AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Cancer Biology & Medicine Article
PDF (776.1 KB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Review | Open Access

The Wnt/β-catenin signaling pathway in the tumor microenvironment of hepatocellular carcinoma

Kaiting Wang1, Xinyao Qiu2, Yan Zhao1, Hongyang Wang3,4( ), Lei Chen4 ( )
School of Life Sciences, Fudan University, Shanghai 200438, China
Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Institute of Metabolism & Integrative Biology (IMIB), Fudan University, Shanghai 200438, China
The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
Show Author Information

Abstract

The Wnt/β-catenin signaling pathway regulates many aspects of tumor biology, and many studies have focused on the role of this signaling pathway in tumor cells. However, it is now clear that tumor development and metastasis depend on the two-way interaction between cancer cells and their environment, thereby forming a tumor microenvironment (TME). In this review, we discuss how Wnt/β-catenin signaling regulates cross-interactions among different components of the TME, including immune cells, stem cells, tumor vasculature, and noncellular components of the TME in hepatocellular carcinoma. We also investigate their preclinical and clinical insights for primary liver cancer intervention, and explore the significance of using Wnt/β-catenin mutations as a biomarker to predict resistance in immunotherapy.

Keywords

immunotherapytumor microenvironmentHCCWnt/β-catenin signaling

References

1

Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016; 67: 103-17.
Crossref Google Scholar
2

Yau T, Tang VYF, Yao T-J, Fan S-T, Lo C-M, Poon RTP. Development of hong kong liver cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology. 2014; 146: 1691-700.e3.
Crossref Google Scholar
3

Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011; 140: 1410-26.
Crossref Google Scholar
4

Nishida N, Kudo M. Immune checkpoint blockade for the treatment of human hepatocellular carcinoma. Hepatol Res. 2018; 48: 622-34.
Crossref Google Scholar
5

Pinyol R, Sia D, Llovet JM. Immune exclusion-wnt/CTNNB1 class predicts resistance to immunotherapies in HCC. Clin Cancer Res. 2019; 25: 2021-3.
Crossref Google Scholar
6

Tang H, Qiao J, Fu Y-X. Immunotherapy and tumor microenvironment. Cancer Lett. 2016; 370: 85-90.
Crossref Google Scholar
7

Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019; 16: 121-36.
Crossref Google Scholar
8

Wang W, Smits R, Hao H, He C. Wnt/β-catenin signaling in liver cancers. Cancers (Basel). 2019; 11: 926.
Crossref Google Scholar
9

Zucman-Rossi J, Villanueva A, Nault J-C, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015; 149: 1226-39.e4.
Crossref Google Scholar
10

Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev. 2018; 62: 50-60.
Crossref Google Scholar
11

Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012; 13: 767-9.
Crossref Google Scholar
12

Kikuchi A, Yamamoto H, Sato A, Matsumoto S. New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol. 2011; 291: 21-71.
Crossref Google Scholar
13

Routledge D, Scholpp S. Mechanisms of intercellular Wnt transport. Development. 2019; 146: dev176073.
Crossref Google Scholar
14

Hua Y, Yang Y, Li Q, He X, Zhu W, Wang J, et al. Oligomerization of frizzled and LRP5/6 protein initiates intracellular signaling for the canonical Wnt/β-catenin pathway. J Biol Chem. 2018; 293: 19710-24.
Crossref Google Scholar
15

Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, et al. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes Cells. 1998; 3: 395-403.
Crossref Google Scholar
16

Kimelman D, Xu W. Beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene. 2006; 25: 7482-91.
Crossref Google Scholar
17

Bryja V, Schulte G, Arenas E. Wnt-3a utilizes a novel low dose and rapid pathway that does not require casein kinase 1-mediated phosphorylation of Dvl to activate beta-catenin. Cell Signal. 2007; 19: 610-6.
Crossref Google Scholar
18

Mosimann C, Hausmann G, Basler K. Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol. 2009; 10: 276-86.
Crossref Google Scholar
19

Teo JL, Kahn M. The Wnt signaling pathway in cellular proliferation and differentiation: a tale of two coactivators. Adv Drug Deliv Rev. 2010; 62: 1149-55.
Crossref Google Scholar
20

Li Z, Wu T, Zheng B, Chen L. Individualized precision treatment: targeting TAM in HCC. Cancer Lett. 2019; 458: 86-91.
Crossref Google Scholar
21

Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015; 212: 435-45.
Crossref Google Scholar
22

Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012; 18: 572-9.
Crossref Google Scholar
23

Debebe A, Medina V, Chen CY, Mahajan IM, Jia C, Fu D, et al. Wnt/β-catenin activation and macrophage induction during liver cancer development following steatosis. Oncogene. 2017; 36: 6020-9.
Crossref Google Scholar
24

Yang J, Mowry LE, Nejak-Bowen KN, Okabe H, Diegel CR, Lang RA, et al. Beta-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology. 2014; 60: 964-76.
Crossref Google Scholar
25

Yang Y, Ye YC, Chen Y, Zhao JL, Gao CC, Han H, et al. Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. Cell Death Dis. 2018; 9: 793.
Crossref Google Scholar
26

Ye Y-C, Zhao J-L, Lu Y-T, Gao C-C, Yang Y, Liang S-Q, et al. Notch signaling via WNT regulates the proliferation of alternative, CCR2-independent tumor-associated macrophages in hepatocellular carcinoma. Cancer Res. 2019; 79: 4160-72.
Crossref Google Scholar
27

Tian X, Wu Y, Yang Y, Wang J, Niu M, Gao S, et al. Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating Wnt/β-catenin signaling. Mol Oncol. 2020; 14: 462-83.
Crossref Google Scholar
28

Zhou J, Cheng P, Youn JI, Cotter MJ, Gabrilovich DI. Notch and wingless signaling cooperate in regulation of dendritic cell differentiation. Immunity. 2009; 30: 845-59.
Crossref Google Scholar
29

Xu WD, Wang J, Yuan TL, Li YH, Yang H, Liu Y, et al. Interactions between canonical Wnt signaling pathway and MAPK pathway regulate differentiation, maturation and function of dendritic cells. Cell Immunol. 2016; 310: 170-7.
Crossref Google Scholar
30

Spranger S, Gajewski TF. Tumor-intrinsic oncogene pathways mediating immune avoidance. Oncoimmunology. 2016; 5: e1086862.
Crossref Google Scholar
31

Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015; 523: 231-5.
Crossref Google Scholar
32

Yaguchi T, Goto Y, Kido K, Mochimaru H, Sakurai T, Tsukamoto N, et al. Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells. J Immunol. 2012; 189: 2110-7.
Crossref Google Scholar
33

Xiao X, Mo H, Tu K. CTNNB1 mutation suppresses infiltration of immune cells in hepatocellular carcinoma through mirna-mediated regulation of chemokine expression. Int Immunopharmacol. 2020; 89: 107043.
Crossref Google Scholar
34

Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, Lindblad KE, Maier B, Sia D, et al. Beta-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019; 9: 1124-41.
Crossref Google Scholar
35

Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019; 18: 197-218.
Crossref Google Scholar
36

Berraondo P, Ochoa MC, Olivera I, Melero I. Immune desertic landscapes in hepatocellular carcinoma shaped by β-catenin activation. Cancer Discov. 2019; 9: 1003-5.
Crossref Google Scholar
37

Luke JJ, Bao R, Sweis RF, Spranger S, Gajewski TF. WNT/beta-catenin pathway activation correlates with immune exclusion across human cancers. Clin Cancer Res. 2019; 25: 3074-83.
Crossref Google Scholar
38

Mei J, Yang X, Xia D, Zhou W, Gu D, Wang H, et al. Systematic summarization of the expression profiles and prognostic roles of the dishevelled gene family in hepatocellular carcinoma. Mol Genet Genomic Med. 2020; 8: e1384.
Crossref Google Scholar
39

Yang Y, Ye Y-C, Chen Y, Zhao J-L, Gao C-C, Han H, et al. Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. Cell Death Dis. 2018; 9: 793.
Crossref Google Scholar
40

Ji L, Qian W, Gui L, Ji Z, Yin P, Lin GN, et al. Blockade of beta-catenin-induced CCL28 suppresses gastric cancer progression via inhibition of Treg cell infiltration. Cancer Res. 2020; 80: 2004-16.
Crossref Google Scholar
41

Feng M, Jin JQ, Xia L, Xiao T, Mei S, Wang X, et al. Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating T(reg) cells. Science Adv. 2019; 5: eaau5240.
Crossref Google Scholar
42

Duwaerts CC, Gregory SH. Targeting the diverse immunological functions expressed by hepatic NKT cells. Expert Opin Ther Targets. 2011; 15: 973-88.
Crossref Google Scholar
43

Bandyopadhyay K, Marrero I, Kumar V. NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol. 2016; 13: 337-46.
Crossref Google Scholar
44

Anson M, Crain-Denoyelle A-M, Baud V, Chereau F, Gougelet A, Terris B, et al. Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest. 2012; 122: 586-99.
Crossref Google Scholar
45

Kling JC, Jordan MA, Pitt LA, Meiners J, Thanh-Tran T, Tran LS, et al. Temporal regulation of natural killer T cell interferon gamma responses by β-catenin-dependent and -independent Wnt signaling. Front Immunol. 2018; 9: 483.
Crossref Google Scholar
46

de Sousa e Melo F, Kurtova AV, Harnoss JM, Kljavin N, Hoeck JD, Hung J, et al. A distinct role for LGR5(+) stem cells in primary and metastatic colon cancer. Nature. 2017; 543: 676-80.
Crossref Google Scholar
47

Koury J, Zhong L, Hao J. Targeting signaling pathways in cancer stem cells for cancer treatment. Stem cells Int. 2017; 2017: 2925869.
Crossref Google Scholar
48

Pandit H, Li Y, Li X, Zhang W, Li S, Martin RCG. Enrichment of cancer stem cells via beta-catenin contributing to the tumorigenesis of hepatocellular carcinoma. BMC Cancer. 2018; 18: 783.
Crossref Google Scholar
49

Katoh M. Canonical and non-canonical wnt signaling in cancer stem cells and their niches: cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (review). Int J Oncol. 2017; 51: 1357-69.
Crossref Google Scholar
50

Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang H-Y, et al. EPCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009; 136: 1012-24.
Crossref Google Scholar
51

Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, et al. CD44V6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 2014; 14: 342-56.
Crossref Google Scholar
52

Liao WY, Hsu CC, Chan TS, Yen CJ, Chen WY, Pan HW, et al. Dishevelled 1-regulated superpotent cancer stem cells mediate Wnt heterogeneity and tumor progression in hepatocellular carcinoma. Stem Cell Reports. 2020; 14: 462-77.
Crossref Google Scholar
53

Khosla R, Rastogi A, Ramakrishna G, Pamecha V, Mukhopadhyay A, Vasudevan M, et al. EPCAM+ liver cancer stem-like cells exhibiting autocrine wnt signaling potentially originate in cirrhotic patients. Stem Cells Transl Med. 2017; 6: 807-18.
Crossref Google Scholar
54

Hilkens J, Timmer NC, Boer M, Ikink GJ, Schewe M, Sacchetti A, et al. RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis. Gut. 2017; 66: 1095-105.
Crossref Google Scholar
55

Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, et al. The long noncoding RNA LNCTCF7 promotes self-renewal of human liver cancer stem cells through activation of wnt signaling. Cell Stem Cell. 2015; 16: 413-25.
Crossref Google Scholar
56

Fan Z, Duan J, Wang L, Xiao S, Li L, Yan X, et al. PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/beta-catenin signaling. Cancer Lett. 2019; 450: 132-43.
Crossref Google Scholar
57
Zhu K, Li J, Li J, Sun J, Guo Y, Tian H, et al. Ring1 promotes the transformation of hepatic progenitor cells into cancer stem cells through the Wnt/β-catenin signaling pathway [Online ahead of print]. J Cell Biochem. 2019; 10.1002/jcb.29496.
Crossref
58

Xiang D, Cheng Z, Liu H, Wang X, Han T, Sun W, et al. Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients. Hepatology. 2017; 65: 1566-80.
Crossref Google Scholar
59

Lai KKY, Kweon SM, Chi F, Hwang E, Kabe Y, Higashiyama R, et al. Stearoyl-coa desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6. Gastroenterology. 2017; 152: 1477-91.
Crossref Google Scholar
60

Książkiewicz M, Markiewicz A, Zaczek AJ. Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology. 2012; 79: 195-208.
Crossref Google Scholar
61

DiMeo TA, Anderson K, Phadke P, Fan C, Feng C, Perou CM, et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res. 2009; 69: 5364-73.
Crossref Google Scholar
62

Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene. 2008; 27: 6958-69.
Crossref Google Scholar
63

Chen D, Yu D, Wang X, Liu Y, He Y, Deng R, et al. Epithelial to mesenchymal transition is involved in ethanol promoted hepatocellular carcinoma cells metastasis and stemness. Mol Carcinog. 2018; 57: 1358-70.
Crossref Google Scholar
64

Guo R, Wu Z, Wang J, Li Q, Shen S, Wang W, et al. Development of a non-coding-RNA-based EMT/CSC inhibitory nanomedicine for in vivo treatment and monitoring of hcc. Adv Sci (Weinh). 2019; 6: 1801885.
Crossref Google Scholar
65

Wang N, Wang S, Li MY, Hu BG, Liu LP, Yang SL, et al. Cancer stem cells in hepatocellular carcinoma: an overview and promising therapeutic strategies. Ther Adv Med Oncol. 2018; 10: 1758835918816287.
Crossref Google Scholar
66

Liu YC, Yeh CT, Lin KH. Cancer stem cell functions in hepatocellular carcinoma and comprehensive therapeutic strategies. Cells. 2020; 9: 1331.
Crossref Google Scholar
67

Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015; 12: 445-64.
Crossref Google Scholar
68

Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM. Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J Clin Med. 2019; 9: 84.
Crossref Google Scholar
69

Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M, et al. The role of angiogenesis in hepatocellular carcinoma. Clin Cancer Res. 2019; 25: 912-20.
Crossref Google Scholar
70

Guo P, Wang Y, Dai C, Tao C, Wu F, Xie X, et al. Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/beta-catenin-induced FGF18 expression in hepatocellular carcinoma. Oncogene. 2018; 37: 1220-36.
Crossref Google Scholar
71

Yang C, Xu Y, Cheng F, Hu Y, Yang S, Rao J, et al. miR-1301 inhibits hepatocellular carcinoma cell migration, invasion, and angiogenesis by decreasing Wnt/beta-catenin signaling through targeting BCL9. Cell Death Dis. 2017; 8: e2999.
Crossref Google Scholar
72

Reis M, Liebner S. Wnt signaling in the vasculature. Exp Cell Res. 2013; 319: 1317-23.
Crossref Google Scholar
73

Hu J, Dong A, Fernandez-Ruiz V, Shan J, Kawa M, Martinez-Anso E, et al. Blockade of Wnt signaling inhibits angiogenesis and tumor growth in hepatocellular carcinoma. Cancer Res. 2009; 69: 6951-9.
Crossref Google Scholar
74

Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature. 2001; 411: 375-9.
Crossref Google Scholar
75

Henke E, Nandigama R, Ergun S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front Mol Biosci. 2019; 6: 160.
Crossref Google Scholar
76

Li ZQ, Ding W, Sun SJ, Li J, Pan J, Zhao C, et al. Cyr61/CCN1 is regulated by Wnt/beta-catenin signaling and plays an important role in the progression of hepatocellular carcinoma. PLoS One. 2012; 7: e35754.
Crossref Google Scholar
77

Li ZQ, Wu WR, Zhao C, Zhao C, Zhang XL, Yang Z, et al. CCN1/Cyr61 enhances the function of hepatic stellate cells in promoting the progression of hepatocellular carcinoma. Int J Mol Med. 2018; 41: 1518-28.
Crossref Google Scholar
78

Liu S, Qiu J, He G, Geng C, He W, Liu C, et al. Dermatopontin inhibits WNT signaling pathway via CXXC finger protein 4 in hepatocellular carcinoma. J Cancer. 2020; 11: 6288-98.
Crossref Google Scholar
79

Wang W, Pan Q, Fuhler GM, Smits R, Peppelenbosch MP. Action and function of Wnt/beta-catenin signaling in the progression from chronic hepatitis c to hepatocellular carcinoma. J Gastroenterol. 2017; 52: 419-31.
Crossref Google Scholar
80

Kim E, Lisby A, Ma C, Lo N, Ehmer U, Hayer KE, et al. Promotion of growth factor signaling as a critical function of beta-catenin during HCC progression. Nat Commun. 2019; 10: 1909.
Crossref Google Scholar
81

Cui G, Martin RC, Jin H, Liu X, Pandit H, Zhao H, et al. Up-regulation of FGF15/19 signaling promotes hepatocellular carcinoma in the background of fatty liver. J Exp Clin Cancer Res. 2018; 37: 136.
Crossref Google Scholar
82

Maass T, Thieringer FR, Mann A, Longerich T, Schirmacher P, Strand D, et al. Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis. Int J Cancer. 2011; 128: 1259-68.
Crossref Google Scholar
83

Liu X, Zhang Z, Pan S, Shang S, Li C. Interaction between the Wnt/beta-catenin signaling pathway and the EMMPRIN/MMP-2, 9 route in periodontitis. J Periodontal Res. 2018; 53: 842-52.
Crossref Google Scholar
84

Liu FH, Cui YP, He YK, Shu RH. FBXO17 promotes malignant progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway. Eur Rev Med Pharmacol Sci. 2019; 23: 8265-73.
Google Scholar
85

Yang X, Du X, Sun L, Zhao X, Zhu J, Li G, et al. SULT2B1b promotes epithelial-mesenchymal transition through activation of the beta-catenin/MMP7 pathway in hepatocytes. Biochem Biophys Res Commun. 2019; 510: 495-500.
Crossref Google Scholar
86

Tan S, Xia L, Yi P, Han Y, Tang L, Pan Q, et al. Exosomal miRNAs in tumor microenvironment. J Exp Clin Cancer Res. 2020; 39: 67.
Crossref Google Scholar
87

Chen L, Guo P, He Y, Chen Z, Chen L, Luo Y, et al. HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway. Cell Death Dis. 2018; 9: 513.
Crossref Google Scholar
88

Wu Q, Zhou L, Lv D, Zhu X, Tang H. Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression. J Hematol Oncol. 2019; 12: 53.
Crossref Google Scholar
89

Yu Y, Min Z, Zhou Z, Linhong M, Tao R, Yan L, et al. Hypoxia-induced exosomes promote hepatocellular carcinoma proliferation and metastasis via miR-1273f transfer. Exp Cell Res. 2019; 385: 111649.
Crossref Google Scholar
90

Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010; 70: 4840-9.
Crossref Google Scholar
91

Wang R, Sun Q, Wang P, Liu M, Xiong S, Luo J, et al. Notch and Wnt/beta-catenin signaling pathway play important roles in activating liver cancer stem cells. Oncotarget. 2016; 7: 5754-68.
Crossref Google Scholar
92

Ye YC, Zhao JL, Lu YT, Gao CC, Yang Y, Liang SQ, et al. NOTCH signaling via WNT regulates the proliferation of alternative, CCR2-independent tumor-associated macrophages in hepatocellular carcinoma. Cancer Res. 2019; 79: 4160-72.
Crossref Google Scholar
93

Kim W, Khan SK, Gvozdenovic-Jeremic J, Kim Y, Dahlman J, Kim H, et al. Hippo signaling interactions with Wnt/beta-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest. 2017; 127: 137-52.
Crossref Google Scholar
94
Wei S, Dai M, Zhang C, Teng K, Wang F, Li H, et al. KIF2C: a novel link between Wnt/beta-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma [Online ahead of print]. Protein Cell. 2020; 10.1007/s13238-020-00766-y.
Crossref
95

Zucchini-Pascal N, Peyre L, Rahmani R. Crosstalk between beta-catenin and snail in the induction of epithelial to mesenchymal transition in hepatocarcinoma: role of the ERK1/2 pathway. Int J Mol Sci. 2013; 14: 20768-92.
Crossref Google Scholar
96

Steinway SN, Zanudo JG, Ding W, Rountree CB, Feith DJ, Loughran Jr TP, et al. Network modeling of TGFbeta signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint sonic hedgehog and Wnt pathway activation. Cancer Res. 2014; 74: 5963-77.
Crossref Google Scholar
97

Zhang Q, Bai X, Chen W, Ma T, Hu Q, Liang C, et al. Wnt/beta-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1alpha signaling. Carcinogenesis. 2013; 34: 962-73.
Crossref Google Scholar
98

Harb J, Lin P-J, Hao J. Recent development of Wnt signaling pathway inhibitors for cancer therapeutics. Curr Oncol Rep. 2019; 21: 12.
Crossref Google Scholar
99

Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013; 59: 1107-17.
Crossref Google Scholar
100

Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/beta-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol. 2016; 22: 823-32.
Crossref Google Scholar
101

Qin X, Zhang H, Zhou X, Wang C, Zhang H, Zhang X, et al. Proliferation and migration mediated by Dkk-1/Wnt/beta-catenin cascade in a model of hepatocellular carcinoma cells. Transl Res. 2007; 150: 281-94.
Crossref Google Scholar
102

Chen L, Li M, Li Q, Wang CJ, Xie SQ. DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway. Mol Cancer. 2013; 12: 157.
Crossref Google Scholar
103

Zhang R, Lin HM, Broering R, Shi XD, Yu XH, Xu LB, et al. Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the Wnt/beta-catenin signaling pathway. Signal Transduct Target Ther. 2019; 4: 54.
Crossref Google Scholar
104

Wall JA, Klempner SJ, Arend RC. The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer. Expert Opin Investig Drugs. 2020; 29: 639-44.
Crossref Google Scholar
105

Liang Y, Feng Y, Zong M, Wei XF, Lee J, Feng Y, et al. Beta-catenin deficiency in hepatocytes aggravates hepatocarcinogenesis driven by oncogenic beta-catenin and met. Hepatology. 2018; 67: 1807-22.
Crossref Google Scholar
106

Zhang LY, Zhang JG, Yang X, Cai MH, Zhang CW, Hu ZM. Targeting tumor immunosuppressive microenvironment for the prevention of hepatic cancer: applications of traditional chinese medicines in targeted delivery. Curr Top Med Chem. 2020; 20: 2789-800.
Crossref Google Scholar
107

Huang M, Wu S, Hu Q, Wu H, Wei S, Xie H, et al. Agkihpin, a novel SVAE may inhibit the migration and invasion of liver cancer cells associated with the inversion of EMT induced by Wnt/beta-catenin signaling inhibition. Biochem Biophys Res Commun. 2016; 479: 283-9.
Crossref Google Scholar
108

Guo Z, Zhou Y, Yang J, Shao X. Dendrobium candidum extract inhibits proliferation and induces apoptosis of liver cancer cells by inactivating Wnt/beta-catenin signaling pathway. Biomed Pharmacother. 2019; 110: 371-9.
Crossref Google Scholar
109

Chen XZ, Cao ZY, Li JN, Hu HX, Zhang YQ, Huang YM, et al. Ethyl acetate extract from jiedu xiaozheng yin inhibits the proliferation of human hepatocellular carcinoma cells by suppressing polycomb gene product Bmi1 and Wnt/beta-catenin signaling. Oncol Rep. 2014; 32: 2710-8.
Crossref Google Scholar
110

Wu HC, Lay IS, Shibu MA, Ho TJ, Cheng SM, Lin CH, et al. Zanthoxylum avicennae extract enhances GSK-3beta to attenuate beta-catenin via phosphatase 2A to block metastatic effects of HA22T cells and hepatocellular carcinoma xenografted nude mice. Environ Toxicol. 2017; 32: 2133-43.
Crossref Google Scholar
111

Wei Y, Shen N, Wang Z, Yang G, Yi B, Yang N, et al. Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/β-catenin signaling. Mol Cell Biochem. 2013; 381: 139-44.
Crossref Google Scholar
112

Deng L, Sun J, Chen X, Liu L, Wu D. Nek2 augments sorafenib resistance by regulating the ubiquitination and localization of beta-catenin in hepatocellular carcinoma. J Exp Clin Cancer Res. 2019; 38: 316.
Crossref Google Scholar
113

Lin HH, Feng WC, Lu LC, Shao YY, Hsu CH, Cheng AL. Inhibition of the Wnt/beta-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma. Cancer Lett. 2016; 381: 58-66.
Crossref Google Scholar
114

Nagel C, Armeanu-Ebinger S, Dewerth A, Warmann SW, Fuchs J. Anti-tumor activity of sorafenib in a model of a pediatric hepatocellular carcinoma. Exp Cell Res. 2015; 331: 97-104.
Crossref Google Scholar
115

Turcios L, Chacon E, Garcia C, Eman P, Cornea V, Jiang J, et al. Autophagic flux modulation by Wnt/beta-catenin pathway inhibition in hepatocellular carcinoma. PLoS One. 2019; 14: e0212538.
Crossref Google Scholar
116

Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase Ⅲ trial. J Clin Oncol. 2020; 38: 193-202.
Crossref Google Scholar
117

Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019; 25: 2116-26.
Crossref Google Scholar
118

Du L, Lee JH, Jiang H, Wang C, Wang S, Zheng Z, et al. Beta-catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion. J Exp Med. 2020; 217: e20191115.
Crossref Google Scholar
119

Deng R, Zuo C, Li Y, Xue B, Xun Z, Guo Y, et al. The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/beta-catenin signaling pathway. Cell Mol Immunol. 2020; 17: 1163-79.
Crossref Google Scholar
Cancer Biology & Medicine
Volume 19 Issue 3,
March 2022
Pages 305-318
DOI: 10.20892/j.issn.2095-3941.2021.0306
Cite this article:
Wang K, Qiu X, Zhao Y, et al. The Wnt/β-catenin signaling pathway in the tumor microenvironment of hepatocellular carcinoma. Cancer Biology & Medicine, 2022, 19(3): 305-318. https://doi.org/10.20892/j.issn.2095-3941.2021.0306

198

Views

2

Downloads

6

Crossref

18

Web of Science

16

Scopus

Altmetrics
Received: 19 May 2021
Accepted: 20 August 2021
Published: 15 March 2022
©2022 Cancer Biology & Medicine.

Creative Commons Attribution-NonCommercial 4.0 International License
Return