Abstract
Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and a major cause of cancer-related deaths worldwide because of its high recurrence rate and poor prognosis. Surgical resection is currently the major treatment measure for patients in the early and middle stages of the disease. Because due to late diagnosis, most patients already miss the opportunity for surgery upon disease confirmation, conservative chemotherapy (drug treatment) remains an important method of comprehensive treatment for patients with middle- and late-stage liver cancer. However, multidrug resistance (MDR) in patients with HCC severely reduces the treatment effect and is an important obstacle to chemotherapeutic success. Alpha-fetoprotein (AFP) is an important biomarker for the diagnosis of HCC. The serum expression levels of AFP in many patients with HCC are increased, and a persistently increased AFP level is a risk factor for HCC progression. Many studies have indicated that AFP functions as an immune suppressor, and AFP can promote malignant transformation during HCC development and might be involved in the process of MDR in patients with liver cancer. This review describes drug resistance mechanisms during HCC drug treatment and reviews the relationship between the mechanism of AFP in HCC development and progression and HCC drug resistance.
Keywords: Hepatocellular carcinoma (HCC), Alphafetoprotein (AFP), malignant transformation, drug resistance, immune suppressor, multidrug resistance (MDR).
[http://dx.doi.org/10.1038/nrdp.2016.18] [PMID: 27158749]
[http://dx.doi.org/10.1053/j.gastro.2015.05.061 ] [PMID: 26099527]
[http://dx.doi.org/10.1016/S0168-8278(01)00130-1] [PMID: 11592607]
[http://dx.doi.org/10.1016/j.ejca.2004.02.027] [PMID: 15196530]
[http://dx.doi.org/10.1111/apt.14913] [PMID: 30039640]
[http://dx.doi.org/10.1038/s41571-018-0073-4] [PMID: 30061739]
[http://dx.doi.org/10.1016/j.clinre.2017.12.006] [PMID: 29544679]
[http://dx.doi.org/10.1634/theoncologist.2015-0478] [PMID: 27185615]
[http://dx.doi.org/10.1016/S0076-6879(05)07047-3] [PMID: 16757355]
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1377] [PMID: 17178882]
[http://dx.doi.org/10.1038/sj.leu.2404508] [PMID: 17205056]
[http://dx.doi.org/10.1038/nrd2130] [PMID: 17016424]
[http://dx.doi.org/10.1056/NEJMoa0708857] [PMID: 18650514]
[http://dx.doi.org/10.1016/S1470-2045(08)70285-7] [PMID: 19095497]
[http://dx.doi.org/10.1002/ijc.27604] [PMID: 22514082]
[http://dx.doi.org/10.1016/j.jhep.2012.02.019] [PMID: 22414764]
[http://dx.doi.org/10.1158/1535-7163.MCT-13-1043] [PMID: 24705351]
[http://dx.doi.org/10.3727/096504017X14886444100783] [PMID: 28276313]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0937] [PMID: 27634758]
[PMID: 21187475]
[http://dx.doi.org/10.1124/jpet.110.175786] [PMID: 21205925]
[http://dx.doi.org/10.1016/j.jss.2016.08.014] [PMID: 27884331]
[http://dx.doi.org/10.1038/srep22976] [PMID: 26964667]
[http://dx.doi.org/10.1371/journal.pone.0174153] [PMID: 28323861]
[http://dx.doi.org/10.1038/bjc.2012.145] [PMID: 22596232]
[http://dx.doi.org/10.1016/j.jhep.2009.12.024] [PMID: 20347499]
[http://dx.doi.org/10.1002/hep.23836] [PMID: 20799354]
[http://dx.doi.org/10.7785/tcrt.2012.500364] [PMID: 23862748]
[http://dx.doi.org/10.1159/000485285] [PMID: 29169150]
[http://dx.doi.org/10.3390/molecules21070965] [PMID: 27455225]
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0917] [PMID: 21364009]
[http://dx.doi.org/10.1371/journal.pone.0078675] [PMID: 24244338]
[http://dx.doi.org/10.1016/j.canlet.2012.10.021] [PMID: 23111106]
[http://dx.doi.org/10.3390/ijms18091854] [PMID: 28841148]
[http://dx.doi.org/10.1002/hep.26224] [PMID: 23299930]
[http://dx.doi.org/10.1016/j.cellsig.2014.01.026] [PMID: 24486412]
[http://dx.doi.org/10.3892/ol.2015.3315] [PMID: 26622569]
[http://dx.doi.org/10.1038/mt.2008.254] [PMID: 19066601]
[http://dx.doi.org/10.1089/scd.2011.0012] [PMID: 21651381]
[http://dx.doi.org/10.1002/ijc.29097] [PMID: 25053293]
[http://dx.doi.org/10.1016/j.jhep.2010.12.043] [PMID: 21334406]
[http://dx.doi.org/10.1634/theoncologist.2019-IO-S1-s01] [PMID: 30819826]
[http://dx.doi.org/10.1016/S0140-6736(15)01281-7] [PMID: 26712084]
[http://dx.doi.org/10.1056/NEJMoa1507643] [PMID: 26412456]
[http://dx.doi.org/10.1056/NEJMoa1504627] [PMID: 26028407]
[http://dx.doi.org/10.1016/S0140-6736(16)00587-0] [PMID: 26970723]
[http://dx.doi.org/10.4049/jimmunol.177.2.1052] [PMID: 16818761]
[http://dx.doi.org/10.1002/j.1460-2075.1992.tb05481.x] [PMID: 1396582]
[http://dx.doi.org/10.1084/jem.192.7.1027] [PMID: 11015443]
[http://dx.doi.org/10.1084/jem.20051776] [PMID: 16606670]
[http://dx.doi.org/10.1053/j.gastro.2008.05.076] [PMID: 18621049]
[http://dx.doi.org/10.1002/hep.23173] [PMID: 19739236]
[http://dx.doi.org/10.1016/j.jhep.2012.09.008] [PMID: 22989568]
[http://dx.doi.org/10.1002/hep.21965] [PMID: 17975811]
[http://dx.doi.org/10.1002/hep.20488] [PMID: 15565659]
[http://dx.doi.org/10.1016/j.cell.2017.01.017] [PMID: 28187290]
[http://dx.doi.org/10.1016/j.ctrv.2016.11.007] [PMID: 27951441]
[http://dx.doi.org/10.3390/ijms19051340] [PMID: 29724044]
[http://dx.doi.org/10.1111/1759-7714.13023] [PMID: 30810279]
[http://dx.doi.org/10.1159/000505933] [PMID: 32101878]
[http://dx.doi.org/10.1111/hepr.13496] [PMID: 32088930]
[http://dx.doi.org/10.1016/j.jhep.2019.09.025] [PMID: 31954494]
[http://dx.doi.org/10.1038/s41388-019-1072-3] [PMID: 31659256]
[http://dx.doi.org/10.1002/hep.30889] [PMID: 31378984]
[http://dx.doi.org/10.1158/2159-8290.CD-19-0074] [PMID: 31186238]
[http://dx.doi.org/10.1159/000339016] [PMID: 24159567]
[PMID: 10626187]
[http://dx.doi.org/10.1016/S0168-8278(01)00025-3] [PMID: 11394662]
[http://dx.doi.org/10.1016/S1499-3872(16)60095-4] [PMID: 27498576]
[http://dx.doi.org/10.1101/cshperspect.a021444] [PMID: 25646384]
[http://dx.doi.org/10.1016/S0167-4838(00)00104-7] [PMID: 11004554]
[http://dx.doi.org/10.7150/jca.13628] [PMID: 27313784]
[PMID: 27448785]
[http://dx.doi.org/10.1371/journal.pone.0090660] [PMID: 24587407]
[http://dx.doi.org/10.1002/ijc.24272] [PMID: 19267404]
[PMID: 26612738]
[http://dx.doi.org/10.1016/j.jhep.2004.08.013] [PMID: 15582134]
[http://dx.doi.org/10.3748/wjg.v11.i17.2564] [PMID: 15849812]
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2175] [PMID: 22374331]
[http://dx.doi.org/10.1158/0008-5472.CAN-07-6013] [PMID: 18316609]
[http://dx.doi.org/10.1007/s12032-010-9600-6] [PMID: 20571936]
[http://dx.doi.org/10.3748/wjg.v17.i41.4563] [PMID: 22147961]
[http://dx.doi.org/10.3748/wjg.v10.i6.819] [PMID: 15040024]
[http://dx.doi.org/10.3748/wjg.v8.i3.469] [PMID: 12046072]
[http://dx.doi.org/10.1016/j.canlet.2008.06.017] [PMID: 18657899]
[http://dx.doi.org/10.1016/S0168-8278(00)80193-2] [PMID: 10673071]
[http://dx.doi.org/10.1002/ijc.25373] [PMID: 20473866]
[http://dx.doi.org/10.1038/gt.2010.34] [PMID: 20336154]
[PMID: 22935208]
[http://dx.doi.org/10.18632/oncotarget.12407] [PMID: 27716619]
[http://dx.doi.org/10.1016/j.canlet.2008.01.027] [PMID: 18407409]
[http://dx.doi.org/10.4103/0973-1482.180681] [PMID: 30249880]
[http://dx.doi.org/10.4238/2015.April.10.30] [PMID: 25966084]
[http://dx.doi.org/10.1016/j.canlet.2009.05.014] [PMID: 19501957]
[http://dx.doi.org/10.1002/ijc.26025] [PMID: 21365646]
[http://dx.doi.org/10.1016/j.jhep.2012.03.029] [PMID: 22521346]
[http://dx.doi.org/10.1111/jcmm.12745] [PMID: 26756858]
[http://dx.doi.org/10.1159/000341697] [PMID: 23108304]
[http://dx.doi.org/10.1155/2018/9049252] [PMID: 29805966]
[http://dx.doi.org/10.4049/jimmunol.1400725] [PMID: 25355916]
[http://dx.doi.org/10.1016/j.taap.2008.03.012] [PMID: 18495191]
[http://dx.doi.org/10.1111/liv.12284] [PMID: 23998316]
[http://dx.doi.org/10.1038/267257a0]] [PMID: 68439]
[PMID: 6173421]
[http://dx.doi.org/10.1007/978-1-4615-1891-4_27] [PMID: 8644510]
[http://dx.doi.org/10.1016/S0161-5890(01)00017-7] [PMID: 11395133]
[http://dx.doi.org/10.1177/153537020122600503] [PMID: 11393167]
[http://dx.doi.org/10.1038/32588] [PMID: 9521319]
[http://dx.doi.org/10.1016/S0092-8674(01)00449-4] [PMID: 11509172]
[http://dx.doi.org/10.1006/scbi.2001.0400] [PMID: 11926410]
[http://dx.doi.org/10.4049/jimmunol.173.3.1772] [PMID: 15265907]
[http://dx.doi.org/10.1016/j.humimm.2009.12.010] [PMID: 20036295]
[http://dx.doi.org/10.1111/j.1478-3231.2005.01235.x] [PMID: 16584401]
[http://dx.doi.org/10.1155/2011/249281] [PMID: 21969837]
[http://dx.doi.org/10.2147/OTT.S97941] [PMID: 27499636]
[http://dx.doi.org/10.1016/j.bpg.2014.07.018] [PMID: 25260312]
[http://dx.doi.org/10.1016/j.jns.2008.12.014] [PMID: 19171355]
[http://dx.doi.org/10.1080/2162402X.2015.1008355] [PMID: 26155417]
[http://dx.doi.org/10.11569/wcjd.v22.i16.2277]
[http://dx.doi.org/10.1002/ijc.30850] [PMID: 28653316]
[http://dx.doi.org/10.3748/wjg.v24.i41.4643] [PMID: 30416312]
[http://dx.doi.org/10.1016/j.virusres.2006.06.010] [PMID: 16872708]
[http://dx.doi.org/10.1002/ijc.30553] [PMID: 27925189]
[http://dx.doi.org/10.1038/s41419-018-1036-5] [PMID: 30301886]
[http://dx.doi.org/10.1002/hep.28710] [PMID: 27359084]
[http://dx.doi.org/10.1186/s40425-018-0394-y] [PMID: 30208947]
[http://dx.doi.org/10.1016/j.tranon.2018.02.014] [PMID: 29525633]
[http://dx.doi.org/10.1136/gutjnl-2013-306627] [PMID: 24531850]
[PMID: 21346848]
[http://dx.doi.org/10.2147/JHC.S114198] [PMID: 27703963]
[http://dx.doi.org/10.7150/jca.22176] [PMID: 29344274]
[http://dx.doi.org/10.1111/j.1365-2249.2010.04246.x] [PMID: 21087443]
[http://dx.doi.org/10.3892/ijo.2012.1626] [PMID: 22971679]
[PMID: 14676113]
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[http://dx.doi.org/10.1002/hep.29844] [PMID: 29443377]
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1203] [PMID: 27535982]