Interplay of autophagy and cancer stem cells in hepatocellular carcinoma

24 April 2021


Magdelyn Mei‑Theng Wong, Hui‑Yin Chan, Norazlin Abdul Aziz, Thamil Selvee Ramasamy, Jan‑Jin Bong, Ewe Seng Ch’ng, Subasri Armon, Suat‑Cheng Peh, Sin‑Yeang Teow


Abstract

Liver cancer is the sixth most common cancer and the fourth leading cause of cancer deaths in the world. The most common type of liver cancers is hepatocellular carcinoma (HCC). Autophagy is the cellular digestion of harmful components by sequestering the waste products into autophagosomes followed by lysosomal degradation for the maintenance of cellular homeostasis. The impairment of autophagy is highly associated with the development and progression of HCC although autophagy may be involved in tumour-suppressing cellular events. In regards to its protecting role, autophagy also shelters the cells from anoikis- a programmed cell death in anchorage-dependent cells detached from the surrounding extracellular matrix which facilitates metastasis in HCC. Liver cancer stem cells (LCSCs) have the ability for self-renewal and differentiation and are associated with the development and progression of HCC by regulating stemness, resistance and angiogenesis. Interestingly, autophagy is also known to regulate normal stem cells by promoting cellular survival and differentiation and maintaining cellular homeostasis. In this review, we discuss the basal autophagic mechanisms and double-faceted roles of autophagy as both tumour suppressor and tumour promoter in HCC, as well as its association with and contribution to self-renewal and differentiation of LCSCs.


Reference

  1. Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7:961–967. https://doi.org/10.1038/nrc2254
  2. King JS (2012) Autophagy across the eukaryotes: is S. cerevisiae the odd one out? Autophagy 8:1159–1162. https://doi.org/10.4161/auto.20527
  3. Tsukada M, Ohsumi Y (1993) Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 333:169–174. https://doi.org/10.1016/0014-5793(93)80398-e
  4. Abounit K, Scarabelli TM, McCauley RB (2012) Autophagy in mammalian cells. World J Biol Chem 3:1–6. https://doi.org/10.4331/wjbc.v3.i1.1
  5. Weidberg H, Shvets E, Elazar Z (2011) Biogenesis and cargo selectivity of autophagosomes. Annu Rev Biochem 80:125–156. https://doi.org/10.1146/annurev-biochem-052709-094552
  6. Lee MS (2014) Role of islet β cell autophagy in the pathogenesis of diabetes. Trends Endocrinol Metab 25:620–627. https://doi.org/10.1016/j.tem.2014.08.005
  7. Yun CW, Lee SH (2018) The roles of autophagy in cancer. Int J Mol Sci 19:3466. https://doi.org/10.3390/ijms19113466
  8. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492
  9. Raihan R, Azzeri A, Shabaruddin FH, Mohamed R (2018) Hepatocellular carcinoma in Malaysia and its changing trend. Euroasian J Hepatogastroenterol 8:54–56. https://doi.org/10.5005/jp-journals-10018-1259
  10. Montella M, Crispo A, Giudice A (2011) HCC, diet, and metabolic factors. Hepat Mon 11:159–162
  11. Bartosch B (2010) Hepatitis B and C viruses and hepatocellular carcinoma. Viruses 2:1504–1509. https://doi.org/10.3390/v2081504
  12. Chisari FV, Isogawa M, Wieland SF (2010) Pathogenesis of hepatitis B virus infection. Parodontol 58:258–266. https://doi.org/10.1016/j.patbio.2009.11.001
  13. Irshad M, Mankotia DS, Irshad K (2013) Diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol 19:7896–7909. https://doi.org/10.3748/wjg.v19.i44.7896
  14. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576. https://doi.org/10.1053/j.gastro.2007.04.061
  15. Heidelbaugh JJ, Bruderly M (2006) Cirrhosis and chronic liver failure: Part I. Diagnosis and evaluation. Am Fam Physician 74:756–762
  16. Sengupta S, Parikh ND (2017) Biomarker development for hepatocellular carcinoma early detection. Hepatic Oncol 4:111–122. https://doi.org/10.2217/hep-2017-0019
  17. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, Gores G (2016) Hepatocellular carcinoma. Nat Rev Dis Prim 2:16018. https://doi.org/10.1038/nrdp.2016.18
  18. Llovet JM, Fuster BJ (2004) The Barcelona approach. Liver Transplant 10:S115–120. https://doi.org/10.1002/lt.20034
  19. Santopaolo F, Lenci I, Milana M, Manzia TM, Baiocchi L (2019) Liver transplantation for HCC. World J Gastroenterol 25:2591–2602. https://doi.org/10.3748/wjg.v25.i21.2591
  20. Di Fazio P, Matrood S (2018) Targeting autophagy in liver cancer. Transl Gastroenterol Hepatol 3:39
  21. White E, Karp C, Strohecker AM, Guo Y, Mathew R (2010) Autophagy in cancer. Curr Opin Cell Biol 22:212–217. https://doi.org/10.1016/j.ceb.2009.12.008
  22. Akkoç Y, Gözüaçık D (2018) Autophagy and liver cancer. Turk J Gastroenterol 29:270–282
  23. Sheng J, Qin H, Zhang K, Li B, Zhang X (2018) Autophagy in chemoresistance of HCC. Am J Cancer Res 8:354–365
  24. Huang F, Wang BR, Wang YG (2018) Autophagy in HCC. World J Gastroenterol 24:4643–4651
  25. Ayob AZ, Ramasamy TS (2018) Cancer stem cells. J Biomed Sci 25:20
  26. Desai A, Yan Y, Gerson SL (2019) Cancer stem cell therapies. Stem Cells Transl Med 8:75–81
  27. Ji J, Wang XW (2012) Cancer stem cell biology in HCC. Semin Oncol 39:461–472
  28. Wang N, Wang S, Li MY, et al. (2018) Cancer stem cells in HCC. Ther Adv Med Oncol 10:1758835918816287
  29. Visvader JE, Lindeman GJ (2012) Cancer stem cells. Cell Stem Cell 10:717–728
  30. Wang K, Sun D (2018) Cancer stem cells of HCC. Prim Liver Cancer Challenges Perspect 9:23306–23314
  31. Zhang H (2020) CCND1 silencing and autophagy in HCC stem cells. Hum Cell 33:140–147
  32. Deter RL, De Duve C (1967) Autophagy and lysosomes. J Cell Biol 33:437–449
  33. De Duve C, Wattiaux R (1966) Functions of lysosomes. Annu Rev Physiol 28:435–492
  34. Ohsumi Y (2014) Autophagy research landmarks. Cell Res 24:9–23
  35. Das G, Shravage BV, Baehrecke EH (2012) Autophagy regulation. Cold Spring Harb Perspect Biol 4:1–14
  36. Filomeni G, De Zio D, Cecconi F (2015) Oxidative stress and autophagy. Cell Death Differ 22:377–388
  37. Backer JM (2008) Class III PI3Ks in autophagy. Biochem J 410:1–17
  38. Ganley IG, Lam DH, Wang J, et al. (2009) ULK1 complex. J Biol Chem 284:12297–12305
  39. Shang L, Chen S, Du F, et al. (2011) Starvation and autophagy. PNAS 108:4788–4793
  40. Kroemer G, Mariño G, Levine B (2010) Autophagy and stress response. Mol Cell 40:280–293
  41. Yang Z, Klionsky DJ (2010) Mammalian autophagy machinery. Curr Opin Cell Biol 22:124–131
  42. Axe EL, Walker SA, Manifava M, et al. (2008) Autophagosome formation. J Cell Biol 182:685–701
  43. Noda NN, Fujioka Y, Hanada T, et al. (2013) Atg12-Atg5 structure. EMBO Rep 14:206–211
  44. Walczak M, Martens S (2013) Atg complex function. Autophagy 9:424–425
  45. Tanida I, Ueno T, Kominami E (2004) LC3 system. Int J Biochem Cell Biol 36:2503–2518
  46. Müller AJ, Proikas-Cezanne T (2015) WIPI proteins. FEBS Lett 589:1546–1551
  47. Feng Y, Klionsky DJ (2017) ATG9 membrane delivery. Cell Res 27:161–162
  48. Ying H, Yue BYJT (2016) Optineurin and autophagy. Exp Eye Res 144:73–80
  49. Viret C, Rozières A, Faure M (2018) NDP52 receptor. Trends Cell Biol 28:255–257
  50. Zhang X, Wang Y (2018) GRASP55 and autophagy. Mol Cell Oncol 5:e1494948
  51. Tong J, Yan X, Yu L (2010) The late stage of autophagy: cellular events and molecular regulation. Protein Cell 1:907–915. https://doi.org/10.1007/s13238-010-0121-z
  52. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, et al. (2010) Autophagy termination and lysosome reformation regulated by mTOR. Nature 465:942–946. https://doi.org/10.1038/nature09076
  53. Berg TO, Fengsrud M, Strømhaug PE, et al. (1998) Isolation and characterization of rat liver amphisomes. J Biol Chem 273:21883–21892. https://doi.org/10.1074/jbc.273.34.21883
  54. Nakamura S, Yoshimori T (2017) New insights into autophagosome-lysosome fusion. J Cell Sci 130:1209–1216. https://doi.org/10.1242/jcs.196352
  55. Mitra V, Metcalf J (2012) Metabolic functions of the liver. Anaesth Intensive Care Med 13:54–55. https://doi.org/10.1016/j.mpaic.2011.11.006
  56. Lavallard VJ, Gual P (2014) Autophagy and non-alcoholic fatty liver disease. Biomed Res Int 2014:120179. https://doi.org/10.1155/2014/120179
  57. Madrigal-Matute J, Cuervo AM (2016) Regulation of liver metabolism by autophagy. Gastroenterology 150:328–339. https://doi.org/10.1053/j.gastro.2015.09.042
  58. Ezaki J, Matsumoto N, Takeda-Ezaki M, et al. (2011) Liver autophagy contributes to maintenance of blood glucose and amino acids. Autophagy 7:727–736. https://doi.org/10.4161/auto.7.7.15371
  59. Singh R, Kaushik S, Wang Y, et al. (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135. https://doi.org/10.1038/nature07976
  60. Akman HO, Raghavan A, Craigen WJ (2011) Animal models of glycogen storage disorders. Prog Mol Biol Transl Sci 100:369–388. https://doi.org/10.1016/B978-0-12-384878-9.00009-1
  61. Ke PY (2019) Diverse functions of autophagy in liver physiology and disease. Int J Mol Sci 20:300. https://doi.org/10.3390/ijms20020300
  62. Afifiyan N, Tillman B, French BA, et al. (2017) Tec kinase signaling in Mallory-Denk bodies. Exp Mol Pathol 103:191–199. https://doi.org/10.1016/j.yexmp.2017.09.001
  63. Ni HM, Woolbright BL, Williams J, et al. (2014) Nrf2 promotes fibrosis and tumorigenesis in defective hepatic autophagy. J Hepatol 61:617–625. https://doi.org/10.1016/j.jhep.2014.04.043
  64. Galluzzi L, Pietrocola F, Bravo-San Pedro JM, et al. (2015) Autophagy in malignant transformation. EMBO J 34:856–880. https://doi.org/10.15252/embj.201490784
  65. Fu Y, Chung FL (2018) Oxidative stress and hepatocarcinogenesis. Hepatoma Res 4:39. https://doi.org/10.20517/2394-5079.2018.29
  66. Ciccarone F, Castelli S, Ciriolo MR (2019) Oxidative stress-driven autophagy in HCC. Oxid Med Cell Longev 2019:6050123. https://doi.org/10.1155/2019/6050123
  67. Jin SM, Youle RJ (2012) PINK1 and Parkin-mediated mitophagy. J Cell Sci 125:795–799. https://doi.org/10.1242/jcs.093849
  68. Zhang T, Xue L, Li L, et al. (2016) BNIP3 promotes mitophagy. J Biol Chem 291:21616–21629. https://doi.org/10.1074/jbc.M116.733410
  69. Fujiwara M, Marusawa H, Wang HQ, et al. (2008) Parkin as tumor suppressor in HCC. Oncogene 27:6002–6011. https://doi.org/10.1038/onc.2008.199
  70. Takamura A, Komatsu M, Hara T, et al. (2011) Autophagy-deficient mice develop liver tumors. Genes Dev 25:795–800. https://doi.org/10.1101/gad.2016211
  71. Mathew R, Karp CM, Beaudoin B, et al. (2009) Autophagy suppresses tumorigenesis via p62. Cell 137:1062–1075. https://doi.org/10.1016/j.cell.2009.03.048
  72. Inami Y, Waguri S, Sakamoto A, et al. (2011) Nrf2 activation via p62 in HCC. J Cell Biol 193:275–284. https://doi.org/10.1083/jcb.201102031
  73. Jaramillo MC, Zhang DD (2013) Nrf2-Keap1 signaling in cancer. Genes Dev 27:2179–2191. https://doi.org/10.1101/gad.225680.113
  74. Yazdani H, Huang H, Tsung A (2019) Dual role of autophagy in HCC. Cells 8:91. https://doi.org/10.3390/cells8020091
  75. Chen C, Lou T (2017) Hypoxia inducible factors in HCC. Oncotarget 8:46691–46703. https://doi.org/10.18632/oncotarget.17358
  76. Bellot G, Garcia-Medina R, Gounon P, et al. (2009) Hypoxia-induced autophagy via BNIP3. Mol Cell Biol 29:2570–2581. https://doi.org/10.1128/MCB.00166-09
  77. Zhang J, Ney PA (2009) BNIP3 and NIX roles. Cell Death Differ 16:939–946. https://doi.org/10.1038/cdd.2009.16
  78. Decuypere JP, Parys JB, Bultynck G (2012) Bcl-2/Beclin-1 regulation. Cells 1:284–312. https://doi.org/10.3390/cells1030284
  79. Sun L, Li T, Wei Q, et al. (2014) BNIP3-mediated anoikis resistance. Future Oncol 10:1387–1398. https://doi.org/10.2217/fon.14.70
  80. Keith B, Johnson RS, Simon MC (2011) HIF1α and HIF2α roles. Nat Rev Cancer 12:9–22. https://doi.org/10.1038/nrc3183
  81. Menrad H, Werno C, Schmid T, et al. (2010) HIF1α vs HIF2α in HCC spheroids. Hepatology 51:2183–2192. https://doi.org/10.1002/hep.23597
  82. Mazure NM, Pouysségur J (2009) BNIP3 in hypoxia autophagy. Autophagy 5:868–869. https://doi.org/10.4161/auto.9042
  83. Leber B, Lin J, Andrews DW (2007) Bcl-2 family and membranes. Apoptosis 12:897–911. https://doi.org/10.1007/s10495-007-0746-4
  84. Dong XF, Liu TQ, Zhi XT, et al. (2018) COX-2/PGE2 axis and HIF2α in HCC. Clin Cancer Res 24:3204–3216. https://doi.org/10.1158/1078-0432.CCR-17-2725
  85. Wu DH, Jia CC, Chen J, et al. (2014) LC3B and prognosis in HCC. Tumour Biol 35:12225–12233. https://doi.org/10.1007/s13277-014-2531-7
  86. Lazova R, Camp RL, Klump V, et al. (2012) LC3B expression in tumors. Clin Cancer Res 18:370–379. https://doi.org/10.1158/1078-0432.CCR-11-1282
  87. Langley RR, Fidler IJ (2011) Seed and soil hypothesis. Int J Cancer 128:2527–2535. https://doi.org/10.1002/ijc.26031
  88. Seyfried TN, Huysentruyt LC (2013) Origin of metastasis. Crit Rev Oncog 18:43–73. https://doi.org/10.1615/critrevoncog.v18.i1-2.40
  89. Kim YN, Koo KH, Sung JY, et al. (2012) Anoikis resistance in metastasis. Int J Cell Biol 2012:306879. https://doi.org/10.1155/2012/306879
  90. Paoli P, Giannoni E, Chiarugi P (2013) Anoikis pathways. Biochim Biophys Acta 1833:3481–3498. https://doi.org/10.1016/j.bbamcr.2013.06.026
  91. Yang J, Zheng Z, Yan X, et al. (2013) Autophagy and anoikis resistance. Anat Rec 296:1501–1508. https://doi.org/10.1002/ar.22769
  92. Avivar-Valderas A, Salas E, Bobrovnikova-Marjon E, et al. (2011) PERK integrates autophagy and stress. Mol Cell Biol 31:3616–3629. https://doi.org/10.1128/MCB.05164-11
  93. Peng YF, Shi YH, Ding ZB, et al. (2013) Autophagy inhibition suppresses metastasis in HCC. Autophagy 9:2056–2068. https://doi.org/10.4161/auto.26398
  94. Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S (2012) TGF-β review. J Transl Med 10:183. https://doi.org/10.1186/1479-5876-10-183
  95. Scandura JM, Boccuni P, Massagué J, et al. (2004) TGF-β cell cycle arrest. PNAS 101:15231–15236. https://doi.org/10.1073/pnas.0406771101
  96. Inman GJ (2011) TGF-β tumor switch. Curr Opin Genet Dev 21:93–99. https://doi.org/10.1016/j.gde.2010.12.004
  97. Tong H, Yin H, Hossain MA, et al. (2019) Starvation-induced autophagy and EMT. J Cell Biochem 120:5118–5127. https://doi.org/10.1002/jcb.27788
  98. Li J, Yang B, Zhou Q, et al. (2013) Autophagy promotes EMT in HCC. Carcinogenesis 34:1343–1351. https://doi.org/10.1093/carcin/bgt063
  99. Roche J (2018) EMT in cancer. Cancers (Basel) 10:52. https://doi.org/10.3390/cancers10020052
  100. Wang J, Chen L, Li Y, Guan XY (2011) Cathepsin Z induces EMT in HCC. PLoS ONE 6:e24967. https://doi.org/10.1371/journal.pone.0024967
  101. Chen HT, Liu H, Mao MJ, et al. (2019) Autophagy-EMT crosstalk. Mol Cancer 18:101. https://doi.org/10.1186/s12943-019-1030-2
  102. Chen C, Liang QY, Chen HK, et al. (2018) DRAM1 regulates EMT via autophagy. Oncol Lett 16:2427–2433. https://doi.org/10.3892/ol.2018.8937
  103. Hu S, Wang L, Zhang X, et al. (2018) Autophagy induces TGF-β EMT signaling. J Cell Mol Med 22:5518–5532. https://doi.org/10.1111/jcmm.13825
  104. Wang Y, Xiong H, Liu D, et al. (2019) Autophagy inhibition promotes EMT in RAS-mutated cells. Autophagy 15:886–899. https://doi.org/10.1080/15548627.2019.1569912
  105. Zhao Z, Zhao J, Xue J, et al. (2016) Autophagy inhibition promotes EMT via ROS. Am J Cancer Res 6:2162–2177
  106. Shaaban S, Negm A, Ibrahim EE, Elrazak AA (2014) Chemotherapy for HCC. Oncol Rev 8:246. https://doi.org/10.4081/oncol.2014.246
  107. Riddell IA, Lippard SJ (2018) Cisplatin and oxaliplatin mechanisms. Metallo-drugs 1–42. https://doi.org/10.1515/9783110470734-001
  108. Chen R, Dai RY, Duan CY, et al. (2011) UPR suppresses cisplatin apoptosis via autophagy. Folia Biol (Praha) 57:87–95
  109. Du H, Yang W, Chen L, et al. (2012) Autophagy and oxaliplatin resistance in HCC. Oncol Rep 27:143–150. https://doi.org/10.3892/or.2011.1464
  110. Nitiss JL (2009) Topoisomerase II in chemotherapy. Nat Rev Cancer 9:338–350. https://doi.org/10.1038/nrc2607
  111. Zhou Y, Chen E, Tang Y, et al. (2019) miR-223 and autophagy in HCC. Cell Death Dis 10:843. https://doi.org/10.1038/s41419-019-2053-8
  112. Jin J, Huang M, Wei HL, Liu GT (2002) 5-FU resistance in HCC. World J Gastroenterol 8:1029–1034
  113. Guo XL, Hu F, Zhang SS, et al. (2014) p53 and autophagy in 5-FU sensitivity. Cancer Lett 346:278–284. https://doi.org/10.1016/j.canlet.2014.01.011
  114. Llovet JM, Ricci S, Mazzaferro V, et al. (2008) Sorafenib in HCC. N Engl J Med 359:378–390. https://doi.org/10.1056/NEJMoa0708857
  115. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390. https://doi.org/10.1056/NEJMoa0708857
  116. Fu XT, Song K, Zhou J, Shi YH, Liu WR, Tian MX, et al. Autophagy activation contributes to glutathione transferase Mu 1-mediated chemoresistance in hepatocellular carcinoma. Oncol Lett. 2018;16:346–352. https://doi.org/10.3892/ol.2018.8667
  117. Zhai B, Hu F, Jiang X, Xu J, Zhao D, Liu B, et al. Inhibition of Akt reverses acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma. Mol Cancer Ther. 2014;13:1589–1598. https://doi.org/10.1158/1535-7163.MCT-13-1043
  118.  Zhao D, Zhai B, He C, Tan G, Jiang X, Pan S, et al. Upregulation of HIF-2α induced by sorafenib contributes to resistance via TGF-α/EGFR pathway activation. Cell Signal. 2014;26:1030–1039. https://doi.org/10.1016/j.cellsig.2014.01.026
  119.  Liang Y, Zheng T, Song R, Wang J, Yin D, Wang L, et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 via VHL-dependent HIF-1α inhibition. Hepatology. 2013;57:1847–1857. https://doi.org/10.1002/hep.26224
  120. Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. Mechanisms of sorafenib resistance in hepatocellular carcinoma. Signal Transduct Target Ther. 2020;5:87. https://doi.org/10.1038/s41392-020-0187-x
  121. Peng WX, Xiong EM, Ge L, Wan YY, Zhang CL, Du FY, et al. Egr-1 promotes hypoxia-induced autophagy to enhance chemoresistance in hepatocellular carcinoma cells. Exp Cell Res. 2016;340:62–70. https://doi.org/10.1016/j.yexcr.2015.12.006
  122.  Xu Y, An Y, Wang Y, Zhang C, Zhang H, Huang C, et al. miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncol Rep. 2013;29:2019–2024. https://doi.org/10.3892/or.2013.2338
  123.  Lanza E, Donadon M, Poretti D, Pedicini V, Tramarin M, Roncalli M, et al. Transarterial therapies for hepatocellular carcinoma. Liver Cancer. 2017;6:27–33. https://doi.org/10.1159/000449347
  124.  Pleguezuelo M, Marelli L, Misseri M, Germani G, Calvaruso V, Xiruochakis E, et al. TACE versus TAE as therapy for hepatocellular carcinoma. Expert Rev Anticancer Ther. 2008;8:1623–1641. https://doi.org/10.1586/14737140.8.10.1623
  125. Rammohan A, Sathyanesan J, Ramaswami S, et al. Embolization of liver tumors: past, present and future. World J Radiol. 2012;4:405–412. https://doi.org/10.4329/wjr.v4.i9.405
  126.  Gade TPF, Tucker E, Nakazawa MS, et al. Ischemia induces quiescence and autophagy dependence in hepatocellular carcinoma. Radiology. 2017;283:702–710. https://doi.org/10.1148/radiol.2017160728
  127. Tao W, Shi JF, Zhang Q, et al. Egr-1 enhances drug resistance of breast cancer by modulating MDR1 expression. Biomed Pharmacother. 2013;67:197–202. https://doi.org/10.1016/j.biopha.2013.01.001
  128. Peng WX, Wan YY, Gong AH, et al. Egr-1 regulates irradiation-induced autophagy via Atg4B promoting radioresistance. Oncogenesis. 2017;6:e292. https://doi.org/10.1038/oncsis.2016.91
  129. Yang Z, Wilkie-Grantham RP, Yanagi T, et al. ATG4B phosphorylation modulates autophagy. J Biol Chem. 2015;290:26549–26561. https://doi.org/10.1074/jbc.M115.658088
  130. Wang Z, Han W, Sui X, Fang Y, Pan H. Autophagy: a novel therapeutic target for hepatocarcinoma (Review). Oncol Lett. 2014;7:1345–1351. https://doi.org/10.3892/ol.2014.1916
  131. Sun T, Liu H, Ming L. Multiple roles of autophagy in sorafenib resistance of hepatocellular carcinoma. Cell Physiol Biochem. 2017;44:716–727. https://doi.org/10.1159/000485285
  132. Shi YH, Ding ZB, Zhou J, et al. Targeting autophagy enhances sorafenib lethality via ER stress-related apoptosis. Autophagy. 2011;7:1159–1172. https://doi.org/10.4161/auto.7.10.16818
  133. Prieto-Vila M, Takahashi RU, Usuba W, et al. Drug resistance driven by cancer stem cells and their niche. Int J Mol Sci. 2017;18:2574. https://doi.org/10.3390/ijms18122574
  134. Nio K, Yamashita T, Kaneko S. The evolving concept of liver cancer stem cells. Mol Cancer. 2017;16:4. https://doi.org/10.1186/s12943-016-0572-9
  135. Yamashita T, Wang XW. Cancer stem cells in liver cancer development. J Clin Invest. 2013;123:1911–1918. https://doi.org/10.1172/JCI66024
  136. Yamashita T, Ji J, Budhu A, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells. Gastroenterology. 2009;136:1012–1024. https://doi.org/10.1053/j.gastro.2008.12.004
  137. Terris B, Cavard C, Perret C. EpCAM as a marker for cancer stem cells in HCC. J Hepatol. 2010;52:280–281. https://doi.org/10.1016/j.jhep.2009.10.026
  138. Ma S, Chan KW, Hu L, et al. Identification of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132:2542–2556. https://doi.org/10.1053/j.gastro.2007.04.025
  139. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, Li J (2010) Cancer stem/progenitor cells are highly enriched in CD133 +CD44+ population in hepatocellular carcinoma. Int J Cancer 126:2067–2078. https://doi.org/10.1002/ijc.24868
  140. Yang FZ, Ngai P, Ho DW, Yu WC, Ng MNP, Lau CK, Li MLY, Tam KH, Lam CT, Poon RTP, Fan ST (2008) Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 47:919–928. https://doi.org/10.1002/hep.22082
  141. Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM, Akita H, Takiuchi D, Hatano H, Nagano H, Barnard GF, Doki Y, Mori M (2010) CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest 120:3326–3339. https://doi.org/10.1172/JCI42550
  142. Qiu L, Li H, Fu S, Chen X, Lu L (2018) Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC. Oncol Lett 15:2039–2048. https://doi.org/10.3892/ol.2017.7568
  143. Govaere O, Komuta M, Berkers J, Spee B, Janssen C, de Luca F, Katoonizadeh A, Wouters J, van Kempen LC, Durnez A, Verslype C, De Kock J, Rogiers V, van Grunsven LA, Topal B, Pirenne J, Vankelecom H, Nevens F, van den Oord J, Pinzani M, Roskams T (2014) Keratin 19: a key role player in the invasion of human hepatocellular carcinomas. Gut 63:674–685. https://doi.org/10.1136/gutjnl-2012-304351
  144. Zheng H, Pomyen Y, Hernandez MO, Li C, Livak F, Tang W, Dang H, Greten TF, Davis JL, Zhao Y, Mehta M, Levin Y, Shetty J, Tran B, Budhu A, Wang XW (2018) Single cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma. Hepatology 68:127–140. https://doi.org/10.1002/hep.29778
  145. Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell 21:283–296. https://doi.org/10.1016/j.ccr.2012.03.003
  146. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850. https://doi.org/10.1038/nature03319
  147. Weinmaster G, Kopan R (2016) A garden of Notch-ly delights. Development 133:3277–3282. https://doi.org/10.1242/dev.02515
  148. Gotoh N (2009) Control of stemness by fibroblast growth factor signaling in stem cells and cancer stem cells. Curr Stem Cell Res Ther 4:9–15. https://doi.org/10.2174/157488809787169048
  149. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425:577–584. https://doi.org/10.1038/nature02006
  150. Sell S (2010) On the stem cell origin of cancer. Am J Pathol 176:2584–2594. https://doi.org/10.2353/ajpath.2010.091064
  151. Lau EYT, Ho NPY, Lee TKW (2017) Cancer stem cells and their microenvironment: biology and therapeutic implications. Stem Cells Int 2017:3714190. https://doi.org/10.1155/2017/3714190
  152. Gao Y, Ruan B, Liu W, Wang J, Yang X, Zhang Z, Li X, Duan J, Zhang F, Ding R, Tao K, Dou K (2015) Knockdown of CD44 inhibits the invasion and metastasis of hepatocellular carcinoma both in vitro and in vivo by reversing epithelial-mesenchymal transition. Oncotarget 6:7828–7837. https://doi.org/10.18632/oncotarget.3488
  153. van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, Machat G, Grubinger M, Huber H, Mikulits W (2009) Epithelial-mesenchymal transition in hepatocellular carcinoma. Futur Oncol 5:1169–1179. https://doi.org/10.2217/fon.09.91
  154. Cazet AS, Hui MN, Elsworth BL, et al. (2018) Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nat Commun 9:2897. https://doi.org/10.1038/s41467-018-05220-6
  155. Dai XM, Yang SL, Zheng XM, Chen GG, Chen J, Zhang T (2018) CD133 expression and α-fetoprotein levels define novel prognostic subtypes of HBV-associated hepatocellular carcinoma. Oncol Lett 15:2985–2991. https://doi.org/10.3892/ol.2017.7704
  156. Yamanaka C, Wada H, Eguchi H, et al. (2018) Clinical significance of CD13 and EMT markers in hepatocellular carcinoma. Jpn J Clin Oncol 48:52–60. https://doi.org/10.1093/jjco/hyx157
  157. Batlle E, Clevers H (2017) Cancer stem cells revisited. Nat Med 23:1124–1134. https://doi.org/10.1038/nm.4409
  158. Trédan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454. https://doi.org/10.1093/jnci/djm135
  159. Baumann M, Krause M, Hill R (2008) Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545–554. https://doi.org/10.1038/nrc2419
  160. Bai X, Ni J, Beretov J, Graham P, Li Y (2018) Cancer stem cell in breast cancer therapeutic resistance. Cancer Treat Rev 69:152–163. https://doi.org/10.1016/j.ctrv.2018.07.004
  161. Sun YL, Patel A, Kumar P, Chen ZS (2012) Role of ABC transporters in cancer chemotherapy. Chin J Cancer 31:51–57. https://doi.org/10.5732/cjc.011.10466
  162. Zhang G, Wang Z, Luo W, Jiao H, Wu J, Jiang C (2013) Expression of ABCG2 in hepatocellular carcinoma. Gastroenterol Res Pract 2013:782581. https://doi.org/10.1155/2013/782581
  163. Jia Q, Zhang X, Deng T, Gao J (2013) Oct4 and ABCG2 in chemoresistance of liver cancer stem cells. Cell Reprogram 15:143–150. https://doi.org/10.1089/cell.2012.0048
  164. Ranji P, et al. (2016) Targeting cancer stem cell markers and signaling pathways. Tumor Biol 37:13059–13075. https://doi.org/10.1007/s13277-016-5294-5
  165. Vassalli G (2019) Aldehyde dehydrogenases as stem cell regulators. Stem Cells Int 2019:3904645. https://doi.org/10.1155/2019/3904645
  166. Carnero A, et al. (2016) Cancer stem-cell signaling and therapy resistance. Cancer Treat Rev 49:25–36. https://doi.org/10.1016/j.ctrv.2016.07.001
  167. Tsai LL, Yu CC, et al. (2012) Cisplatin resistance in oral cancer stem-like cells. J Dent Sci 7:111–117. https://doi.org/10.1016/j.jds.2012.03.006
  168. Kim HJ, Maiti P, Barrientos A (2017) Mitochondrial ribosomes in cancer. Semin Cancer Biol 47:67–81. https://doi.org/10.1016/j.semcancer.2017.04.004
  169. Cheng J, Liu C, et al. (2016) MEK1 signaling in liver cancer stem cells. Oncotarget 7:20597–20611. https://doi.org/10.18632/oncotarget.7972
  170. Pearson G, Robinson F, et al. (2001) MAP kinase pathways. Endocr Rev 22:153–183. https://doi.org/10.1210/edrv.22.2.0428
  171. Mortensen M, Simon AK (2010) Autophagy in erythroid development. Autophagy 6:423–425. https://doi.org/10.4161/auto.6.3.11528
  172. Miyajima A, Tanaka M, Itoh T (2014) Liver stem/progenitor cells. Cell Stem Cell 14:561–574. https://doi.org/10.1016/j.stem.2014.04.010
  173. Cheng Y, Wang B, et al. (2015) Autophagy in liver progenitor cells. Cell Physiol Biochem 36:1163–1174. https://doi.org/10.1159/000430287
  174. Xue F, Hu L, et al. (2016) Autophagy deficiency and tumorigenesis. Cancer Lett 371:38–47. https://doi.org/10.1016/j.canlet.2015.11.022
  175. Bu Y, Cao D (2012) Origin of cancer stem cells. Front Biosci 4:819–830. https://doi.org/10.2741/s302
  176. Zender L, Spector MS, et al. (2006) Oncogenomic screening in liver cancer. Cell 125:1253–1267. https://doi.org/10.1016/j.cell.2006.05.030
  177. Tang Y, et al. (2008) Stem cells in liver cancer via TGF-β and IL-6. PNAS 105:2445–2450. https://doi.org/10.1073/pnas.0705395105
  178. Liu K, Lee J, et al. (2017) Mitophagy and p53 in liver cancer stem cells. Mol Cell 68:281–292.e5. https://doi.org/10.1016/j.molcel.2017.09.022
  179. Li J, Hu SB, et al. (2017) Autophagy and Axin2+ cancer stem cells. Oncogene 36:6725–6737. https://doi.org/10.1038/onc.2017.272
  180. Song YJ, et al. (2013) Autophagy in CD133+ liver cancer stem cells. Cancer Lett 339:70–81. https://doi.org/10.1016/j.canlet.2013.07.021
  181. Li Z, et al. (2019) Cyclin D1 and histone methylation. Oncogene 38:4232–4249. https://doi.org/10.1038/s41388-019-0723-8
  182. Zheng N, Wei W, Wang Z (2016) FGF signaling in HCC. Transl Cancer Res 5:1–6
  183. Ocker M (2020) FGF signaling in liver disease and cancer. World J Gastroenterol 26:279–290. https://doi.org/10.3748/wjg.v26.i3.279
  184. Gauglhofer C, et al. (2011) FGF8 in hepatocellular carcinoma. Hepatology 53:854–864. https://doi.org/10.1002/hep.24099
  185. Sawey ET, et al. (2011) Targeting FGF19 in liver cancer. Cancer Cell 19:347–358. https://doi.org/10.1016/j.ccr.2011.01.040
  186. Hagel M, et al. (2015) FGFR4 inhibitor development. Cancer Discov 5:424–437. https://doi.org/10.1158/2159-8290.CD-14-1029
  187. French DM, et al. (2012) FGFR4 inhibition in HCC. PLoS ONE 7:e36713. https://doi.org/10.1371/journal.pone.0036713
  188. Mavila N, et al. (2012) FGFR-AKT-β-catenin pathway in tumor stem cells. PLoS ONE 7:e50401. https://doi.org/10.1371/journal.pone.0050401
  189. Zhang J, Liu J, et al. (2012) FGF signaling and autophagy. Autophagy 8:690–691. https://doi.org/10.4161/auto.19290
  190. Cinque L, et al. (2015) FGF signaling and autophagy in bone growth. Nature 528:272–275. https://doi.org/10.1038/nature16063
  191. Yuan H, et al. (2017) FGF2/FGFR1 and autophagy in cancer. J Exp Clin Cancer Res 36:72. https://doi.org/10.1186/s13046-017-0534-0
  192. Kiyono K, Suzuki HI, et al. (2009) TGF-β and autophagy in HCC. Cancer Res 69:8844–8852. https://doi.org/10.1158/0008-5472.CAN-08-4401
  193. Ma CL, et al. (2017) TGF-β1 and autophagy in invasion. Eur Rev Med Pharmacol Sci 21:2604–2610
  194. Zong Y, et al. (2009) Notch in liver development. Development 136:1727–1739. https://doi.org/10.1242/dev.029140
  195. Zeng J, et al. (2016) Autophagy and Notch1 in hepatic progenitors. Cell Cycle 15:1602–1610. https://doi.org/10.1080/15384101.2016.1181234
  196. Wu X, et al. (2016) Autophagy regulates Notch degradation. Nat Commun 7:10533. https://doi.org/10.1038/ncomms10533
  197. Vujovic F, Hunter N, Farahani RM (2019) Notch signaling noise. Cell Commun Signal 17:133. https://doi.org/10.1186/s12964-019-0453-0
  198. Wang M, et al. (2009) Notch1, Jagged1 and β-catenin in HCC. Neoplasma 56:533–541
  199. Croquelois A, et al. (2005) Notch1 in liver regeneration. Hepatology 41:487–496. https://doi.org/10.1002/hep.20571
  200. Khalaf AM, et al. (2018) Wnt/β-catenin in HCC. J Hepatocell Carcinoma 5:61–73. https://doi.org/10.2147/JHC.S156701
  201. Turcios L, et al. (2019) Autophagy and Wnt/β-catenin. PLoS One 14:e0212538. https://doi.org/10.1371/journal.pone.0212538
  202. Petherick KJ, et al. (2013) β-catenin degradation and autophagy. EMBO J 32:1903–1916. https://doi.org/10.1038/emboj.2013.123
  203. Fan Q, et al. (2018) Autophagy and metastasis via Wnt signaling. J Exp Clin Cancer Res 37:9. https://doi.org/10.1186/s13046-018-0673-y
  204. Ma Z, et al. (2019) Autophagy in hepatic differentiation. J Mol Histol 50:75–90. https://doi.org/10.1007/s10735-018-9808-x
  205. Kim JY, et al. (2016) Wnt/β-catenin targeting in liver CSCs. Oncotarget 7:20395–20409. https://doi.org/10.18632/oncotarget.7954
  206. Bhat P, et al. (2018) Autophagy modulation in cancer therapy. Biochem Pharmacol 147:170–182. https://doi.org/10.1016/j.bcp.2017.11.021
  207. Galluzzi L, et al. (2017) Pharmacological autophagy modulation. Nat Rev Drug Discov 16:487–511. https://doi.org/10.1038/nrd.2017.22

Cite

Wong, M. M., Chan, H. Y., Aziz, N. A., Ramasamy, T. S., Bong, J. J., Ch'ng, E. S., Armon, S., Peh, S. C., & Teow, S. Y. (2021). Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Molecular biology reports48(4), 3695–3717. https://doi.org/10.1007/s11033-021-06334-9

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