and resulted in a single band ~48 kDa in SDS-PAGE gels that lacked biological activity These studies provided evidence that attachment and growth-promoting properties of Pedersen fetuin-A were due to the contaminating protein factors that co-purified with fetuin-A. The tumors cells in which ectopic synthesis of fetuin-A has been determined, namely glioblastoma and pancreatic cancer, happen to be some of the most invasive tumor types [56], suggesting that the glycoprotein plays a significant and yet to be fully appreciated role in tumor progression. It can be extrapolated from these studies that in any given tumor, there will be a subset that synthesize fetuin-A, and that these are likely to be the most aggressive tumor cells, possibly tumor stem cells [61]
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