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Interplay of autophagy and cancer stem cells in hepatocellular carcinoma

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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.

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Abbreviations

HCC:

Hepatocellular carcinoma

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

CSC:

Cancer stem cell

PI3K:

Phosphatidylinositol 3-kinase

VPS34:

Vacuolar protein sorting 34

mTORC1:

Mammalian target of rapamycin complex

ULK1:

Unc-51 like kinase 1

ATG:

Autophagy related protein

FIP200:

Focal adhesion kinase family-interacting protein 200 kDa

AMPK:

5` Adenosine monophosphate-activated protein kinase

PI3P:

Phosphatidylinositol triphosphate

LC3:

Microtubule-associated protein 1A/1B-light chain 3

PE:

Phosphatidylethanolamine

SQSTM1/p62:

Sequestosome-1/ubiquitin-binding protein p62

NIX:

BNIP3L/Receptor for mitochondrial protein

OPTN:

Optineurin

LAMP2:

Lysosome-associated membrane protein 2

GRASP55:

Golgi reassembly-stacking protein 55

EMS:

Eukaryotic endomembrane system

ILVs:

Intraluminal vesicles

MVBs:

Multivesicular bodies

MDB:

Mallory-Denk bodies

ATP:

Adenosine triphosphate

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

Nrf2-Keap1:

Nuclear factor erythroid 2-related factor 2-kelch-like ECH-associated protein 1

HIF:

Hypoxia inducible factor

BNIP3:

BCL2 and adenovirus E1B 19-kDa-interacting protein 3

BNIP3L:

BCL2: adenovirus E1B 19-kDa-interacting protein 3-like

COX2:

Cyclooxygenase-2

PGE2:

Prostaglandin E(2)

TNM:

Tumour, node, metastasis

CTC:

Circulatory tumour cells

EMT:

Epithelial-mesenchymal transition

TGF-β:

Transforming growth factor β

TRAF6:

Tumour necrosis factor receptor-associated factor-6

TAK1:

TGF-β activated kinase 1

DRAM1:

DNA damage modulator 1

CREB:

CAMP response element binding

HO-1:

ROS/heme oxygenase 1

UPR:

Unfolded protein response

HSP:

Heat shock protein

5-FU:

5-Fluorouracil

TAE:

Transarterial embolization

TACE:

Transarterial chemoembolization

Egr-1:

Early growth response-1

IR:

Ionizing radiation

VEGFR:

Vascular endothelial growth factor receptor

PDGFR-β:

Platelet-derived growth factor receptor β

GSTM1:

Glutathione transferase Mu 1

LCSC:

Liver cancer stem cells

AFP:

Alpha fetoprotein

FGFs:

Fibroblast growth factors

ECM:

Extracellular matrix

SIRT1 :

Gene encoding Sirtuin1 protein

ALDH:

Aldehyde dehydrogenase

ABC:

ATP-binding cassette

4-HNE:

4-Hydroxy-2-nonenal

NAD:

Nicotinamide adenosine dinucleotide

MEK:

Mitogen-activated protein kinase

MRPS5:

Mitochondrial ribosomal protein S5

AC:

Acetyl

TCF/LEF:

T-cell factor/lymphoid enhancer factor

CSL, CBF-1:

Suppressor hairless lag-1

MAML:

Mastermind-like protein

NICD:

Notch intracellular domain

NECD:

Notch extracellular domain

LSD1:

Lysine demethylase 1

UPRmt:

Mitochondrial unfolded protein response

HPC/LPC:

Hepatic/liver progenitor cells

PINK1:

PTEN-induced putative kinase

HGF:

Hepatocyte growth factor

FGFR:

Fibroblast growth factor receptor

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Acknowledgements

We would like to thank Sunway University Postgraduate Degree by Research Scholarship for supporting M. M-.T.W. and H-.Y.C. This work was partly funded by Ministry of Higher Education Malaysia (FRGS/1/2019/SKK08/SYUC/02/1); and Sunway Medical Centre Research Funds (SRC/002/2017/FR and SRC/003/ 2017/FR).

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Authors and Affiliations

  1. Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, 47500 Subang Jaya, Bandar Sunway, Selangor Darul Ehsan, Malaysia

    Magdelyn Mei-Theng Wong, Hui-Yin Chan, Ewe Seng Ch’ng, Suat-Cheng Peh & Sin-Yeang Teow

  2. Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health (NIH Complex), Ministry of Health Malaysia, Level 4, Block C7, No: 1, Jalan Setia Murni U13/52, Section U13, Setia Alam, 40170 Shah Alam, 50588, Kuala Lumpur, Selangor, Malaysia

    Norazlin Abdul Aziz

  3. Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Thamil Selvee Ramasamy

  4. Sunway Medical Centre, Jalan Lagoon Selatan, 47500 Subang Jaya, Bandar Sunway, Selangor, Malaysia

    Jan-Jin Bong & Suat-Cheng Peh

  5. Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia

    Ewe Seng Ch’ng

  6. Pathology Department, Hospital Kuala Lumpur, Jalan Pahang, 50588, Kuala Lumpur, Malaysia

    Subasri Armon

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Contributions

SYT, TSR and SCP conceived and designed the analysis, MMTW and HYC wrote the paper, JJB, NAA, ESC and SA reviewed and edited the paper. All authors have read and agreed to the manuscript submission.

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Correspondence to Sin-Yeang Teow.

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Wong, M.MT., Chan, HY., Aziz, N.A. et al. Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Mol Biol Rep 48, 3695–3717 (2021). https://doi.org/10.1007/s11033-021-06334-9

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