Therapeutic use of human alpha‐fetoprotein in clinical patients: Is a cancer risk involved?

Mizejewski, Gerald J.

doi:10.1002/ijc.25292

Cited by 17 publications

(19 citation statements)

References 59 publications

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“…Hepatocellular carcinoma (HCC) is the fifth most frequent neoplasm worldwide, and accounts for 5.6% of all human cancers [1][2][3]. There is an increasing incidence of HCC in China, and this neoplasm has become China's second most frequent cause of cancer-related death [4].…”

Section: Discussionmentioning

confidence: 99%

“…Although it has been widely used as a marker in clinical diagnosis, compelling progress made in determining the biological role of AFP has recently attracted considerable interest, as AFP shows a close association with HCC carcinogenesis and the high mortality rate of this tumor [1][2][3]. In addition, there has been increasing focus on the role of AFP in promoting cell growth in cultured cells, and this ''growth factor'' function is yet another intriguing aspect of AFP biology.…”

Section: Introductionmentioning

confidence: 98%

“…This suggests that ATRA chemotherapy for hepatocellular carcinoma should be combined with afp gene silencing to achieve maximum efficiency of this agent. The biological roles and clinical significance of AFP have been recently summarized and discussed [3]. However, findings to date have been insufficient to entirely clarify the intrinsic mechanism underlying the impact of cytoplasmic AFP, and in particular have been insufficient to clarify its clinical significance.…”

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

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

Wang

Jiang

Chen

et al. 2012

Journal of Hepatology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

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

Wang

Jiang

Chen

et al. 2012

Journal of Hepatology

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“…Gang Li and his team following their meticulous studies of the effect of AFP on growth enhancement of human liver cancer cells [40][41][42][43]. It was then demonstrated by Li et al in 2009 that CyAFP played a role in caspase-3-mediated cell signaling affecting apoptosis [44].…”

Section: Cyafp Involvement In Intracellular Signaling and Regulationmentioning

confidence: 95%

“…The cancer risk of using recombinant human AFP as a therapeutic agent has already been addressed by the author [43]. Although AFP is a beneficial growth enhancing agent during pregnancy, full-length AFP may play a lethal role in adults in the initiation of growth, proliferation, and metastasis of human liver cancer.…”

Section: Postscript: a Cancer Warningmentioning

confidence: 99%

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

Mizejewski

2015

Tumor Biol.

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The concept of a non-secreted cytoplasmic-bound form of alpha-fetoprotein is not a new notion in AFP biological activities. Cytoplasmic AFP (CyAFP) is a long known but forgotten protein in search of a function other than a histochemical biomarker. In this report, CyAFP is presented as an "old" protein with a newly described intracellular function. In 1976, CyAFP was shown to be a product of hepatoma cells utilizing 14Cleucine incorporation and demonstrated by autoradiographic procedures. The synthesis of CyAFP without secretion was demonstrated to occur in both malignant and non-malignant cells encompassing hepatomas, ascite fluid cells, immature rodent uterus, MCF-7 breast cancers, and cytosols from human breast cancer patients. Using computer protein matching and alignments in AFP versus members of the nuclear receptor superfamily, a consecutive series of leucine zipper (heptad) repeats in AFP was previously reported, suggesting the possibility for protein-to-protein interactions. The potential for heptad heterodimerization between protein-binding partners provided the rationale for proposing that CyAFP might have the capability to form molecular hetero-complexes with cytoplasmic based transcription factors. More recent investigations have now provided experimental evidence that CyAFP is capable of colocalizing and interacting with transcription-associated factors. Such proteins can modulate intracellular signaling leading to regulation of transcription factors and initiation of growth in human cancer cells. Although circulating serum AFP is known as a growth-enhancing factor during development, cytoplasmic AFP has a lethal role in the oncogenesis, growth, and metastasis of adult liver cancer.

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Impact of intracellular alpha fetoprotein on retinoic acid receptors‐mediated expression of GADD153 in human hepatoma cell lines

Wang

Jiang

et al. 2011

Intl Journal of Cancer

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The aim of our study was to gain a better understanding of the molecular mechanism underlying the previously unrecognized role of cytoplasmic alpha fetoprotein (AFP) in retinoic acid receptors (RAR) mediated expression and biological effects of GADD153. Using microarray analysis, the expression of the GADD153 gene showed the greatest fold change among apoptosis/growth related genes in response to ATRA. AFP was able to interact with RAR in HepG2 cells, which was undetectable in HLE cells owing to absence of AFP. ATRA promoted nuclei entrance of RAR, expression of GADD153 and apoptosis, and these changes were reversed after transfection with the afp gene or addition of AGN193109. The level of GADD153 was gradually elevated as the effect of AFP was counteracted by increasing dose or prolonging treatment time with ATRA in HepG2 cells. Knockdown of AFP in siRNA-transfected HepG2 cells or over-expression of AFP in afp gene-transfected HLE cells was synchronously associated with up-regulation or down-regulation, respectively, of GADD153 expression. Both ATRA administration and AFP knockdown were each able to promote greater binding of RAR to its response element with consequent elevation of the proportion of apoptotic cells. Conversely, transfection of HLE cells with pcDNA3.1-afp resulted in apparent reduction of RAR binding to DNA and change of biological effect. These data taken together demonstrate the involvement of AFP in RAR-mediated expression and biological effects of GADD153. These findings provide a novel insight into the mechanism underlying the impact of AFP on the RAR signal network.

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Therapeutic use of human alpha‐fetoprotein in clinical patients: Is a cancer risk involved?

Cited by 17 publications

References 59 publications

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

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

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

Impact of intracellular alpha fetoprotein on retinoic acid receptors‐mediated expression of GADD153 in human hepatoma cell lines

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