Alpha-fetoprotein Promotes the Malignant Phenotype of Hepatocellular Carcinoma Cells: The Drugs Resistance Origination

Xue Shan ( Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, 3 Xueyuan Road, Longhua District, Haikou 571199, Hainan, P.R China. )

Minni Zhang ( Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, 3 Xueyuan Road, Longhua District, Haikou 571199, Hainan, P.R China. )

Haifeng Lin ( Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou 570311, Hainan, P.R China. )

Mingyue Zhu ( Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, 3 Xueyuan Road, Longhua District, Haikou 571199, Hainan, P.R China. )

Mengsen Li ( Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, 3 Xueyuan Road, Longhua District, Haikou 571199, Hainan, P.R China; Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou 570311, Hainan, P.R China; Institution of Tumour, Hainan Medical College, Haikou 570102, Hainan, P.R China. )

https://doi.org/10.37155/2717-5278-2021-03-02-1

Abstract

Hepatocellular carcinoma (HCC) has a high increase, recurrence and mortality rate, but the signs of pathogenesis are not clear. At the time of diagnosis, most patients were advanced stage and missed the optimal period of surgical resection. Pharmacotherapy is the primary choice in this period, but the efficacy of anticancer drugs is poor and the patient survival rate is low. Drugs resistance is the primary cause of the poor efficacy of anticancer drugs. HCC cells have innate drugs resistance and acquired drugs resistance, and understanding the drugs resistance mechanism of HCC cells has an important help in the treatment of HCC. Alpha fetoprotein (AFP) is a tumor-associated protein, about 70% high expression of AFP in HCC patients, and AFP has a trait to induce malignant phenotype, stimulate cancer cells with a highly aggressive, antiapoptotic, proliferated phenotype, etc. AFP can also promote HCC drugs resistance through regulating the transduction of signaling pathways and ultimately lead to drugs resistance. This review analyze AFP influences the origination of cancer stem cells, promotes malignant phenotype of cancer cells, and the mechanism that promote HCC cells drugs resistance.

Keywords

Hepatocellular carcinoma; Alpha fetoprotein(AFP); Drugs resistance; Cancer stem cells; Malignant phenotype

Full Text

PDF

References

[1]Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN sstimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660.
[2]Kim DW, Talati C, Kim R. Hepatocellular carcinoma (HCC): beyond sorafenib-chemotherapy. J Gastrointest Oncol. 2017 Apr;8(2):256-265. doi: 10.21037/jgo.2016.09.07.
[3]He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020 Dec;132:110851. doi: 10.1016/j.biopha.2020.110851.[4]Liu X, Qin S. Immune checkpoint inhibitors in hepatocellular carcinoma: Opportunities and challenges. Oncologist. 2019 Feb; 24(Suppl 1):S3-S10. doi: 10.1634/theoncologist.2019-IO-S1-s01.
[5]Wei L, Wang X, Lv L, Liu J, Xing H, Song Y, Xie M, Lei T, Zhang N, Yang M. The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma. Mol Cancer. 2019 Oct 25;18(1):147. doi: 10.1186/s12943-019-1086-z.
[6]Wei L, Lee D, Law CT, Zhang MS, Shen J, Chin DW, Zhang A, Tsang FH, Wong CL, Ng IO, Wong CC, Wong CM. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun. 2019 Oct 15;10(1):4681. doi: 10.1038/s41467-019-12606-7.
[6]Wang X, Chen Y, Kuang H, Yang R, Chen D, Chen A, Feng Y, Dai J, Wang T, Wang Y. Associations between Maternal AFP and HCG and Preterm Birth. Am J Perinatol. 2019 Dec;36(14):1459-1463. doi: 10.1055/s-0038-1677017.
[7]García-García AG, Polo-Hernández E, Tabernero A, Medina JM. Alpha-fetoprotein (AFP) modulates the effect of serum albumin on brain development by restraining the neurotrophic effect of oleic acid. Brain Res. 2015 Oct 22;1624:45-58. doi: 10.1016/j.brainres.2015.07.021.
[8]Ishii T, Yasuchika K, Suemori H, Nakatsuji N, Ikai I, Uemoto S. Alpha-fetoprotein producing cells act as cancer progenitor cells in human cholangiocarcinoma. Cancer Lett. 2010 Aug 1;294(1):25-34. doi: 10.1016/j.canlet.2010.01.019.
[9]Yang X, Chen L, Liang Y, Si R, Jiang Z, Ma B, Gao P. Knockdown of alpha-fetoprotein expression inhibits HepG2 cell growth and induces apoptosis. J Cancer Res Ther. 2018 Sep;14(Supplement):S634-S643. doi: 10.4103/0973-1482.180681.
[10] Song S, Shi Y, Wu W, Wu H, Chang L, Peng P, Zhang L, Fan J, Gu J, Ruan Y. Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus. Gut. 2021 Nov;70(11):2159-2171. doi: 10.1136/gutjnl-2020-321386.
[11] Wilkinson DS, Ogden SK, Stratton SA, Piechan JL, Nguyen TT, Smulian GA, Barton MC. A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol. 2005 Feb; 25(3):1200-12. doi: 10.1128/MCB.25.3.1200-1212.2005.
[12] Xu GW, Sun ZT, Forrester K, Wang XW, Coursen J, Harris CC. Tissue-specific growth suppression and chemosensitivity promotion in human hepatocellular carcinoma cells by retroviral-mediated transfer of the wild-type p53 gene. Hepatology. 1996 Nov;24(5):1264-8. doi: 10.1002/hep.510240546.
[13] Li H, Liu Y, Jiang W, Xue J, Cheng Y, Wang J, Yang R, Zhang X. Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma. BMC Cancer. 2021 Mar 25;21(1):318. doi: 10.1186/s12885-021-08043-9.
[14] Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M. Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology. 2010 Sep;52(3):966-74. doi: 10.1002/hep.23769.
[15] Zhou X, Li R, Jing R, Zuo B, Zheng Q. Genome-wide CRISPR knockout screens identify ADAMTSL3 and PTEN genes as suppressors of HCC proliferation and metastasis, respectively. J Cancer Res Clin Oncol. 2020 Jun;146(6):1509-1521. doi: 10.1007/s00432-020-03207-9.
[16]Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009;102:19-65. doi: 10.1016/S0065-230X(09)02002-8.
[17]Wang SS, Chen YH, Chen N, Wang LJ, Chen DX, Weng HL, Dooley S, Ding HG. Hydrogen sulfide promotes autophagy of hepatocellular carcinoma cells through the PI3K/Akt/mTOR signaling pathway. Cell Death Dis. 2017 Mar 23;8(3):e2688. doi: 10.1038/cddis.2017.18.
[18]Li M, Li H, Li C, Guo L, Liu H, Zhou S, Liu X, Chen Z, Shi S, Wei J, McNutt MA, Li G. Cytoplasmic alpha-fetoprotein functions as a co-repressor in RA-RAR signaling to promote the growth of human hepatoma Bel 7402 cells. Cancer Lett. 2009 Nov 28;285(2):190-9. doi: 10.1016/j.canlet.2009.05.014.
[19] Li M, Li H, Li C, Zhou S, Guo L, Liu H, Jiang W, Liu X, Li P, McNutt MA, Li G. Alpha fetoprotein is a novel protein-binding partner for caspase-3 and blocks the apoptotic signaling pathway in human hepatoma cells. Int J Cancer. 2009 Jun 15;124(12):2845-54. doi: 10.1002/ijc.24272.
[20] Dudich E, Semenkova L, Dudich I, Gorbatova E, Tochtamisheva N, Tatulov E, Nikolaeva M, Sukhikh G. alpha-fetoprotein causes apoptosis in tumor cells via a pathway independent of CD95, TNFR1 and TNFR2 through activation of caspase-3-like proteases. Eur J Biochem. 1999 Dec;266(3):750-61. doi: 10.1046/j.1432-1327.1999.00868.x.
[21]Yang X, Zhang Y, Zhang L, Zhang L, Mao J. Silencing alpha-fetoprotein expression induces growth arrest and apoptosis in human hepatocellular cancer cell. Cancer Lett. 2008 Nov 28;271(2):281-93. doi: 10.1016/j.canlet.2008.06.017.
[22] Zhang L, He T, Cui H, Wang Y, Huang C, Han F. Effects of AFP gene silencing on apoptosis and proliferation of a hepatocellular carcinoma cell line. Discov Med. 2012 Aug;14(75):115-24.
[23] Si YQ, Wang XQ, Fan G, Wang CY, Zheng YW, Song X, Pan CC, Chu FL, Liu ZF, Lu BR, Lu ZM. Value of AFP and PIVKA-II in diagnosis of HBV-related hepatocellular carcinoma and prediction of vascular invasion and tumor differentiation. Infect Agent Cancer. 2020 Nov 23;15(1):70. doi: 10.1186/s13027-020-00337-0.
[24]Cucchetti A, Serenari M, Sposito C, Di Sandro S, Mosconi C, Vicentin I, Garanzini E, Mazzaferro V, De Carlis L, Golfieri R, Spreafico C, Vanzulli A, Buscemi V, Ravaioli M, Ercolani G, Pinna AD, Cescon M. Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant. J Hepatol. 2020 Aug;73(2):342-348. doi: 10.1016/j.jhep.2020.03.018.
[25] Cao Z, Cheng Y, Wang J, Liu Y, Yang R, Jiang W, Li H, Zhang X. HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression. J Exp Clin Cancer Res. 2021 Apr 1;40(1):118. doi: 10.1186/s13046-021-01881-2.
[26] Li M, Li H, Li C, Wang S, Jiang W, Liu Z, Zhou S, Liu X, McNutt MA, Li G. Alpha-fetoprotein: a new member of intracellular signal molecules in regulation of the PI3K/AKT signaling in human hepatoma cell lines. Int J Cancer. 2011 Feb 1;128(3):524-32. doi: 10.1002/ijc.25373
[27] Zhu M, Guo J, Xia H, Li W, Lu Y, Dong X, Chen Y, Xie X, Fu S, Li M. Alpha-fetoprotein activates AKT/mTOR signaling to promote CXCR4 expression and migration of hepatoma cells. Oncoscience. 2015 Jan 6;2(1):59-70. doi: 10.18632/oncoscience.115. eCollection 2015.
[28]Xue J, Cao Z, Cheng Y, Wang J, Liu Y, Yang R, Li H, Jiang W, Li G, Zhao W, Zhang X. Acetylation of alpha-fetoprotein promotes hepatocellular carcinoma progression. Cancer Lett. 2020 Feb 28;471:12-26. doi: 10.1016/j.canlet.2019.11.043.
[29]Bozkaya Y, Demirci NS, Kurtipek A, Erdem GU, Ozdemir NY, Zengin N. Clinicopathological and prognostic characteristics in patients with AFP-secretinggastric carcinoma. Mol Clin Oncol. 2017 Aug;7(2):267-274. doi: 10.3892/mco.2017.1288.
[30]Ren F, Weng W, Zhang Q, Tan C, Xu M, Zhang M, Wang L, Sheng W, Ni S, Huang D. Clinicopathological features and prognosis of AFP-producing colorectal cancer: a single-center analysis of 20 cases. Cancer Manag Res. 2019 May 16;11:4557-4567. doi: 10.2147/CMAR.S196919.
[31] Zhangyuan G, Wang F, Zhang H, Jiang R, Tao X, Yu D, Jin K, Yu W, Liu Y, Yin Y, Shen J, Xu Q, Zhang W, Sun B. VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR-PI3K-AKT pathway. Oncogene. 2020 Feb;39(6):1213-1230. doi: 10.1038/s41388-019-1052-7.
[32] Huang JL, Cao SW, Ou QS, Yang B, Zheng SH, Tang J, Chen J, Hu YW, Zheng L, Wang Q. The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma. Mol Cancer. 2018 May 26;17(1):93. doi: 10.1186/s12943-018-0841-x.
[33] Lu Y, Li X, Liu H, Xue J, Zeng Z, Dong X, Zhang T, Wu G, Yang K, Xu S. Beta-Trcp and CK1delta-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma. Oncogene. 2021 Feb;40(7):1269-1283. doi: 10.1038/s41388-020-01596-2.
[34] Lu Y, Zhu M, Li W, Lin B, Dong X, Chen Y, Xie X, Guo J, Li M. Alpha fetoprotein plays a critical role in promoting metastasis of hepatocellular carcinoma cells. J Cell Mol Med. 2016 Mar;20(3):549-58. doi: 10.1111/jcmm.12745.
[35] Lima LDP, Machado CJ, Rodrigues JBSR, Vasconcellos LS, Junior EP, Vidigal PVT, Resende V. Immunohistochemical coexpression of epithelial cell adhesion molecule and alpha-Fetoprotein in hepatocellular carcinoma. Can J Gastroenterol Hepatol. 2018 Jul 19;2018:5970852. doi: 10.1155/2018/5970852. eCollection 2018.
[36] Qin LX, Tang ZY. Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature. J Cancer Res Clin Oncol. 2004 Sep;130(9):497-513. doi: 10.1007/s00432-004-0572-9.
[37] Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006 Nov 3;127(3):469-80. doi: 10.1016/j.cell.2006.10.018.
[38] Steinhart Z, Angers S. Wnt signaling in development and tissue homeostasis. Development. 2018 Jun 8;145(11):dev146589. doi: 10.1242/dev.146589.
[39] Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, Bujanda L, Banales JM. Wnt-beta-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019 Feb;16(2):121-136. doi: 10.1038/s41575-018-0075-9.
[40] Kim W, Khan SK, Gvozdenovic-Jeremic J, Kim Y, Dahlman J, Kim H, Park O, Ishitani T, Jho EH, Gao B, Yang Y. Hippo signaling interactions with Wnt/beta-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest. 2017 Jan 3;127(1):137-152. doi: 10.1172/JCI88486.
[41] Fu X, Zhu X, Qin F, Zhang Y, Lin J, Ding Y, Yang Z, Shang Y, Wang L, Zhang Q, Gao Q. Linc00210 drives Wnt/beta-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner. Mol Cancer. 2018 Mar 14;17(1):73. doi: 10.1186/s12943-018-0783-3.
[42]Fan Z, Duan J, Wang L, Xiao S, Li L, Yan X, Yao W, Wu L, Zhang S, Zhang Y, Li Y, Zhu X, Hu Y, Zhang D, Jiao S, Xu X. PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/beta-catenin signaling. Cancer Lett. 2019 May 28;450:132-143. doi: 10.1016/j.canlet.2019.02.040.
[43] Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY,Wang XW. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009 Mar;136(3):1012-24. doi: 10.1053/j.gastro.2008.12.004.
[44]Yassin NYS, AbouZid SF, El-Kalaawy AM, Ali TM, Almehmadi MM, Ahmed OM. Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/beta-catenin, and PI3K/Akt/mTOR signaling pathways. Biomed Pharmacother. 2021 Nov 12;145:112409. doi: 10.1016/j.biopha.2021.112409. Online ahead of print.
[45] Terris B, Cavard C, Perret C. EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma. J Hepatol. 2010 Feb;52(2):280-1. doi: 10.1016/j.jhep.2009.10.026.
[46] Lin B, Zhu M, Wang W, Li W, Dong X, Chen Y, Lu Y, Guo J, Li M. Structural basis for alpha fetoprotein-mediated inhibition of caspase-3 activity inhepatocellular carcinoma cells. Int J Cancer. 2017 Oct 1;141(7):1413-1421. doi:10.1002/ijc.30850. Epub 2017 Jul 7.
[47]Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018 Oct;15(10):599-616. doi: 10.1038/s41571-018-0073-4.
[48]Zhu YJ, Zheng B, Wang HY, Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 2017 May;38(5):614-622. doi: 10.1038/aps.2017.5.
[49]Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006 Dec 15;66(24):11851-8. doi: 10.1158/0008-5472.
[50]Blivet-Van Eggelpoel MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, Priam S, Housset C, Rosmorduc O, Desbois-Mouthon C. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012 Jul;57(1):108-15. doi: 10.1016/j.jhep.2012.02.019.
[51]Sheen IS, Jeng KS, Shih SC, Kao CR, Chang WH, Wang HY, Wang PC, Wang TE, Shyung LR, Chen CZ. Clinical significance of the expression of isoform 165 vascular endothelial growth factor mRNA in noncancerous liver remnants of patients with hepatocellular carcinoma. World J Gastroenterol. 2005 Jan 14;11(2):187-92. doi: 10.3748/wjg.v11.i2.187.
[52]Kessler SM, Laggai S, Barghash A, Schultheiss CS, Lederer E, Artl M, Helms V, Haybaeck J, Kiemer AK. IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype. Cell Death Dis. 2015 Oct 1;6(10):e1894. doi: 10.1038/cddis.2015.241.
[53]Carr BI, Guerra V, Giannini EG, Farinati F, Ciccarese F, Rapaccini GL, Di Marco M, Benvegn L, Zoli M, Borzio F, Caturelli E, Chiaramonte M, Trevisani F. Significance of platelet and AFP levels and liver function parameters for HCC size and survival. Int J Biol Markers. 2014 Sep 30;29(3):e215-23. doi: 10.5301/jbm.5000064.
[54]Wang H, Li W, Jin X, Cui S, Zhao L. LIM and SH3 protein 1, a promoter of cell proliferation and migration, is a novel independent prognostic indicator in hepatocellular carcinoma. Eur J Cancer. 2013 Mar;49(4):974-83. doi: 10.1016/j.ejca.2012.09.032.
[55]Saidak Z, Giacobbi AS, Louandre C, Sauzay C, Mammeri Y, Galmiche A. Mathematical modelling unveils the essential role of cellular phosphatases in the inhibition of RAF-MEK-ERK signalling by sorafenib in hepatocellular carcinoma cells. Cancer Lett. 2017 Apr 28;392:1-8. doi: 10.1016/j.canlet.2017.01.038.
[56] Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, Wang Q, Wang S, Rong D, Reiter FP, De Toni EN, Wang X. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020 Jun 10;5(1):87. doi: 10.1038/s41392-020-0187-x.
[57] Lu S, Yao Y, Xu G, Zhou C, Zhang Y, Sun J, Jiang R, Shao Q, Chen Y. CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis. 2018 May 29;9(6):646. doi: 10.1038/s41419-018-0681-z.
[58] Ji L, Lin Z, Wan Z, Xia S, Jiang S, Cen D, Cai L, Xu J, Cai X. miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR. Cell Death Dis. 2020 Apr 20;11(4):250. doi: 10.1038/s41419-020-2413-4.
[59] Kuczynski EA, Yin M, Bar-Zion A, Lee CR, Butz H, Man S, Daley F, Vermeulen PB, Yousef GM, Foster FS, Reynolds AR, Kerbel RS. Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma. J Natl Cancer Inst. 2016 Apr 8;108(8):djw030. doi: 10.1093/jnci/djw030.
[60] Dai J, Huang Q, Niu K, Wang B, Li Y, Dai C, Chen Z, Tao K, Dai J. Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma. Cancer Med. 2018 Nov;7(11):5691-5703. doi: 10.1002/cam4.1826.
[61] Galle PR, Foerster F, Kudo M, Chan SL, Llovet JM, Qin S, Schelman WR, Chintharlapalli S, Abada PB, Sherman M, Zhu AX. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int. 2019 Dec;39(12):2214-2229. doi: 10.1111/liv.14223.
[62] Shan YF, Huang YL, Xie YK, Tan YH, Chen BC, Zhou MT, Shi HQ, Yu ZP, Song QT, Zhang QY. Angiogenesis and clinicopathologic characteristics in different hepatocellular carcinoma subtypes defined by EpCAM and alpha-fetoprotein expression status. Med Oncol. 2011 Dec;28(4):1012-6. doi: 10.1007/s12032-010-9600-6.
[63]Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J Hepatol. 2017 Nov;67(5):999-1008. doi: 10.1016/j.jhep.2017.06.026.
[64]Personeni N, Bozzarelli S, Pressiani T, Rimassa L, Tronconi MC, Sclafani F, Carnaghi C, Pedicini V, Giordano L, Santoro A. Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2012 Jul;57(1):101-7. doi: 10.1016/j.jhep.2012.02.016.
[65]Negri F, Gnetti L, Pedrazzi G, Silini EM, Porta C. Sorafenib and hepatocellular carcinoma: is alpha-fetoprotein a biomarker predictive of tumor biology and primary resistance. Future Oncol. 2021 Sep;17(27):3579-3584. doi: 10.2217/fon-2021-0083.
[66] Vu NB, Nguyen TT, Tran LC, Do CD, Nguyen BH, Phan NK, Pham PV. Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem-like properties. Cytotechnology. 2013 Aug;65(4):491-503. doi: 10.1007/s10616-012-9511-9.
[67] Chang AY, Wang M. In-vitro growth inhibition of chemotherapy and molecular targeted agents in hepatocellular carcinoma. Anticancer Drugs. 2013 Mar;24(3):251-9. doi: 10.1097/CAD.0b013e32835ba289.
[68]Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643.
[69]Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. doi: 10.1016/S0140-6736(16)00587-0.
[70] Cheng AL, Hsu C, Chan SL, Choo SP, Kudo M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol. 2020 Feb;72(2):307-319. doi: 10.1016/j.jhep.2019.09.025.
[71] Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett. 2020 Feb 1;470:8-17. doi: 10.1016/j.canlet.2019.12.002.
[72] Lee PC, Chao Y, Chen MH, Lan KH, Lee CJ, Lee IC, Chen SC, Hou MC, Huang YH. Predictors of Response and Survival in Immune Checkpoint Inhibitor-Treated Unresectable Hepatocellular Carcinoma. Cancers (Basel). 2020 Jan 11;12(1):182. doi: 10.3390/cancers12010182.
[73] Shao YY, Liu TH, Hsu C, Lu LC, Shen YC, Lin ZZ, Cheng AL, Hsu CH. Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma. Liver Int. 2019 Nov;39(11):2184-2189. doi: 10.1111/liv.14210.
[74]Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene. 2006 Jun 26;25(27):3866-84. doi: 10.1038/sj.onc.1209550.
[75] Li C, Song B, Santos PM, Butterfield LH. Hepatocellular cancer-derived alpha fetoprotein uptake reduces CD1 molecules on monocyte-derived dendritic cells. Cell Immunol. 2019 Jan;335:59-67. doi: 10.1016/j.cellimm.2018.10.011
[76] Pardee AD, Shi J, Butterfield LH. Tumor-derived alpha-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. J Immunol. 2014 Dec 1;193(11):5723-32. doi: 10.4049/jimmunol.1400725.
[77]Li MS, Ma QL, Chen Q, Liu XH, Li PF, Du GG, Li G. 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. 2005 May 7;11(17):2564-9. doi: 10.3748/wjg.v11.i17.2564.
[78] Zamorina SA, Litvinova LS, Yurova KA, Khaziakhmatova OG, Timganova VP, Bochkova MS, Khramtsov PV, Raev MB, Chereshnev VA. Role of alpha-fetoprotein in regulation of proliferation and functional activity of naive T cells and immune memory T cells. Bull Exp Biol Med. 2019 Aug;167(4):470-474. doi: 10.1007/s10517-019-04552-7.
[79] Santos PM, Menk AV, Shi J, Tsung A, Delgoffe GM, Butterfield LH. Tumor-derived alpha-fetoprotein suppresses fatty acid metabolism and oxidative phosphorylation in dendritic cells. Cancer Immunol Res. 2019 Jun;7(6):1001-1012. doi: 10.1158/2326-6066.CIR-18-0513.
[80] Ritter M, Ali MY, Grimm CF, Weth R, Mohr L, Bocher WO, Endrulat K, Wedemeyer H, Blum HE, Geissler M. Immunoregulation of dendritic and T cells by alpha-fetoprotein in patients with hepatocellular carcinoma. J Hepatol. 2004 Dec;41(6):999-1007. doi: 10.1016/j.jhep.2004.08.013.
[81] Wang X, Wang Q. Alpha-fetoprotein and hepatocellular carcinoma immunity. Can J Gastroenterol Hepatol. 2018 Apr 1;2018:9049252. doi: 10.1155/2018/9049252. eCollection 2018.
[82]Lu Z, Zuo B, Jing R, Gao X, Rao Q, Liu Z, Qi H, Guo H, Yin H. Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models. J Hepatol. 2017 Oct;67(4):739-748. doi: 10.1016/j.jhep.2017.05.019.
[83]Drake LE, Springer MZ, Poole LP, Kim CJ, Macleod KF. Expanding perspectives on the significance of mitophagy in cancer. Semin Cancer Biol. 2017 Dec;47:110-124. doi: 10.1016/j.semcancer.2017.04.008.
[84]Zong WX, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016 Mar 3;61(5):667-676. doi: 10.1016/j.molcel.2016.02.011.
[85]Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017 May 2;25(5):1037-1043. doi: 10.1016/j.cmet.2017.04.004.
[86]Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005 Sep;5(9):726-34. doi: 10.1038/nrc1692.
[87]Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, DiPaola RS, Lotze MT, White E. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011 Feb 15;17(4):654-66. doi: 10.1158/1078-0432.CCR-10-2634.
[88]Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017 Sep;17(9):528-542. doi: 10.1038/nrc.2017.53.
[89] Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020 Jan 22;19(1):12. doi: 10.1186/s12943-020-1138-4.
[90] Ye R, Dai N, He Q, Guo P, Xiang Y, Zhang Q, Hong Z, Zhang Q. 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. 2018 Sep;105:962-973. doi: 10.1016/j.biopha.2018.06.065.
[91]Ajabnoor GM, Crook T, Coley HM. Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells. Cell Death Dis. 2012 Jan 26;3(1):e260. doi: 10.1038/cddis.2011.139.
[92] Qadir MA, Kwok B, Dragowska WH, To KH, Le D, Bally MB, Gorski SM. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cellsand enhances mitochondrial depolarization. Breast Cancer Res Treat. 2008 Dec;112(3):389-403. doi: 10.1007/s10549-007-9873-4.
[93]Qu X, Sheng J, Shen L, Su J, Xu Y, Xie Q, Wu Y, Zhang X, Sun L. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells bymitochondrial ROS. PLoS One. 2017 Mar 16;12(3):e0173712. doi: 10.1371/journal.pone.0173712.
[94]Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011 Sep;10(9):1533-41. doi: 10.1158/1535-7163.MCT-11-0047.
[95]Kumar A, Singh UK, Chaudhary A. Targeting autophagy to overcome drug resistance in cancer therapy. Future Med Chem. 2015 Aug;7(12):1535-42. doi: 10.4155/fmc.15.88.
[96]Aredia F, Scovassi AI. Manipulation of autophagy in cancer cells: an innovative strategy to fight drug resistance. Future Med Chem. 2013 Jun;5(9):1009-21. doi: 10.4155/fmc.13.85.
[97] Wang S, Zhu M, Wang Q, Hou Y, Li L, Weng H, Zhao Y, Chen D, Ding H, Guo J, Li M. Alpha-fetoprotein inhibits autophagy to promote malignant behaviour in hepatocellular carcinoma cells by activating PI3K/AKT/mTOR signalling. Cell Death Dis. 2018 Oct 9;9(10):1027. doi: 10.1038/s41419-018-1036-5.
[98]Wu FQ, Fang T, Yu LX, Lv GS, Lv HW, Liang D, Li T, Wang CZ, Tan YX, Ding J, Chen Y, Tang L, Guo LN, Tang SH, Yang W, Wang HY. ADRB2 signaling promotes HCC progression and sorafenib resistance by inhibiting autophagic degradation of HIF1a. J Hepatol. 2016 Aug;65(2):314-24. doi: 10.1016/j.jhep.2016.04.019.
[99] Cao W, Liu X, Zhang Y, Li A, Xie Y, Zhou S, Song L, Xu R, Ma Y, Cai S, Tang X. BEZ235 increases the sensitivity of hepatocellular carcinoma to sorafenib by inhibiting PI3K/AKT/mTOR and inducing autophagy. Biomed Res Int. 2021 Apr 16;2021:5556306. doi: 10.1155/2021/5556306. eCollection 2021.
[100]Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis. 2010 Feb;30(1):35-51. doi: 10.1055/s-0030-1247131.
[101]Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015 Oct;149(5):1226-1239.e4. doi: 10.1053/j.gastro.2015.05.061.
[102] Makowska Z, Boldanova T, Adametz D, Quagliata L, Vogt JE, Dill MT, Matter MS, Roth V, Terracciano L, Heim MH. Gene expression analysis of biopsy samples reveals critical limitations of transcriptome-based molecular classifications of hepatocellular carcinoma. J Pathol Clin Res. 2016 Feb 5;2(2):80-92. doi: 10.1002/cjp2.37.
[103]Yang C, Huang X, Liu Z, Qin W, Wang C. Metabolism-associated molecular classification of hepatocellular carcinoma. Mol Oncol. 2020 Apr;14(4):896-913. doi: 10.1002/1878-0261.12639.
[104]Zhang C, Li J, Huang T, Duan S, Dai D, Jiang D, Sui X, Li D, Chen Y, Ding F, Huang C, Chen G, Wang K. Meta-analysis of DNA methylation biomarkers in hepatocellular carcinoma. Oncotarget. 2016 Dec 6;7(49):81255-81267. doi: 10.18632/oncotarget.13221.
[105]Nishida N, Nishimura T, Nagasaka T, Ikai I, Goel A, Boland CR. Extensive methylation is associated with beta-catenin mutations in hepatocellular carcinoma: evidence for two distinct pathways of human hepatocarcinogenesis. Cancer Res. 2007 May 15;67(10):4586-94. doi: 10.1158/0008-5472.CAN-06-3464.
[106] El-Bendary M, Nour D, Arafa M, Neamatallah M. Methylation of tumour suppressor genes RUNX3, RASSF1A and E-Cadherin in HCV-related liver cirrhosis and hepatocellular carcinoma. Br J Biomed Sci. 2020 Jan;77(1):35-40. doi: 10.1080/09674845.2019.1694123.
[107] Chen W, Peng J, Ye J, Dai W, Li G, He Y. Aberrant AFP expression characterizes a subset of hepatocellular carcinoma with distinct gene expression patterns and inferior prognosis. J Cancer. 2020 Jan 1;11(2):403-413. doi: 10.7150/jca.31435. eCollection 2020.
[108] Han LY, Fan YC, Mu NN, Gao S, Li F, Ji XF, Dou CY, Wang K. Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a potential biomarker for hepatitis B Virus associated hepatocellular carcinoma. Int J Med Sci. 2014 Jan 7;11(2):164-71. doi: 10.7150/ijms.6745. eCollection 2014.
[109] Cui R, Nguyen TT, Taube JH, Stratton SA, Feuerman MH, Barton MC. Family members p53 and p73 act together in chromatin modification and direct repression of alpha-fetoprotein transcription. J Biol Chem. 2005 Nov 25;280(47):39152-60. doi: 10.1074/jbc.M504655200.
[110]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.

Copyright © 2021 Mengsen Li, Mingyue Zhu, Xue Shan, Minni Zhang, Haifeng Lin Creative Commons License Publishing time:2021-12-30
This work is licensed under a Creative Commons Attribution 4.0 International License