Skip to main content

Advertisement

Log in

Effects of alpha-fetoprotein on the occurrence and progression of hepatocellular carcinoma

  • Review – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Alpha-fetoprotein (AFP) is considered as a diagnostic and prognostic tumorous marker for HCC, and up to 70% of HCC patients showed elevated serum levels of AFP. In the past two decades, evidences have shown that AFP not only is a tumorous biomarker for diagnosing HCC, but also plays a very complicated role in regulating proliferation, apoptosis, and autophagy and inhibiting the immune response of cells. Because AFP is significantly elevated during hepatocarcinogenesis, the role of AFP in the development of HCC is a scientific problem worthy of further exploration. In this review, we reviewed the effects of AFP on hepatocyte malignant transformation and the underlying mechanisms involved in the progression of HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

HCC:

Hepatocellular carcinoma

AFP:

Alpha-fetoprotein

HBV:

Hepatitis B virus

HBx:

HBV- X protein

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

ATRA:

All-trans retinoic acid

PTEN:

Phosphate and tension homology deleted on chromosome ten

DCs:

Dendritic cells

References

  • Agarwal R, Narayan J, Bhattacharyya A, Saraswat M, Tomar AK (2017) Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets. Cancer Genet 216–217:37–51

    PubMed  Google Scholar 

  • Bai DS, Zhang C, Chen P, Jin SJ, Jiang GQ (2017) The prognostic correlation of AFP level at diagnosis with pathological grade, progression, and survival of patients with hepatocellular carcinoma. Sci Rep 7:12870

    PubMed  PubMed Central  Google Scholar 

  • Bei R, Mizejewski GJ (2011) Alpha fetoprotein is more than a hepatocellular cancer biomarker: from spontaneous immune response in cancer patients to the development of an AFP-based cancer vaccine. Curr Mol Med 11(7):564–581

    CAS  PubMed  Google Scholar 

  • Bosetti C, Turati F, Vecchia La (2014) Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol 28(5):753–770

    PubMed  Google Scholar 

  • Bouattour M, Mehta N, He AR, Cohen EI, Nault JC (2019) Systemic treatment for advanced hepatocellular carcinoma. Liver Cancer 8(5):341–358

    CAS  PubMed  Google Scholar 

  • Bray SM, Vujanovic L, Butterfield LH (2011) Dendritic cell-based vaccines positively impact natural killer and regulatory T cells in hepatocellular carcinoma patients. Clin Dev Immunol 2011:249281

    PubMed  PubMed Central  Google Scholar 

  • Chen KJ, Zhou L, Xie HY, Ahmed TE, Feng XW, Zheng SS (2012) Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection. Med Oncol 29(3):1817–1826

    PubMed  Google Scholar 

  • Chen W, Peng J, Ye J, Dai W, Li G, He Y (2020) Aberrant AFP expression characterizes a subset of hepatocellular carcinoma with distinct gene expression patterns and inferior prognosis. J Cancer 11(2):403–413

    CAS  PubMed  PubMed Central  Google Scholar 

  • D'Alessandro R, Refolo MG, Iacovazzi PA, Pesole PL, Messa C, Carr BI (2019) Ramucirumab and GSK1838705A enhance the inhibitory effects of low concentration sorafenib and regorafenib combination on HCC cell growth and motility. Cancers (Basel) 11(6):787

    CAS  Google Scholar 

  • Fossum CC, Alabbad JY, Romak LB, Hallemeier CL, Haddock MG, Huebner M, Dozois EJ, Larson DW (2017) The role of neoadjuvant radiotherapy for locally-advanced rectal cancer with resectable synchronous metastasis. J Gastrointest Oncol 8(4):650–658

    PubMed  PubMed Central  Google Scholar 

  • Gao J, Song P (2017) Combination of triple biomarkers AFP, AFP-L3, and PIVAKII for early detection of hepatocellular carcinoma in China: Expectation. Drug Discov Ther 11(3):168–169

    CAS  PubMed  Google Scholar 

  • Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25(18):2586–2593

    PubMed  Google Scholar 

  • Gao R, Cai C, Gan J, Yang X, Shuang Z, Liu M, Li S, Tang H (2015) miR-1236 down-regulates alpha-fetoprotein, thus causing PTEN accumulation, which inhibits the PI3K/Akt pathway and malignant phenotype in hepatoma cells. Oncotarget 6(8):6014–6028

    PubMed  PubMed Central  Google Scholar 

  • Gao F, Zhu HK, Zhu YB, Shan QN, Ling Q, Wei XY, Xie HY, Zhou L, Xu X, Zheng SS (2016) Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern. Hepatobiliary Pancreat Dis Int 15(4):371–377

    PubMed  Google Scholar 

  • Gillespie JR, Uversky VN (2000) Structure and function of alpha-fetoprotein: a biophysical overview. Biochim Biophys Acta 1480:14–56

    Google Scholar 

  • Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH (2008) NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunityv 28(4):571–580

    CAS  Google Scholar 

  • Hickman JA (2002) Apoptosis and tumourigenesis. Curr Opin Genet Dev 12(1):67–72

    CAS  PubMed  Google Scholar 

  • Laderoute MP (2015) A new paradigm about HERV-K102 particle production and blocked release to explain cortisol mediated immunosenescence and age-associated risk of chronic disease. Discov Med 20(112):379–391

    PubMed  Google Scholar 

  • Lazarevich NL (2000) Molecular mechanisms of alpha-fetoprotein gene expression. Biochemistry (Mosc) 65(1):117–133

    CAS  Google Scholar 

  • Li MS, Li PF, He SP, Du GG, Li G (2002) The promoting molecular mechanism of alpha-fetoprotein on the growth of human hepatoma Bel7402 cell line. World J Gastroenterol 8(3):469–475

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li MS, Ma QL, Chen Q, Liu XH, Li PF, Du GG, Li G (2005) Alpha-fetoprotein triggers hepatoma cells escaping from immune surveillance through altering the expression of Fas/FasL and tumor necrosis factor related apoptosis-inducing ligand and its receptor of lymphocytes and liver cancer cells. World J Gastroenterol 11(17):2564–2569

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Wang S, Jiang W, Li H, Liu Z, Zhang C, McNutt MA, Li G (2012) Impact of intracellular alpha fetoprotein on retinoic acid receptors-mediated expression of GADD153 in human hepatoma cell lines. Int J Cancer 130(4):754–764

    CAS  PubMed  Google Scholar 

  • Li M, Zhu M, Li W, Lu Y, Xie X, Wu Y, Zheng S (2013) Alpha-fetoprotein receptor as an early indicator of HBx-driven hepatocarcinogenesis and its applications in tracing cancer cell metastasis. Cancer Lett 330(2):170–180

    CAS  PubMed  Google Scholar 

  • Li C, Song B, Santos PM, Butterfield LH (2019) Hepatocellular cancer-derived alpha fetoprotein uptake reduces CD1 molecules on monocyte-derived dendritic cells. Cell Immunol 335:59–67

    CAS  PubMed  Google Scholar 

  • Lin YS, Zhu MY, Zhou S, Xie XJ, Li MS (2010) Effects of alpha-fetoprotein on the expression of TRAIL death receptor-2 and its role on resisting the cytotoxicity of TRAIL in hepatoma cells. Zhonghua Gan Zang Bing Za Zhi 18(12):745–750. (In China)

    CAS  PubMed  Google Scholar 

  • Lin B, Zhu M, Wang W, Li W, Dong X, Chen Y, Lu Y, Guo J, Li M (2017) Structural basis for alpha fetoprotein-mediated inhibition of caspase-3 activity in hepatocellular carcinoma cells. Int J Cancer 141(7):1413–1421

    CAS  PubMed  Google Scholar 

  • Liu Y, Wang YR, Ding GH, Yang TS, Yao L, Hua J, He ZG, Qian MP (2016) JAK2 inhibitor combined with DC-activated AFP-specific T-cells enhances antitumor function in a Fas/FasL signal-independent pathway. Onco Targets Ther 9:4425–4433

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Lin Y, Zhang J, Zhang Y, Li Y, Liu Z, Li Q, Luo M, Liang R, Ye J (2019) Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. J Exp Clin Cancer Res 38(1):447

    PubMed  PubMed Central  Google Scholar 

  • Llovet JM, Montal R, Villanueva A (2019) Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J Hepatol 70(6):1262–1277

    PubMed  Google Scholar 

  • Lu Y, Zhu M, Li W, Lin B, Dong X, Chen Y, Xie X, Guo J, Li M (2016) Alpha fetoprotein plays a critical role in promoting metastasis of hepatocellular carcinoma cells. J Cell Mol Med 20(3):549–558

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma SH, Chen GG, Yip J, Lai PB (2010) Therapeutic effect of alpha-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice. Gene Ther 17(7):905–912

    CAS  PubMed  Google Scholar 

  • Magee TR, Cai Y, El-Houseini ME, Locker J, Wan YJ (1998) Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. J Biol Chem 273(45):30024–30032

    CAS  PubMed  Google Scholar 

  • Mizejewski GJ (1995) The phylogeny of alpha-fetoprotein in vertebrates: survey of biochemical and physiological data. Crit Rev Eukaryot Gene Expr 5(3–4):281–316

    CAS  PubMed  Google Scholar 

  • Nakagawa H, Mizukoshi E, Kobayashi E, Tamai T, Hamana H, Ozawa T, Kishi H, Kitahara M, Yamashita T, Arai K, Terashima T, Iida N, Fushimi K, Muraguchi A, Kaneko S (2017) Association between high-avidity T-cell receptors, induced by α-fetoprotein-derived peptides, and anti-tumor effects in patients with hepatocellular carcinoma. Gastroenterology 152(6):1395–406.e10

    CAS  PubMed  Google Scholar 

  • Ogden SK, Lee KC, Barton MC (2000) Hepatitis B viral transactivator HBx alleviates p53-mediated repression of alpha-fetoprotein gene expression. J Biol Chem 275(36):27806–27814

    CAS  PubMed  Google Scholar 

  • Pardee AD, Shi J, Butterfield LH (2014) Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. J Immunol 193(11):5723–5732

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peck AB, Murgita RA, Wigzell H (1982) Cellular and genetic restrictions in the immunoregulatory activity of alpha-fetoprotein. III. Role of the MLC-stimulating cell population in alpha-fetoprotein-induced suppression of T cell-mediated cytotoxicity. J Immunol 128(3):1134–1140

    CAS  PubMed  Google Scholar 

  • Pucci P, Siciliano R, Malorni A, Marino G, Tecce MF, Ceccarini C, Terrana B (1991) Human alpha-fetoprotein primary structure: a mass spectrometric study. Biochemistry 30(20):5061–5066

    CAS  PubMed  Google Scholar 

  • Reed JC (1999) Mechanisms of apoptosis avoidance in cancer. Curr Opin Oncol 11(1):68–75

    CAS  PubMed  Google Scholar 

  • Santos PM, Menk AV, Shi J, Tsung A, Delgoffe GM, Butterfield LH (2019) Tumor-derived α-fetoprotein suppresses fatty acid metabolism and oxidative phosphorylation in dendritic cells. Cancer Immunol Res 7(6):1001–1012

    CAS  PubMed  Google Scholar 

  • Schmidt N, Neumann-Haefelin C, Thimme R (2012) Cellular immune responses to hepatocellular carcinoma: lessons for immunotherapy. Dig Dis 30(5):483–491

    PubMed  Google Scholar 

  • Suryatenggara J, Wibowo H, Atmodjo WL, Mathew G (2017) Characterization of alpha-fetoprotein effects on dendritic cell and its function as effector immune response activator. J Hepatocell Carcinoma 4:139–151

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tang H, Tang XY, Liu M, Li X (2008) Targeting alpha-fetoprotein represses the proliferation of hepatoma cells via regulation of the cell cycle. Clin Chim Acta 394(1–2):81–88

    CAS  PubMed  Google Scholar 

  • Thomas MB, Zhu AX (2005) Hepatocellular carcinoma: the need for progress. J Clin Oncol 23(13):2892–2899

    PubMed  Google Scholar 

  • Wang X, Wang Q (2018) Alpha-Fetoprotein and hepatocellular carcinoma immunity. Can J Gastroenterol Hepatol 2018:9049252

    PubMed  PubMed Central  Google Scholar 

  • Wang H, Xu L, Zhu X, Wang P, Chi H, Meng Z (2014) Activation of phosphatidylinositol 3-kinase/Akt signaling mediates sorafenib-induced invasion and metastasis in hepatocellular carcinoma. Oncol Rep 32(4):1465–1472

    CAS  PubMed  Google Scholar 

  • Wang SS, Chen YH, Chen N, Wang LJ, Chen DX, Weng HL, Dooley S, Ding HG (2017a) Hydrogen sulfide promotes autophagy of hepatocellular carcinoma cells through the PI3K/Akt/mTOR signaling pathway. Cell Death Dis 8:e2688

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang G, Liu J, Cai Y, Chen XW, Kong X, Huang W, Guo H, Zhao X, Lu Y, Niu L, Li X, Zhang H, Lei C, Lei Z, Yin J, Hu H, Yu F, Nie Y, Xia L, Wu K (2017b) Loss of Barx1 promotes hepatocellular carcinoma metastasis through up-regulating MGAT5 and MMP9 expression and indicates poor prognosis. Oncotarget 8(42):71867–71880

    PubMed  PubMed Central  Google Scholar 

  • Wang S, Zhu M, Wang Q, Hou Y, Li L, Weng H, Zhao Y, Chen D, Ding H, Guo J, Li M (2018a) Alpha-fetoprotein inhibits autophagy to promote malignant behaviour in hepatocellular carcinoma cells by activating PI3K/AKT/mTOR signalling. Cell Death Dis 9:1027

    PubMed  PubMed Central  Google Scholar 

  • Wang H, Ou Y, Ou J, Jian Z (2018b) Fli-1 promotes metastasis by regulating MMP2 signaling in hepatocellular carcinoma. Mol Med Rep 17(1):1986–1992

    CAS  PubMed  Google Scholar 

  • Xu LX, He MH, Dai ZH, Yu J, Wang JG, Li XC, Jiang BB, Ke ZF, Su TH, Peng ZW, Guo Y, Chen ZB, Chen SL, Peng S, Kuang M (2019) Genomic and transcriptional heterogeneity of multifocal hepatocellular carcinoma. Ann Oncol 30(6):990–997

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xue J, Cao Z, Cheng Y, Wang J, Liu Y, Yang R, Li H, Jiang W, Li G, Zhao W, Zhang X (2020) Acetylation of alpha-fetoprotein promotes hepatocellular carcinoma progression. Cancer Lett 471:12–26

    CAS  PubMed  Google Scholar 

  • Yamamoto M, Tatsumi T, Miyagi T, Tsunematsu H, Aketa H, Hosui A, Kanto T, Hiramatsu N, Hayashi N, Takehara T (2011) α-Fetoprotein impairs activation of natural killer cells by inhibiting the function of dendritic cells. Clin Exp Immunol 165(2):211–219

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang X, Zhang Y, Zhang L, Zhang L, Mao J (2008) Silencing alpha-fetoprotein expression induces growth arrest and apoptosis in human hepatocellular cancer cell. Cancer Lett 271(2):281–293

    CAS  PubMed  Google Scholar 

  • Yang X, Chen L, Liang Y, Si R, Jiang Z, Ma B, Gao P (2018a) Knockdown of alpha-fetoprotein expression inhibits HepG2 cell growth and induces apoptosis. J Cancer Res Ther 14(Supplement):S634–S643

    CAS  PubMed  Google Scholar 

  • Yang Y, Ye YC, Chen Y, Zhao JL, Gao CC, Han H, Liu WC, Qin HY (2018b) Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. Cell Death Dis 9:793

    PubMed  PubMed Central  Google Scholar 

  • Yasinska IM, Gibbs BF, Lall GS, Sumbayev VV (2014) The HIF-1 transcription complex is essential for translational control of myeloid hematopoietic cell function by maintaining mTOR phosphorylation. Cell Mol Life Sci 71(4):699–710

    CAS  PubMed  Google Scholar 

  • Ye R, Dai N, He Q, Guo P, Xiang Y, Zhang Q, Hong Z, Zhang Q (2018) Comprehensive anti-tumor effect of Brusatol through inhibition of cell viability and promotion of apoptosis caused by autophagy via the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Biomed Pharmacother 105:962–973

    CAS  PubMed  Google Scholar 

  • Zhang L, He T, Cui H, Wang Y, Huang C, Han F (2012) Effects of AFP gene silencing on apoptosis and proliferation of a hepatocellular carcinoma cell line. Discov Med 14(75):115–124

    PubMed  Google Scholar 

  • Zhang H, Cao D, Zhou L, Zhang Y, Guo X, Li H, Chen Y, Spear BT, Wu JW, Xie Z, Zhang WJ (2015) ZBTB20 is a sequence-specific transcriptional repressor of alpha-fetoprotein gene. Sci Rep 5:11979

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao T, Jia L, Li J, Ma C, Wu J, Shen J, Dang L, Zhu B, Li P, Zhi Y, Lan R, Xu Y, Hao Z, Chai Y, Li Q, Hu L, Sun S (2020) Heterogeneities of site-specific N-Glycosylation in HCC tumors with low and high AFP concentrations. Front Oncol 21(10):496

    Google Scholar 

  • Zhu M, Guo J, Li W, Lu Y, Fu S, Xie X, Xia H, Dong X, Chen Y, Quan M, Zheng S, Xie K, Li M (2015) Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells. Oncotarget 6(14):12196–12208

    PubMed  PubMed Central  Google Scholar 

  • Zhu M, Li W, Lu Y, Dong X, Lin B, Chen Y, Zhang X, Guo J, Li M (2017) HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway. Int J Cancer 140(6):1346–1355

    CAS  PubMed  Google Scholar 

  • Zhu W, Peng Y, Wang L, Hong Y, Jiang X, Li Q, Liu H, Huang L, Wu J, Celis E, Merchen T, Kruse E, He Y (2018) Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy. Hepatology 68(2):574–589

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Hainan Medical College Council of Medical Research for their help and Kun Liu prepared the figure.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81960519, 81660463, 81560450, 31560243); The Natural Science Foundation of Hainan Province (Nos. 2019CXTD406, 2019CR204 and 20168263); Hainan Provincial Association for Science and Technology Program of Youth Science Talent and Academic Innovation (No. QCXM 201922).

Author information

Authors and Affiliations

Authors

Contributions

YZ prepared the manuscript, ZM and LM designed the concepts and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Mingyue Zhu or Mengsen Li.

Ethics declarations

Conflict of interest

The authors confirm that this article content has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines were followed.

Consent for publication

All authors of this paper consent for publishing the manuscript and figure in the Journal.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, Y., Zhu, M. & Li, M. Effects of alpha-fetoprotein on the occurrence and progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 146, 2439–2446 (2020). https://doi.org/10.1007/s00432-020-03331-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-020-03331-6

Keywords

Navigation