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
- 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
- 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
- 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
- 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
- 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
- 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
- Yun CW, Lee SH (2018) The roles of autophagy in cancer. Int J Mol Sci 19:3466. https://doi.org/10.3390/ijms19113466
- 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
- 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
- Montella M, Crispo A, Giudice A (2011) HCC, diet, and metabolic factors. Hepat Mon 11:159–162
- Bartosch B (2010) Hepatitis B and C viruses and hepatocellular carcinoma. Viruses 2:1504–1509. https://doi.org/10.3390/v2081504
- 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
- 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
- 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
- Heidelbaugh JJ, Bruderly M (2006) Cirrhosis and chronic liver failure: Part I. Diagnosis and evaluation. Am Fam Physician 74:756–762
- 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
- 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
- Llovet JM, Fuster BJ (2004) The Barcelona approach. Liver Transplant 10:S115–120. https://doi.org/10.1002/lt.20034
- 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
- Di Fazio P, Matrood S (2018) Targeting autophagy in liver cancer. Transl Gastroenterol Hepatol 3:39
- 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
- Akkoç Y, Gözüaçık D (2018) Autophagy and liver cancer. Turk J Gastroenterol 29:270–282
- Sheng J, Qin H, Zhang K, Li B, Zhang X (2018) Autophagy in chemoresistance of HCC. Am J Cancer Res 8:354–365
- Huang F, Wang BR, Wang YG (2018) Autophagy in HCC. World J Gastroenterol 24:4643–4651
- Ayob AZ, Ramasamy TS (2018) Cancer stem cells. J Biomed Sci 25:20
- Desai A, Yan Y, Gerson SL (2019) Cancer stem cell therapies. Stem Cells Transl Med 8:75–81
- Ji J, Wang XW (2012) Cancer stem cell biology in HCC. Semin Oncol 39:461–472
- Wang N, Wang S, Li MY, et al. (2018) Cancer stem cells in HCC. Ther Adv Med Oncol 10:1758835918816287
- Visvader JE, Lindeman GJ (2012) Cancer stem cells. Cell Stem Cell 10:717–728
- Wang K, Sun D (2018) Cancer stem cells of HCC. Prim Liver Cancer Challenges Perspect 9:23306–23314
- Zhang H (2020) CCND1 silencing and autophagy in HCC stem cells. Hum Cell 33:140–147
- Deter RL, De Duve C (1967) Autophagy and lysosomes. J Cell Biol 33:437–449
- De Duve C, Wattiaux R (1966) Functions of lysosomes. Annu Rev Physiol 28:435–492
- Ohsumi Y (2014) Autophagy research landmarks. Cell Res 24:9–23
- Das G, Shravage BV, Baehrecke EH (2012) Autophagy regulation. Cold Spring Harb Perspect Biol 4:1–14
- Filomeni G, De Zio D, Cecconi F (2015) Oxidative stress and autophagy. Cell Death Differ 22:377–388
- Backer JM (2008) Class III PI3Ks in autophagy. Biochem J 410:1–17
- Ganley IG, Lam DH, Wang J, et al. (2009) ULK1 complex. J Biol Chem 284:12297–12305
- Shang L, Chen S, Du F, et al. (2011) Starvation and autophagy. PNAS 108:4788–4793
- Kroemer G, Mariño G, Levine B (2010) Autophagy and stress response. Mol Cell 40:280–293
- Yang Z, Klionsky DJ (2010) Mammalian autophagy machinery. Curr Opin Cell Biol 22:124–131
- Axe EL, Walker SA, Manifava M, et al. (2008) Autophagosome formation. J Cell Biol 182:685–701
- Noda NN, Fujioka Y, Hanada T, et al. (2013) Atg12-Atg5 structure. EMBO Rep 14:206–211
- Walczak M, Martens S (2013) Atg complex function. Autophagy 9:424–425
- Tanida I, Ueno T, Kominami E (2004) LC3 system. Int J Biochem Cell Biol 36:2503–2518
- Müller AJ, Proikas-Cezanne T (2015) WIPI proteins. FEBS Lett 589:1546–1551
- Feng Y, Klionsky DJ (2017) ATG9 membrane delivery. Cell Res 27:161–162
- Ying H, Yue BYJT (2016) Optineurin and autophagy. Exp Eye Res 144:73–80
- Viret C, Rozières A, Faure M (2018) NDP52 receptor. Trends Cell Biol 28:255–257
- Zhang X, Wang Y (2018) GRASP55 and autophagy. Mol Cell Oncol 5:e1494948
- 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
- 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
- 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
- Nakamura S, Yoshimori T (2017) New insights into autophagosome-lysosome fusion. J Cell Sci 130:1209–1216. https://doi.org/10.1242/jcs.196352
- 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
- Lavallard VJ, Gual P (2014) Autophagy and non-alcoholic fatty liver disease. Biomed Res Int 2014:120179. https://doi.org/10.1155/2014/120179
- 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
- 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
- Singh R, Kaushik S, Wang Y, et al. (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135. https://doi.org/10.1038/nature07976
- 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
- Ke PY (2019) Diverse functions of autophagy in liver physiology and disease. Int J Mol Sci 20:300. https://doi.org/10.3390/ijms20020300
- 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
- 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
- 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
- Fu Y, Chung FL (2018) Oxidative stress and hepatocarcinogenesis. Hepatoma Res 4:39. https://doi.org/10.20517/2394-5079.2018.29
- 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
- Jin SM, Youle RJ (2012) PINK1 and Parkin-mediated mitophagy. J Cell Sci 125:795–799. https://doi.org/10.1242/jcs.093849
- 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
- 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
- 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
- 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
- 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
- Jaramillo MC, Zhang DD (2013) Nrf2-Keap1 signaling in cancer. Genes Dev 27:2179–2191. https://doi.org/10.1101/gad.225680.113
- Yazdani H, Huang H, Tsung A (2019) Dual role of autophagy in HCC. Cells 8:91. https://doi.org/10.3390/cells8020091
- Chen C, Lou T (2017) Hypoxia inducible factors in HCC. Oncotarget 8:46691–46703. https://doi.org/10.18632/oncotarget.17358
- 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
- Zhang J, Ney PA (2009) BNIP3 and NIX roles. Cell Death Differ 16:939–946. https://doi.org/10.1038/cdd.2009.16
- Decuypere JP, Parys JB, Bultynck G (2012) Bcl-2/Beclin-1 regulation. Cells 1:284–312. https://doi.org/10.3390/cells1030284
- 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
- Keith B, Johnson RS, Simon MC (2011) HIF1α and HIF2α roles. Nat Rev Cancer 12:9–22. https://doi.org/10.1038/nrc3183
- 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
- Mazure NM, Pouysségur J (2009) BNIP3 in hypoxia autophagy. Autophagy 5:868–869. https://doi.org/10.4161/auto.9042
- 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
- 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
- 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
- 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
- Langley RR, Fidler IJ (2011) Seed and soil hypothesis. Int J Cancer 128:2527–2535. https://doi.org/10.1002/ijc.26031
- Seyfried TN, Huysentruyt LC (2013) Origin of metastasis. Crit Rev Oncog 18:43–73. https://doi.org/10.1615/critrevoncog.v18.i1-2.40
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Inman GJ (2011) TGF-β tumor switch. Curr Opin Genet Dev 21:93–99. https://doi.org/10.1016/j.gde.2010.12.004
- 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
- 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
- Roche J (2018) EMT in cancer. Cancers (Basel) 10:52. https://doi.org/10.3390/cancers10020052
- 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
- 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
- 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
- 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
- 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
- Zhao Z, Zhao J, Xue J, et al. (2016) Autophagy inhibition promotes EMT via ROS. Am J Cancer Res 6:2162–2177
- Shaaban S, Negm A, Ibrahim EE, Elrazak AA (2014) Chemotherapy for HCC. Oncol Rev 8:246. https://doi.org/10.4081/oncol.2014.246
- Riddell IA, Lippard SJ (2018) Cisplatin and oxaliplatin mechanisms. Metallo-drugs 1–42. https://doi.org/10.1515/9783110470734-001
- Chen R, Dai RY, Duan CY, et al. (2011) UPR suppresses cisplatin apoptosis via autophagy. Folia Biol (Praha) 57:87–95
- 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
- Nitiss JL (2009) Topoisomerase II in chemotherapy. Nat Rev Cancer 9:338–350. https://doi.org/10.1038/nrc2607
- 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
- Jin J, Huang M, Wei HL, Liu GT (2002) 5-FU resistance in HCC. World J Gastroenterol 8:1029–1034
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Yamashita T, Wang XW. Cancer stem cells in liver cancer development. J Clin Invest. 2013;123:1911–1918. https://doi.org/10.1172/JCI66024
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850. https://doi.org/10.1038/nature03319
- Weinmaster G, Kopan R (2016) A garden of Notch-ly delights. Development 133:3277–3282. https://doi.org/10.1242/dev.02515
- 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
- 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
- Sell S (2010) On the stem cell origin of cancer. Am J Pathol 176:2584–2594. https://doi.org/10.2353/ajpath.2010.091064
- 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
- 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
- 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
- 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
- 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
- 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
- Batlle E, Clevers H (2017) Cancer stem cells revisited. Nat Med 23:1124–1134. https://doi.org/10.1038/nm.4409
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Vassalli G (2019) Aldehyde dehydrogenases as stem cell regulators. Stem Cells Int 2019:3904645. https://doi.org/10.1155/2019/3904645
- 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
- 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
- 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
- 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
- Pearson G, Robinson F, et al. (2001) MAP kinase pathways. Endocr Rev 22:153–183. https://doi.org/10.1210/edrv.22.2.0428
- Mortensen M, Simon AK (2010) Autophagy in erythroid development. Autophagy 6:423–425. https://doi.org/10.4161/auto.6.3.11528
- 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
- Cheng Y, Wang B, et al. (2015) Autophagy in liver progenitor cells. Cell Physiol Biochem 36:1163–1174. https://doi.org/10.1159/000430287
- 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
- Bu Y, Cao D (2012) Origin of cancer stem cells. Front Biosci 4:819–830. https://doi.org/10.2741/s302
- 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
- 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
- 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
- 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
- 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
- Li Z, et al. (2019) Cyclin D1 and histone methylation. Oncogene 38:4232–4249. https://doi.org/10.1038/s41388-019-0723-8
- Zheng N, Wei W, Wang Z (2016) FGF signaling in HCC. Transl Cancer Res 5:1–6
- 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
- Gauglhofer C, et al. (2011) FGF8 in hepatocellular carcinoma. Hepatology 53:854–864. https://doi.org/10.1002/hep.24099
- 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
- Hagel M, et al. (2015) FGFR4 inhibitor development. Cancer Discov 5:424–437. https://doi.org/10.1158/2159-8290.CD-14-1029
- French DM, et al. (2012) FGFR4 inhibition in HCC. PLoS ONE 7:e36713. https://doi.org/10.1371/journal.pone.0036713
- 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
- Zhang J, Liu J, et al. (2012) FGF signaling and autophagy. Autophagy 8:690–691. https://doi.org/10.4161/auto.19290
- Cinque L, et al. (2015) FGF signaling and autophagy in bone growth. Nature 528:272–275. https://doi.org/10.1038/nature16063
- 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
- 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
- Ma CL, et al. (2017) TGF-β1 and autophagy in invasion. Eur Rev Med Pharmacol Sci 21:2604–2610
- Zong Y, et al. (2009) Notch in liver development. Development 136:1727–1739. https://doi.org/10.1242/dev.029140
- Zeng J, et al. (2016) Autophagy and Notch1 in hepatic progenitors. Cell Cycle 15:1602–1610. https://doi.org/10.1080/15384101.2016.1181234
- Wu X, et al. (2016) Autophagy regulates Notch degradation. Nat Commun 7:10533. https://doi.org/10.1038/ncomms10533
- Vujovic F, Hunter N, Farahani RM (2019) Notch signaling noise. Cell Commun Signal 17:133. https://doi.org/10.1186/s12964-019-0453-0
- Wang M, et al. (2009) Notch1, Jagged1 and β-catenin in HCC. Neoplasma 56:533–541
- Croquelois A, et al. (2005) Notch1 in liver regeneration. Hepatology 41:487–496. https://doi.org/10.1002/hep.20571
- Khalaf AM, et al. (2018) Wnt/β-catenin in HCC. J Hepatocell Carcinoma 5:61–73. https://doi.org/10.2147/JHC.S156701
- Turcios L, et al. (2019) Autophagy and Wnt/β-catenin. PLoS One 14:e0212538. https://doi.org/10.1371/journal.pone.0212538
- Petherick KJ, et al. (2013) β-catenin degradation and autophagy. EMBO J 32:1903–1916. https://doi.org/10.1038/emboj.2013.123
- 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
- Ma Z, et al. (2019) Autophagy in hepatic differentiation. J Mol Histol 50:75–90. https://doi.org/10.1007/s10735-018-9808-x
- Kim JY, et al. (2016) Wnt/β-catenin targeting in liver CSCs. Oncotarget 7:20395–20409. https://doi.org/10.18632/oncotarget.7954
- 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
- 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 reports, 48(4), 3695–3717. https://doi.org/10.1007/s11033-021-06334-9


