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
PDF (2.5 MB)
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Review Article | Open Access

Diverse functions of SOX9 in liver development and homeostasis and hepatobiliary diseases

Taiyu Shanga,1Tianyi Jiangb,c,1Xiaowen CuibYufei PanbXiaofan Fengb,cLiwei Dongb,c( )Hongyang Wanga,b,c,d,( )
School of Life Sciences, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
National Center for Liver Cancer, The Naval Medical University, Shanghai 201805, China
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China
Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University & Ministry of Education, Shanghai 200438, China

1 These authors contributed equally to this work.

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative capacities. The hepatobiliary system originates from the foregut endoderm, in which cells undergo multiple events of cell proliferation, migration, and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription factors. Studies on liver development and diseases have revealed that SRY-related high-mobility group box 9 (SOX9) plays an important role in liver embryogenesis and the progression of hepatobiliary diseases. SOX9 is not only a master regulator of cell fate determination and tissue morphogenesis, but also regulates various biological features of cancer, including cancer stemness, invasion, and drug resistance, making SOX9 a potential biomarker for tumor prognosis and progression. This review systematically summarizes the latest findings of SOX9 in hepatobiliary development, homeostasis, and disease. We also highlight the value of SOX9 as a novel biomarker and potential target for the clinical treatment of major liver diseases.

References

1

Paulusma CC, Lamers WH, Broer S, et al. Amino acid metabolism, transport and signalling in the liver revisited. Biochem Pharmacol. 2022;201:115074.

2

Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27(21):R1147-R1151.

3

Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450-1462.

4

Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20.

5

Song Q, Chen Y, Wang J, et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development. J Hepatol. 2020;73(4):783-793.

6

He L, Pu W, Liu X, et al. Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair. Science. 2021;371(6532):eabc4346.

7

Jin B, Wu XA, Du SD. Human pluripotent stem cell-derived hepatic organoids: a promising novel model of liver diseases. Gastroenterology. 2021;160(6):2208.

8

Liu Y, Zhuo S, Zhou Y, et al. Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis. J Hepatol. 2022;76(3):652-664.

9

Luo X, Ji X, Xie M, et al. Advance of SOX transcription factors in hepatocellular carcinoma: from role, tumor immune relevance to targeted therapy. Cancers. 2022;14(5):1165.

10

Grimm D, Bauer J, Wise P, et al. The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol. 2020;67:122-153.

11

Ren Z, Chen Y, Shi L, et al. Sox9/CXCL5 axis facilitates tumour cell growth and invasion in hepatocellular carcinoma. FEBS J. 2022;289(12):3535-3549.

12

Li J, Chen X, Zhu L, et al. SOX9 is a critical regulator of TSPAN8-mediated metastasis in pancreatic cancer. Oncogene. 2021;40(30):4884-4893.

13

Chen S, Huang H, Liu Y, et al. Renal subcapsular delivery of PGE2 promotes kidney repair by activating endogenous Sox9+ stem cells. iScience. 2021;24(11):103243.

14

Yuan X, Li J, Coulouarn C, et al. SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance. Br J Cancer. 2018;119(11):1358-1366.

15

Prévostel C, Blache P. The dose-dependent effect of SOX9 and its incidence in colorectal cancer. Eur J Cancer. 2017;86:150-157.

16

Liu C, Liu L, Chen X, et al. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology. 2016;64(1):117-129.

17

Ma F, Ye H, He HH, et al. SOX9 drives WNT pathway activation in prostate cancer. J Clin Invest. 2016;126(5):1745-1758.

18

Aleman A, Adrien L, Lopez-Serra L, et al. Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays. Br J Cancer. 2008;98(2):466-473.

19

Yang X, Liang R, Liu C, et al. SOX9 is a dose-dependent metastatic fate determinant in melanoma. J Exp Clin Cancer Res. 2019;38(1):17.

20

He S, Feng Y, Zou W, et al. The role of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 regulatory loop in cervical cancer cell growth and resistance to cisplatin. Front Oncol. 2021;11:784525.

21

Gubbay J, Collignon J, Koopman P, et al. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature. 1990;346(6281):245-250.

22

Kumar P, Mistri TK. Transcription factors in SOX family: potent regulators for cancer initiation and development in the human body. Semin Cancer Biol. 2020;67(Pt 1):105-113.

23

Zhang Y, Hou L. Alternate roles of sox transcription factors beyond transcription initiation. Int J Mol Sci. 2021;22(11):5949.

24

Liu CF, Lefebvre V. The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis. Nucleic Acids Res. 2015;43(17):8183-8203.

25

Harley VR, Lovell-Badge R, Goodfellow PN. Definition of a consensus DNA binding site for SRY. Nucleic Acids Res. 1994;22(8):1500-1501.

26

Wegner M. All purpose Sox: the many roles of Sox proteins in gene expression. Int J Biochem Cell Biol. 2010;42(3):381-390.

27

Miyagi S, Kato H, Okuda A. Role of SoxB1 transcription factors in development. Cell Mol Life Sci. 2009;66(23):3675-3684.

28

Kavyanifar A, Turan S, Lie DC. SoxC transcription factors: multifunctional regulators of neurodevelopment. Cell Tissue Res. 2018;371(1):91-103.

29

Bernard P, Tang P, Liu S, et al. Dimerization of SOX9 is required for chondrogenesis, but not for sex determination. Hum Mol Genet. 2003;12(14):1755-1765.

30

Francois M, Koopman P, Beltrame M. SoxF genes: key players in the development of the cardio-vascular system. Int J Biochem Cell Biol. 2010;42(3):445-448.

31

Lefebvre V. The SoxD transcription factors–Sox5, Sox6, and Sox13–are key cell fate modulators. Int J Biochem Cell Biol. 2010;42(3):429-432.

32

Zhang D, Guo S, Wang H, et al. SOX15 exerts antitumor function in glioma by inhibiting cell proliferation and invasion via downregulation of Wnt/β-catenin signaling. Life Sci. 2020;255:117792.

33

Ding Y, Feng Y, Huang Z, et al. SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer. Cell Death Dis. 2022;13(8):673.

34

Osaki E, Nishina Y, Inazawa J, et al. Identification of a novel Sry-related gene and its germ cell-specific expression. Nucleic Acids Res. 1999;27(12):2503-2510.

35

Han F, Liu WB, Li JJ, et al. SOX30 is a prognostic biomarker and chemotherapeutic indicator for advanced-stage ovarian cancer. Endocr Relat Cancer. 2020;27(2):X1-X2.

36

Han F, Liu WB, Shi XY, et al. SOX30 inhibits tumor metastasis through attenuating wnt-signaling via transcriptional and posttranslational regulation of β-catenin in lung cancer. EBioMedicine. 2018;31:253-266.

37

Symon A, Harley V. SOX9: a genomic view of tissue specific expression and action. Int J Biochem Cell Biol. 2017;87:18-22.

38

Nakamura Y, Yamamoto K, He X, et al. Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25. Nat Commun. 2011;2:251.

39

Ohba S, He X, Hojo H, et al. Distinct transcriptional programs underlie Sox9 regulation of the mammalian chondrocyte. Cell Rep. 2015;12(2):229-243.

40

Panda M, Tripathi SK, Biswal BK. SOX9: an emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta Rev Cancer. 2021;1875(2):188517.

41

Gasca S, Canizares J, De Santa Barbara P, et al. A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination. Proc Natl Acad Sci U S A. 2002;99(17):11199-11204.

42

Foster JW, Dominguez-Steglich MA, Guioli S, et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994;372(6506):525-530.

43

Wagner T, Wirth J, Meyer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994;79(6):1111-1120.

44

Akiyama H. Control of chondrogenesis by the transcription factor Sox9. Mod Rheumatol. 2008;18(3):213-219.

45

Topol L, Chen W, Song H, et al. Sox9 inhibits Wnt signaling by promoting β-catenin phosphorylation in the nucleus. J Biol Chem. 2009;284(5):3323-3333.

46

Antoniou A, Raynaud P, Cordi S, et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology. 2009;136(7):2325-2333.

47

Piper Hanley K, Oakley F, Sugden S, et al. Ectopic SOX9 mediates extracellular matrix deposition characteristic of organ fibrosis. J Biol Chem. 2008;283(20):14063-14071.

48

Jana S, Madhu Krishna B, Singhal J, et al. SOX9: the master regulator of cell fate in breast cancer. Biochem Pharmacol. 2020;174:113789.

49

Jeselsohn R, Cornwell M, Pun M, et al. Embryonic transcription factor SOX9 drives breast cancer endocrine resistance. Proc Natl Acad Sci U S A. 2017;114(22):E4482-E4491.

50

Ma Y, Shepherd J, Zhao D, et al. SOX9 is essential for triple-negative breast cancer cell survival and metastasis. Mol Cancer Res. 2020;18(12):1825-1838.

51

Huang JQ, Wei FK, Xu XL, et al. SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/β-catenin pathway. J Transl Med. 2019;17(1):143.

52

Turcatel G, Rubin N, Menke DB, et al. Lung mesenchymal expression of Sox9 plays a critical role in tracheal development. BMC Biol. 2013;11:117.

53

Wang X, Yin Y, Du R. SOX9 dependent FOXA1 expression promotes tumorigenesis in lung carcinoma. Biochem Biophys Res Commun. 2019;516(1):236-244.

54

Gonen N, Lovell-Badge R. The regulation of Sox9 expression in the gonad. Curr Top Dev Biol. 2019;134:223-252.

55

Sim H, Argentaro A, Harley VR. Boys, girls and shuttling of SRY and SOX9. Trends Endocrinol Metabol. 2008;19(6):213-222.

56

Chang L, An Z, Zhang J, et al. RETRACTED: H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation. Mol Ther Nucleic Acids. 2021;24:622-633.

57

Sun W, Cornwell A, Li J, et al. SOX9 is an astrocyte-specific nuclear marker in the adult brain outside the neurogenic regions. J Neurosci. 2017;37(17):4493-4507.

58

Chen Z, Huang J, Liu Y, et al. FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands. Development. 2014;141(13):2691-2701.

59

Cohen-Tayar Y, Cohen H, Mitiagin Y, et al. Pax6 regulation of Sox9 in the mouse retinal pigmented epithelium controls its timely differentiation and choroid vasculature development. Development. 2018;145(15):dev163691.

60

Yokoi H, Yan YL, Miller MR, et al. Expression profiling of zebrafish sox9 mutants reveals that Sox9 is required for retinal differentiation. Dev Biol. 2009;329(1):1-15.

61

Moniot B, Biau S, Faure S, et al. SOX9 specifies the pyloric sphincter epithelium through mesenchymal-epithelial signals. Development. 2004;131(15):3795-3804.

62

Santos JC, Carrasco-Garcia E, Garcia-Puga M, et al. SOX9 elevation acts with canonical WNT signaling to drive gastric cancer progression. Cancer Res. 2016;76(22):6735-6746.

63

McDonald E, Li J, Krishnamurthy M, et al. SOX9 regulates endocrine cell differentiation during human fetal pancreas development. Int J Biochem Cell Biol. 2012;44(1):72-83.

64

Seymour PA, Freude KK, Tran MN, et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci U S A. 2007;104(6):1865-1870.

65

Ma Q, Wang Y, Zhang T, et al. Notch-mediated Sox9+ cell activation contributes to kidney repair after partial nephrectomy. Life Sci. 2018;193:104-109.

66

Raza S, Jokl E, Pritchett J, et al. SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function. Sci Signal. 2021;14(672):eabb4282.

67

Reginensi A, Clarkson M, Neirijnck Y, et al. SOX9 controls epithelial branching by activating RET effector genes during kidney development. Hum Mol Genet. 2011;20(6):1143-1153.

68

Akiyama H, Chaboissier MC, Behringer RR, et al. Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa. Proc Natl Acad Sci U S A. 2004;101(17):6502-6507.

69

Lincoln J, Kist R, Scherer G, et al. Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development. Dev Biol. 2007;305(1):120-132.

70

Thomsen MK, Francis JC, Swain A. The role of Sox9 in prostate development. Differentiation. 2008;76(6):728-735.

71

Wang H, McKnight NC, Zhang T, et al. SOX9 is expressed in normal prostate basal cells and regulates androgen receptor expression in prostate cancer cells. Cancer Res. 2007;67(2):528-536.

72

Liu JAJ, Wu MH, Yan CH, et al. Phosphorylation of Sox9 is required for neural crest delamination and is regulated downstream of BMP and canonical Wnt signaling. Proc Natl Acad Sci U S A. 2013;110(8):2882-2887.

73

Scott CE, Wynn SL, Sesay A, et al. SOX9 induces and maintains neural stem cells. Nat Neurosci. 2010;13(10):1181-1189.

74

Passeron T, Valencia JC, Namiki T, et al. Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid. J Clin Invest. 2009;119(4):954-963.

75

Vidal VPI, Chaboissier MC, Lützkendorf S, et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr Biol. 2005;15(15):1340-1351.

76

Weider M, Wegner M. SoxE factors: transcriptional regulators of neural differentiation and nervous system development. Semin Cell Dev Biol. 2017;63:35-42.

77

Scharf GM, Kilian K, Cordero J, et al. Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation. JCI Insight. 2019;5(15):e126721.

78

Song H, Park KH. Regulation and function of SOX9 during cartilage development and regeneration. Semin Cancer Biol. 2020;67(Pt 1):12-23.

79

Leung VY, Gao B, Leung KK, et al. SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet. 2011;7(11):e1002356.

80

Kamachi Y, Uchikawa M, Kondoh H. Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet. 2000;16(4):182-187.

81

Ikeda T, Kamekura S, Mabuchi A, et al. The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis Rheum. 2004;50(11):3561-3573.

82

Lefebvre V, Li P, de Crombrugghe B. A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. EMBO J. 1998;17(19):5718-5733.

83

Zhang B, Zhang Y, Wu N, et al. Integrated analysis of COL2A1 variant data and classification of type II collagenopathies. Clin Genet. 2020;97(3):383-395.

84

Tsuda M, Takahashi S, Takahashi Y, et al. Transcriptional Co-activators CREB-binding protein and p300 regulate chondrocyte-specific gene expression via association with Sox9. J Biol Chem. 2003;278(29):27224-27229.

85

Sekido R, Lovell-Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature. 2008;453(7197):930-934.

86

Pastore N, Huynh T, Herz NJ, et al. TFEB regulates murine liver cell fate during development and regeneration. Nat Commun. 2020;11(1):2461.

87

Sun L, Mathews LA, Cabarcas SM, et al. Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells. Stem Cell. 2013;31(8):1454-1466.

88

Ushita M, Saito T, Ikeda T, et al. Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells. Osteoarthritis Cartilage. 2009;17(8):1065-1075.

89

Amarilio R, Viukov SV, Sharir A, et al. HIF1alpha regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Development. 2007;134(21):3917-3928.

90

Chen S, Tao J, Bae Y, et al. Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9. J Bone Miner Res. 2013;28(3):649-659.

91

Lefebvre V, Dvir-Ginzberg M. SOX9 and the many facets of its regulation in the chondrocyte lineage. Connect Tissue Res. 2017;58(1):2-14.

92

Deng Y, Li M, Zhuo M, et al. Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression. J Biol Chem. 2021;296:100121.

93

Cheng PF, Shakhova O, Widmer DS, et al. Methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma. Genome Biol. 2015;16(1):42.

94

Zhang H, Dong S, Feng J. Epigenetic profiling and mRNA expression reveal candidate genes as biomarkers for colorectal cancer. J Cell Biochem. 2019;120(6):10767-10776.

95

Abadi AJ, Zarrabi A, Gholami MH, et al. Small in size, but large in action: microRNAs as potential modulators of PTEN in breast and lung cancers. Biomolecules. 2021;11(2):304.

96

Zhang Y, Guo X, Xiong L, et al. microRNA-101 suppresses SOX9-dependent tumorigenicity and promotes favorable prognosis of human hepatocellular carcinoma. FEBS Lett. 2012;586(24):4362-4370.

97

Li B, Liu D, Yang P, et al. miR-613 inhibits liver cancer stem cell expansion by regulating SOX9 pathway. Gene. 2019;707:78-85.

98

Xiao Y, Sun Y, Liu G, et al. Androgen receptor (AR)/miR-520f-3p/SOX9 signaling is involved in altering hepatocellular carcinoma (HCC) cell sensitivity to the Sorafenib therapy under hypoxia via increasing cancer stem cells phenotype. Cancer Lett. 2019;444:175-187.

99

Salah Z, Abd El Azeem EM, Youssef HF, et al. Effect of tumor suppressor miR-34a loaded on ZSM-5 nanozeolite in hepatocellular carcinoma: In vitro and in vivo approach. Curr Gene Ther. 2019;19(5):342-354.

100

Gao L, Yan P, Guo FF, et al. miR-1-3p inhibits cell proliferation and invasion by regulating BDNF-TrkB signaling pathway in bladder cancer. Neoplasma. 2018;65(1):89-96.

101

Zhang H, Zhang Z, Gao L, et al. miR-1-3p suppresses proliferation of hepatocellular carcinoma through targeting SOX9. OncoTargets Ther. 2019;12:2149-2157.

102

Liu Y, Zhang W, Liu K, et al. miR-138 suppresses cell proliferation and invasion by inhibiting SOX9 in hepatocellular carcinoma. Am J Transl Res. 2016;8(5):2159-2168.

103

Yan Y, Wang R, Hu X, et al. MiR-126 regulates properties of SOX9+ liver progenitor cells during liver repair by targeting Hoxb6. Stem Cell Rep. 2020;15(3):706-720.

104

Chen X, Tang FR, Arfuso F, et al. The emerging role of long non-coding RNAs in the metastasis of hepatocellular carcinoma. Biomolecules. 2019;10(1):66.

105

Wu M, Zhang X, Han X, et al. The potential of long noncoding RNAs for precision medicine in human cancer. Cancer Lett. 2021;501:12-19.

106

Ashrafizaveh S, Ashrafizadeh M, Zarrabi A, et al. Long non-coding RNAs in the doxorubicin resistance of cancer cells. Cancer Lett. 2021;508:104-114.

107

Shen C, Yang C, Xia B, et al. Long non-coding RNAs: emerging regulators for chemo/immunotherapy resistance in cancer stem cells. Cancer Lett. 2021;500:244-252.

108

Wang Q, Wei S, Li L, et al. miR-139-5p sponged by LncRNA NEAT1 regulates liver fibrosis via targeting β-catenin/SOX9/TGF-β1 pathway. Cell Death Dis. 2021;7(1):243.

109

Zeng R, Wang C, Wang W, et al. Long non-coding RNA DUXAP9 promotes hepatocellular carcinoma cell stemness via directly interacting with sox9. Environ Toxicol. 2021;36(9):1793-1801.

110

Zhang W, Wu Y, Hou B, et al. A SOX9-AS1/miR-5590-3p/SOX9 positive feedback loop drives tumor growth and metastasis in hepatocellular carcinoma through the Wnt/β-catenin pathway. Mol Oncol. 2019;13(10):2194-2210.

111

Yan S, Shan X, Chen K, et al. LINC00052/miR-101-3p axis inhibits cell proliferation and metastasis by targeting SOX9 in hepatocellular carcinoma. Gene. 2018;679:138-149.

112

Wang W, Li Y, Li X, et al. Circular RNA circ-FOXP1 induced by SOX9 promotes hepatocellular carcinoma progression via sponging miR-875-3p and miR-421. Biomed Pharmacother. 2020;121:109517.

113

Huang W, Zhou X, Lefebvre V, et al. Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. Mol Cell Biol. 2000;20(11):4149-4158.

114

Malki S, Nef S, Notarnicola C, et al. Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation. EMBO J. 2005;24(10):1798-1809.

115

Chen LY, Lotz M, Terkeltaub R, et al. Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes. J Biol Chem. 2018;293(31):12259-12270.

116

Bar Oz M, Kumar A, Elayyan J, et al. Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes. Aging Cell. 2016;15(3):499-508.

117

Buhrmann C, Busch F, Shayan P, et al. Sirtuin-1 (SIRT1) is required for promoting chondrogenic differentiation of mesenchymal stem cells. J Biol Chem. 2014;289(32):22048-22062.

118

Ito T, Yadav N, Lee J, et al. Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification. BMC Dev Biol. 2009;9:47.

119

Hattori T, Kishino T, Stephen S, et al. E6-AP/UBE3A protein acts as a ubiquitin ligase toward SOX9 protein. J Biol Chem. 2013;288(49):35138-35148.

120

Akiyama H, Lyons JP, Mori-Akiyama Y, et al. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 2004;18(9):1072-1087.

121

van Es JH, Jay P, Gregorieff A, et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol. 2005;7(4):381-386.

122

Xu C, Ding YH, Wang K, et al. Claudin-7 deficiency promotes stemness properties in colorectal cancer through Sox9-mediated Wnt/β-catenin signalling. J Transl Med. 2021;19(1):311.

123

Grogan SP, Olee T, Hiraoka K, et al. Repression of chondrogenesis through binding of Notch signaling proteins HES-1 and HEY-1 to N-box domains in the COL2A1 enhancer site. Arthritis Rheum. 2008;58(9):2754-2763.

124

Kohn A, Rutkowski TP, Liu Z, et al. Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9. Bone Res. 2015;3:15021.

125

Martini S, Bernoth K, Main H, et al. A critical role for Sox9 in Notch-induced astrogliogenesis and stem cell maintenance. Stem Cell. 2013;31(4):741-751.

126

Mead TJ, Yutzey KE. Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development. Proc Natl Acad Sci U S A. 2009;106(34):14420-14425.

127

Wang W, Feng Y, Aimaiti Y, et al. TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1-Notch-Sox9 signaling axis. J Cell Physiol. 2018;233(8):5780-5791.

128

Park J, Zhang JJR, Moro A, et al. Regulation of Sox9 by Sonic Hedgehog (Shh) is essential for patterning and formation of tracheal cartilage. Dev Dynam. 2010;239(2):514-526.

129

Pritchett J, Harvey E, Athwal V, et al. Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans. Hepatology. 2012;56(3):1108-1116.

130

Nguyen MB, Cohen I, Kumar V, et al. FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells. Nat Commun. 2018;9(1):2333.

131

Seymour PA, Shih HP, Patel NA, et al. A Sox9/Fgf feed-forward loop maintains pancreatic organ identity. Development. 2012;139(18):3363-3372.

132

Wang H, Chen Y, Zhao S, et al. Effect of Sox9 on TGF-β1-mediated atrial fibrosis. Acta Biochim Biophys Sin. 2021;53(11):1450-1458.

133

Deschaseaux F, Pontikoglou C, Sensébé L. Bone regeneration: the stem/progenitor cells point of view. J Cell Mol Med. 2010;14(1–2):103-115.

134

Li T, Huang H, Shi G, et al. TGF-β1-SOX9 axis-inducible COL10A1 promotes invasion and metastasis in gastric cancer via epithelial-to-mesenchymal transition. Cell Death Dis. 2018;9(9):849.

135

Pan Q, Yu Y, Chen Q, et al. Sox9, a key transcription factor of bone morphogenetic protein-2-induced chondrogenesis, is activated through BMP pathway and a CCAAT box in the proximal promoter. J Cell Physiol. 2008;217(1):228-241.

136

Xu X, Browning VL, Odorico JS. Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells. Mech Dev. 2011;128(7–10):412-427.

137

Zhao B, Etter L, , et al. BMP and FGF regulatory pathways in semilunar valve precursor cells. Dev Dynam. 2007;236(4):971-980.

138

Lorent K, Moore JC, Siekmann AF, et al. Reiterative use of the Notch signal during zebrafish intrahepatic biliary development. Dev Dynam. 2010;239(3):855-864.

139

Manfroid I, Ghaye A, Naye F, et al. Zebrafish sox9b is crucial for hepatopancreatic duct development and pancreatic endocrine cell regeneration. Dev Biol. 2012;366(2):268-278.

140

Yan YL, Willoughby J, Liu D, et al. A pair of Sox: distinct and overlapping functions of zebrafish sox9 co-orthologs in craniofacial and pectoral fin development. Development. 2005;132(5):1069-1083.

141

Furuyama K, Kawaguchi Y, Akiyama H, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43(1):34-41.

142

Hofmann JJ, Zovein AC, Koh H, et al. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development. 2010;137(23):4061-4072.

143

Poncy A, Antoniou A, Cordi S, et al. Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. Dev Biol. 2015;404(2):136-148.

144

Font-Burgada J, Shalapour S, Ramaswamy S, et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell. 2015;162(4):766-779.

145

Cardinale V, Wang Y, Carpino G, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology. 2011;54(6):2159-2172.

146

Carpino G, Cardinale V, Onori P, et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J Anat. 2012;220(2):186-199.

147

Carpentier R, Suñer RE, van Hul N, et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology. 2011;141(4):1432-1438.e14384.

148

Tarlow BD, Finegold MJ, Grompe M. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology. 2014;60(1):278-289.

149

Guo W, Keckesova Z, Donaher JL, et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell. 2012;148(5):1015-1028.

150

Zhang H, Huang X, Liu K, et al. Fibroblasts in an endocardial fibroelastosis disease model mainly originate from mesenchymal derivatives of epicardium. Cell Res. 2017;27(9):1157-1177.

151

Yanger K, Zong Y, Maggs LR, et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 2013;27(7):719-724.

152

Han X, Wang Y, Pu W, et al. Lineage tracing reveals the bipotency of SOX9+ hepatocytes during liver regeneration. Stem Cell Rep. 2019;12(3):624-638.

153

Liu S, Qin D, Yan Y, et al. Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9+ hepatocyte fate. iScience. 2021;24(9):103003.

154

Yimlamai D, Christodoulou C, Galli GG, et al. Hippo pathway activity influences liver cell fate. Cell. 2014;157(6):1324-1338.

155

Fan B, Malato Y, Calvisi DF, et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122(8):2911-2915.

156

Schaub JR, Huppert KA, Kurial SNT, et al. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature. 2018;557(7704):247-251.

157

Miyajima A, Tanaka M, Itoh T. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell. 2014;14(5):561-574.

158

Lu WY, Bird TG, Boulter L, et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol. 2015;17(8):971-983.

159

Ko S, Russell JO, Tian J, et al. Hdac1 regulates differentiation of bipotent liver progenitor cells during regeneration via Sox9b and Cdk8. Gastroenterology. 2019;156(1):187-202.e14.

160

Russell JO, Ko S, Monga SP, et al. Notch inhibition promotes differentiation of liver progenitor cells into hepatocytes via sox9b repression in zebrafish. Stem Cell Int. 2019;2019:8451282.

161

So J, Kim M, Lee SH, et al. Attenuating the epidermal growth factor receptor-extracellular signal-regulated kinase-sex-determining region Y-box 9 axis promotes liver progenitor cell-mediated liver regeneration in zebrafish. Hepatology. 2021;73(4):1494-1508.

162

Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol. 2021;18(1):40-55.

163

Alison MR, Islam S, Lim S. Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol. 2009;217(2):282-298.

164

Alison MR, Lin WR. Periportal SRY (sex determining region Y)-box 9-positive hepatocytes: progenitors with a biliary leaning. Hepatology. 2019;70(4):1470-1473.

165

Terada M, Horisawa K, Miura S, et al. Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma. Sci Rep. 2016;6:34691.

166

Akateh C, Beal EW, Kim JL, et al. Intrahepatic delivery of pegylated catalase is protective in a rat ischemia/reperfusion injury model. J Surg Res. 2019;238:152-163.

167

Tang SP, Mao XL, Chen YH, et al. Reactive oxygen species induce fatty liver and ischemia-reperfusion injury by promoting inflammation and cell death. Front Immunol. 2022;13:870239.

168

Jo A, Denduluri S, Zhang B, et al. The versatile functions of Sox9 in development, stem cells, and human diseases. Genes Dis. 2014;1(2):149-161.

169

Fan XD, Zheng HB, Fan XS, et al. Increase of SOX9 promotes hepatic ischemia/reperfusion (IR) injury by activating TGF-β1. Biochem Biophys Res Commun. 2018;503(1):215-221.

170

Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2021;18(3):151-166.

171

Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspect Med. 2019;65:37-55.

172

Pritchett J, Athwal VS, Harvey E, et al. Epimorphin alters the inhibitory effects of SOX9 on Mmp13 in activated hepatic stellate cells. PLoS One. 2014;9(6):e100091.

173

Pritchett J, Athwal V, Roberts N, et al. Understanding the role of SOX9 in acquired diseases: lessons from development. Trends Mol Med. 2011;17(3):166-174.

174

Athwal VS, Pritchett J, Llewellyn J, et al. SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis. EMBO Mol Med. 2017;9(12):1696-1710.

175

Athwal VS, Pritchett J, Martin K, et al. SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis. Sci Rep. 2018;8:17905.

176

Zhang Y, Liu C, Barbier O, et al. Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci Rep. 2016;6:20559.

177

Liu R, Li X, Zhu W, et al. Cholangiocyte-derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis. Hepatology. 2019;70(4):1317-1335.

178

Xiao Y, Liu R, Li X, et al. Long noncoding RNA H19 contributes to cholangiocyte proliferation and cholestatic liver fibrosis in biliary atresia. Hepatology. 2019;70(5):1658-1673.

179

Wang C, Deng J, Deng H, et al. A novel Sox9/lncRNA H19 axis contributes to hepatocyte death and liver fibrosis. Toxicol Sci. 2020;177(1):214-225.

180

Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84.

181

Friedman SL, Neuschwander-Tetri BA, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-922.

182

Brunt EM, Tiniakos DG. Histopathology of nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16(42):5286-5296.

183

Wang Z, Zhao Z, Xia Y, et al. Potential biomarkers in the fibrosis progression of nonalcoholic steatohepatitis (NASH). J Endocrinol Invest. 2022;45(7):1379-1392.

184

Pajvani UB, Shawber CJ, Samuel VT, et al. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat Med. 2011;17(8):961-967.

185

Valenti L, Mendoza RM, Rametta R, et al. Hepatic Notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. Diabetes. 2013;62(12):4052-4062.

186

Zhu C, Kim K, Wang X, et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2018;10(468):eaat0344.

187

Yang H, Zhou Y, Mo J, et al. SOX9 represses hepatitis B virus replication through binding to HBV EnhII/Cp and inhibiting the promoter activity. Antivir Res. 2020;177:104761.

188

Xu WP, Cui YL, Chen LL, et al. Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63. J Pathol. 2021;254(1):57-69.

189

Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca - Cancer J Clin. 2018;68(6):394-424.

190

Lu L, Li Y, Kim SM, et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci U S A. 2010;107(4):1437-1442.

191

Zheng Y, Pan D. The Hippo signaling pathway in development and disease. Dev Cell. 2019;50(3):264-282.

192

Ma S, Chan K, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132(7):2542-2556.

193

Chen HA, Kuo TC, Tseng CF, et al. Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma. Hepatology. 2016;64(5):1637-1651.

194

Wei X, You X, Zhang J, et al. MicroRNA-1305 inhibits the stemness of LCSCs and tumorigenesis by repressing the UBE2T-dependent Akt-signaling pathway. Mol Ther Nucleic Acids. 2019;16:721-732.

195

Zhang PP, Wang PQ, Qiao CP, et al. Differentiation therapy of hepatocellular carcinoma by inhibiting the activity of AKT/GSK-3β/β-catenin axis and TGF-β induced EMT with sophocarpine. Cancer Lett. 2016;376(1):95-103.

196

Ma XL, Shen MN, Hu B, et al. CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K/AKT signaling by inducing Rap1-mediated membrane localization of P110β and predicts poor prognosis. J Hematol Oncol. 2019;12(1):37.

197

Ma XL, Hu B, Tang WG, et al. CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma. J Hematol Oncol. 2020;13:11.

198

Álvarez-Garcia V, Tawil Y, Wise HM, et al. Mechanisms of PTEN loss in cancer: it's all about diversity. Semin Cancer Biol. 2019;59:66-79.

199

Jiang TY, Pan YF, Wan ZH, et al. PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma. Sci Transl Med. 2020;12(562):eaay0152.

200

Debebe A, Medina V, Chen CY, et al. Wnt/β-catenin activation and macrophage induction during liver cancer development following steatosis. Oncogene. 2017;36(43):6020-6029.

201

Galicia VA, He L, Dang H, et al. Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology. 2010;139(6):2170-2182.

202

Chen J, Debebe A, Zeng N, et al. Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma. Sci Rep. 2021;11:11823.

203

Leung CON, Mak WN, Kai AKL, et al. Sox9 confers stemness properties in hepatocellular carcinoma through Frizzled-7 mediated Wnt/β-catenin signaling. Oncotarget. 2016;7(20):29371-29386.

204

Shukla S, Meeran SM. Epigenetics of cancer stem cells: pathways and therapeutics. Biochim Biophys Acta. 2014;1840(12):3494-3502.

205

Toh TB, Lim JJ, Chow EKH. Epigenetics in cancer stem cells. Mol Cancer. 2017;16:29.

206

Li M, Deng Y, Zhuo M, et al. Demethylase-independent function of JMJD2D as a novel antagonist of p53 to promote Liver Cancer initiation and progression. Theranostics. 2020;10(19):8863-8879.

207

Peng K, Kou L, Yu L, et al. Histone demethylase JMJD2D interacts with β-catenin to induce transcription and activate colorectal cancer cell proliferation and tumor growth in mice. Gastroenterology. 2019;156(4):1112-1126.

208

Zhuo M, Chen W, Shang S, et al. Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling. Oncogene. 2020;39(16):3336-3353.

209

Lan T, Yuan K, Yan X, et al. LncRNA SNHG10 facilitates hepatocarcinogenesis and metastasis by modulating its homolog SCARNA13 via a positive feedback loop. Cancer Res. 2019;79(13):3220-3234.

210

Wang M, Wang Z, Zhi X, et al. SOX9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma. Biomed Pharmacother. 2020;129:110315.

211

Chen Y, Qian B, Sun X, et al. Sox9/INHBB axis-mediated crosstalk between the hepatoma and hepatic stellate cells promotes the metastasis of hepatocellular carcinoma. Cancer Lett. 2021;499:243-254.

212

Huang YT, Jen CL, Yang HI, et al. Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol. 2011;29(27):3643-3650.

213

Rich NE, Murphy CC, Yopp AC, et al. Sex disparities in presentation and prognosis of 1110 patients with hepatocellular carcinoma. Aliment Pharmacol Ther. 2020;52(4):701-709.

214

Torre LA, Siegel RL, Ward EM, et al. Global cancer incidence and mortality rates and trends: an update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16-27.

215

Liu C, Ren YF, Dong J, et al. Activation of SRY accounts for male-specific hepatocarcinogenesis: implication in gender disparity of hepatocellular carcinoma. Cancer Lett. 2017;410:20-31.

216

Xue TC, Zhang L, Ren ZG, et al. Sex-determination gene SRY potentially associates with poor prognosis but not sex bias in hepatocellular carcinoma. Dig Dis Sci. 2015;60(2):427-435.

217

Matsushima H, Kuroki T, Kitasato A, et al. Sox9 expression in carcinogenesis and its clinical significance in intrahepatic cholangiocarcinoma. Dig Liver Dis. 2015;47(12):1067-1075.

218

Lozano E, Asensio M, Perez-Silva L, et al. MRP3-mediated chemoresistance in cholangiocarcinoma: target for chemosensitization through restoring SOX17 expression. Hepatology. 2020;72(3):949-964.

219

Bezerra JA, Wells RG, Mack CL, et al. Biliary atresia: clinical and research challenges for the twenty-first century. Hepatology. 2018;68(3):1163-1173.

220

Arboleda-Bustan JE, Ribalta T, Albert A, et al. Expression of protein SOX9 in biliary atresia. J Pediatr Gastroenterol Nutr. 2022;74(2):e21-e26.

221

El-Araby HA, Saber MA, Radwan NM, et al. SOX9 in biliary atresia: new insight for fibrosis progression. Hepatobiliary Pancreat Dis Int. 2021;20(2):154-162.

222

Uemura M, Higashi M, Pattarapanawan M, et al. Gallbladder wall abnormality in biliary atresia of mouse Sox17+/− neonates and human infants. Dis Model Mech. 2020;13(4):dmm042119.

223

Mitchell E, Gilbert M, Loomes KM. Alagille syndrome. Clin Liver Dis. 2018;22(4):625-641.

224

Sanchez P, Farkhondeh A, Pavlinov I, et al. Therapeutics development for alagille syndrome. Front Pharmacol. 2021;12:704586.

225

Adams JM, Huppert KA, Castro EC, et al. Sox9 is a modifier of the liver disease severity in a mouse model of alagille syndrome. Hepatology. 2020;71(4):1331-1349.

226

Uemura M, Hara K, Shitara H, et al. Expression and function of mouse Sox17 gene in the specification of gallbladder/bile-duct progenitors during early foregut morphogenesis. Biochem Biophys Res Commun. 2010;391(1):357-363.

227

Spence JR, Lange AW, Lin SCJ, et al. Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev Cell. 2009;17(1):62-74.

228

Fida S, Myers MA, Whittingham S, et al. Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases. J Autoimmun. 2002;19(4):251-257.

229

Feng M, Fang F, Fang T, et al. Sox13 promotes hepatocellular carcinoma metastasis by transcriptionally activating Twist1. Lab Invest. 2020;100(11):1400-1410.

230

Tao J, Liu Z, Wang Y, et al. MicroRNA-645 represses hepatocellular carcinoma progression by inhibiting SOX30-mediated p53 transcriptional activation. Int J Biol Macromol. 2019;121:214-222.

231

Shen C, Chen JH, Oh HR, et al. Transcription factor SOX2 contributes to nonalcoholic fatty liver disease development by regulating the expression of the fatty acid transporter CD36. FEBS Lett. 2021;595(19):2493-2503.

232

Zhao W, Mo H, Liu R, et al. Matrix stiffness-induced upregulation of histone acetyltransferase KAT6A promotes hepatocellular carcinoma progression through regulating SOX2 expression. Br J Cancer. 2022;127(2):202-210.

233

Gressner OA, Weiskirchen R, Gressner AM. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J Cell Mol Med. 2007;11(5):1031-1051.

Genes & Diseases
Article number: 100996
Cite this article:
Shang T, Jiang T, Cui X, et al. Diverse functions of SOX9 in liver development and homeostasis and hepatobiliary diseases. Genes & Diseases, 2024, 11(4): 100996. https://doi.org/10.1016/j.gendis.2023.03.035

166

Views

1

Downloads

1

Crossref

0

Web of Science

0

Scopus

0

CSCD

Altmetrics

Received: 26 July 2022
Revised: 13 February 2023
Accepted: 19 March 2023
Published: 24 June 2023
© 2023 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Return