Anat Cell Biol.  2023 Mar;56(1):94-108. 10.5115/acb.22.161.

Genetic heterogeneity of liver cancer stem cells

• Kim M
• Jo KW
• Kim H
• Han ME
• Oh SO

• KMID: 2540989
• DOI: http://doi.org/10.5115/acb.22.161

Abstract

Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer. Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.

Keyword

Genetic heterogeneity; Cancer stem cell; Liver cancer

Figure

• 

  Fig. 1 Gene mutations associated with CD133 (A) or CD44 (B) expression level in liver cancer (TCGA, n=366). The frequency is based on the number of patients who harbor a specific gene mutation and is shown to depend on the level of CD133 or CD44 (high, intermediate, and low). The Ki-square analysis showed a significant association between the CD133 or CD44 expression level, and the gene mutations. CD, cluster of differentiation; TCGA, The Cancer Genome Atlas.

• 

  Fig. 2 Gene mutations associated with CD24 (A) or CD47 (B) expression level in liver cancer (TCGA, n=366). The frequency is based on the number of patients who harbor a specific gene mutation and is shown to depend on the level of CD24 or CD47 (high, intermediate, and low). The Ki-square analysis showed a significant association between the CD24 or CD47 expression level, and the gene mutations. CD, cluster of differentiation; TCGA, The Cancer Genome Atlas.

• 

  Fig. 3 Gene mutations associated with CD13 (A) or CD90 (B) expression level in liver cancer (TCGA, n=366). The frequency is based on the number of patients who harbor a specific gene mutation and is shown to depend on the level of CD13 or CD90 (high, intermediate, and low). The Ki-square analysis showed a significant association between the CD13 or CD90 expression level, and the gene mutations. CD, cluster of differentiation; TCGA, The Cancer Genome Atlas.

• 

  Fig. 4 Gene mutations associated with ICAM1 (A) or EpCAM (B) expression level in liver cancer (TCGA, n=366). The frequency is based on the number of patients who harbor a specific gene mutation and is shown to depend on the level of ICAM1 or EpCAM (high, intermediate, and low). The Ki-square analysis showed a significant association between the ICAM1 or EpCAM expression level, and the gene mutations. ICAM1, Intercellular adhesion molecule 1; EpCAM, epithelial cell adhesion molecule; TCGA, The Cancer Genome Atlas.

• 

  Fig. 5 Gene mutations associated with LGR5 (A) or KRT19 (B) expression level in liver cancer (TCGA, n=366). The frequency is based on the number of patients who harbor a specific gene mutation and is shown to depend on the level of LGR5 or KRT19 (high, intermediate and low). The Ki-square analysis showed a significant association between the LGR5 or KRT expression level, and the gene mutations. LGR5, leucine-rich repeat-containing G protein-coupled receptor 5; KRT19, keratin 19; TCGA, The Cancer Genome Atlas.

Reference

References

1. Batlle E, Clevers H. 2017; Cancer stem cells revisited. Nat Med. 23:1124–34. DOI: 10.1038/nm.4409. PMID: 28985214.

2. Castelli G, Pelosi E, Testa U. 2017; Liver cancer: molecular characterization, clonal evolution and cancer stem cells. Cancers (Basel). 9:127. DOI: 10.3390/cancers9090127. PMID: 28930164. PMCID: PMC5615342.

3. Lee TK, Guan XY, Ma S. 2022; Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 19:26–44. DOI: 10.1038/s41575-021-00508-3. PMID: 34504325.

4. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. 2012; Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 366:883–92. Erratum in: N Engl J Med 2012;367:976. DOI: 10.1056/NEJMoa1113205. PMID: 22397650. PMCID: PMC4878653.

5. Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW. 1997; AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 90:5002–12. DOI: 10.1182/blood.V90.12.5002. PMID: 9389720.

6. Corbeil D, Röper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB. 2000; The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem. 275:5512–20. DOI: 10.1074/jbc.275.8.5512. PMID: 10681530.

7. Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW. 1997; A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood. 90:5013–21. DOI: 10.1182/blood.V90.12.5013. PMID: 9389721.

8. Grosse-Gehling P, Fargeas CA, Dittfeld C, Garbe Y, Alison MR, Corbeil D, Kunz-Schughart LA. 2013; CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. J Pathol. 229:355–78. DOI: 10.1002/path.4086. PMID: 22899341.

9. Weigmann A, Corbeil D, Hellwig A, Huttner WB. 1997; Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci U S A. 94:12425–30. DOI: 10.1073/pnas.94.23.12425. PMID: 9356465. PMCID: PMC24979.

10. Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H. 2006; Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun. 351:820–4. DOI: 10.1016/j.bbrc.2006.10.128. PMID: 17097610.

11. Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A, Ng I, Man K, Wong N, To KF, Zheng BJ, Lai PB, Lo CM, Chan KW, Guan XY. 2010; miR-130b promotes CD133+ liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell. 7:694–707. DOI: 10.1016/j.stem.2010.11.010. PMID: 21112564.

12. Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. 2008; CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 27:1749–58. DOI: 10.1038/sj.onc.1210811. PMID: 17891174.

13. Tong CM, Ma S, Guan XY. 2011; Biology of hepatic cancer stem cells. J Gastroenterol Hepatol. 26:1229–37. DOI: 10.1111/j.1440-1746.2011.06762.x. PMID: 21557770.

14. Liu YM, Li XF, Liu H, Wu XL. 2015; Ultrasound-targeted microbubble destruction-mediated downregulation of CD133 inhibits epithelial-mesenchymal transition, stemness and migratory ability of liver cancer stem cells. Oncol Rep. 34:2977–86. DOI: 10.3892/or.2015.4270. PMID: 26370320.

15. Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, Ng IO, Man K, To KF, Lai PB, Lo CM, Guan XY, Chan KW. 2012; CD133+ liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology. 55:807–20. DOI: 10.1002/hep.24739. PMID: 21994122.

16. Li J, Chen JN, Zeng TT, He F, Chen SP, Ma S, Bi J, Zhu XF, Guan XY. 2016; CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy. BMC Cancer. 16:15. DOI: 10.1186/s12885-016-2050-6. PMID: 26758620. PMCID: PMC4711109.

17. Chen H, Luo Z, Sun W, Zhang C, Sun H, Zhao N, Ding J, Wu M, Li Z, Wang H. 2013; Low glucose promotes CD133mAb-elicited cell death via inhibition of autophagy in hepatocarcinoma cells. Cancer Lett. 336:204–12. Erratum in: Cancer Lett 2014;349:152. DOI: 10.1016/j.canlet.2013.08.012. PMID: 23652197.

18. Piao LS, Hur W, Kim TK, Hong SW, Kim SW, Choi JE, Sung PS, Song MJ, Lee BC, Hwang D, Yoon SK. 2012; CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett. 315:129–37. DOI: 10.1016/j.canlet.2011.10.012. PMID: 22079466.

19. Rountree CB, Ding W, He L, Stiles B. 2009; Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensin homolog deleted on chromosome 10-deleted mice. Stem Cells. 27:290–9. DOI: 10.1634/stemcells.2008-0332. PMID: 19008348. PMCID: PMC2847372.

20. Chen H, Luo Z, Dong L, Tan Y, Yang J, Feng G, Wu M, Li Z, Wang H. 2013; CD133/prominin-1-mediated autophagy and glucose uptake beneficial for hepatoma cell survival. PLoS One. 8:e56878. DOI: 10.1371/journal.pone.0056878. PMID: 23437259. PMCID: PMC3577658.

21. Zhang HL, Wang MD, Zhou X, Qin CJ, Fu GB, Tang L, Wu H, Huang S, Zhao LH, Zeng M, Liu J, Cao D, Guo LN, Wang HY, Yan HX, Liu J. 2017; Blocking preferential glucose uptake sensitizes liver tumor-initiating cells to glucose restriction and sorafenib treatment. Cancer Lett. 388:1–11. DOI: 10.1016/j.canlet.2016.11.023. PMID: 27894955.

22. Zhang SS, Han ZP, Jing YY, Tao SF, Li TJ, Wang H, Wang Y, Li R, Yang Y, Zhao X, Xu XD, Yu ED, Rui YC, Liu HJ, Zhang L, Wei LX. 2012; CD133+CXCR4+ colon cancer cells exhibit metastatic potential and predict poor prognosis of patients. BMC Med. 10:85. DOI: 10.1186/1741-7015-10-85. PMID: 22871210. PMCID: PMC3424958.

23. Okudela K, Woo T, Mitsui H, Tajiri M, Masuda M, Ohashi K. 2012; Expression of the potential cancer stem cell markers, CD133, CD44, ALDH1, and β-catenin, in primary lung adenocarcinoma--their prognostic significance. Pathol Int. 62:792–801. DOI: 10.1111/pin.12019. PMID: 23252868.

24. Chan AW, Tong JH, Chan SL, Lai PB, To KF. 2014; Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology. 64:935–50. DOI: 10.1111/his.12342. PMID: 24506513.

25. Liu F, Qian Y. 2021; The role of CD133 in hepatocellular carcinoma. Cancer Biol Ther. 22:291–300. DOI: 10.1080/15384047.2021.1916381. PMID: 33899676. PMCID: PMC8183534.

26. Hagiwara S, Kudo M, Nagai T, Inoue T, Ueshima K, Nishida N, Watanabe T, Sakurai T. 2012; Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br J Cancer. 106:1997–2003. DOI: 10.1038/bjc.2012.145. PMID: 22596232. PMCID: PMC3388555.

27. Tang Y, Berlind J, Mavila N. 2018; Inhibition of CREB binding protein-beta-catenin signaling down regulates CD133 expression and activates PP2A-PTEN signaling in tumor initiating liver cancer cells. Cell Commun Signal. 16:9. DOI: 10.1186/s12964-018-0222-5. PMID: 29530069. PMCID: PMC5848530.

28. Marcucci F, Caserta CA, Romeo E, Rumio C. 2019; Antibody-drug conjugates (ADC) against cancer stem-like cells (CSC)-is there still room for optimism? Front Oncol. 9:167. DOI: 10.3389/fonc.2019.00167. PMID: 30984612. PMCID: PMC6449442.

29. Zhou G, Da Won Bae S, Nguyen R, Huo X, Han S, Zhang Z, Hebbard L, Duan W, Eslam M, Liddle C, Yuen L, Lam V, Qiao L, George J. 2021; An aptamer-based drug delivery agent (CD133-apt-Dox) selectively and effectively kills liver cancer stem-like cells. Cancer Lett. 501:124–32. DOI: 10.1016/j.canlet.2020.12.022. PMID: 33352247.

30. Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, Liu Y, Huang J, Lv H, Luo C, Feng KC, Yang QM, Li XL, Han W. 2018; CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology. 7:e1440169. DOI: 10.1080/2162402X.2018.1440169. PMID: 29900044. PMCID: PMC5993480. PMID: f3e7c9850ad74bd1afb8b2aa4cd9e521.

31. Bach P, Abel T, Hoffmann C, Gal Z, Braun G, Voelker I, Ball CR, Johnston IC, Lauer UM, Herold-Mende C, Mühlebach MD, Glimm H, Buchholz CJ. 2013; Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus. Cancer Res. 73:865–74. DOI: 10.1158/0008-5472.CAN-12-2221. PMID: 23293278.

32. Song Y, Kim IK, Choi I, Kim SH, Seo HR. 2018; Oxytetracycline have the therapeutic efficiency in CD133+ HCC population through suppression CD133 expression by decreasing of protein stability of CD133. Sci Rep. 8:16100. DOI: 10.1038/s41598-018-34301-1. PMID: 30382122. PMCID: PMC6208387.

33. Woo HG, Choi JH, Yoon S, Jee BA, Cho EJ, Lee JH, Yu SJ, Yoon JH, Yi NJ, Lee KW, Suh KS, Kim YJ. 2017; Integrative analysis of genomic and epigenomic regulation of the transcriptome in liver cancer. Nat Commun. 8:839. DOI: 10.1038/s41467-017-00991-w. PMID: 29018224. PMCID: PMC5635060. PMID: 8a60c24eeaad425dbc3d1059ee545d95.

34. Mavila N, James D, Utley S, Cu N, Coblens O, Mak K, Rountree CB, Kahn M, Wang KS. 2012; Fibroblast growth factor receptor-mediated activation of AKT-β-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells. PLoS One. 7:e50401. DOI: 10.1371/journal.pone.0050401. PMID: 23308088. PMCID: PMC3540100.

35. Huang W, Bei L, Eklund EA. 2018; Inhibition of Fas associated phosphatase 1 (Fap1) facilitates apoptosis of colon cancer stem cells and enhances the effects of oxaliplatin. Oncotarget. 9:25891–902. DOI: 10.18632/oncotarget.25401. PMID: 29899829. PMCID: PMC5995227.

36. Hagiwara M, Fushimi A, Yamashita N, Bhattacharya A, Rajabi H, Long MD, Yasumizu Y, Oya M, Liu S, Kufe D. 2021; MUC1-C activates the PBAF chromatin remodeling complex in integrating redox balance with progression of human prostate cancer stem cells. Oncogene. 40:4930–40. DOI: 10.1038/s41388-021-01899-y. PMID: 34163028. PMCID: PMC8321896.

37. Kumar D, Kumar S, Gorain M, Tomar D, Patil HS, Radharani NNV, Kumar TVS, Patil TV, Thulasiram HV, Kundu GC. 2016; Notch1-MAPK signaling axis regulates CD133+ cancer stem cell-mediated melanoma growth and angiogenesis. J Invest Dermatol. 136:2462–74. DOI: 10.1016/j.jid.2016.07.024. PMID: 27476721.

38. Konishi H, Asano N, Imatani A, Kimura O, Kondo Y, Jin X, Kanno T, Hatta W, Ara N, Asanuma K, Koike T, Shimosegawa T. 2016; Notch1 directly induced CD133 expression in human diffuse type gastric cancers. Oncotarget. 7:56598–607. DOI: 10.18632/oncotarget.10967. PMID: 27489358. PMCID: PMC5302937.

39. Duhem-Tonnelle V, Bièche I, Vacher S, Loyens A, Maurage CA, Collier F, Baroncini M, Blond S, Prevot V, Sharif A. 2010; Differential distribution of erbB receptors in human glioblastoma multiforme: expression of erbB3 in CD133-positive putative cancer stem cells. J Neuropathol Exp Neurol. 69:606–22. Erratum in: J Neuropathol Exp Neurol 2010;69:1176. DOI: 10.1097/NEN.0b013e3181e00579. PMID: 20467331. PMCID: PMC3173752.

40. De Bacco F, Orzan F, Erriquez J, Casanova E, Barault L, Albano R, D'Ambrosio A, Bigatto V, Reato G, Patanè M, Pollo B, Kuesters G, Dell'Aglio C, Casorzo L, Pellegatta S, Finocchiaro G, Comoglio PM, Boccaccio C. 2021; ERBB3 overexpression due to miR-205 inactivation confers sensitivity to FGF, metabolic activation, and liability to ERBB3 targeting in glioblastoma. Cell Rep. 36:109455. DOI: 10.1016/j.celrep.2021.109455. PMID: 34320350.

41. Gallatin WM, Weissman IL, Butcher EC. 1983; A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature. 304:30–4. DOI: 10.1038/304030a0. PMID: 6866086.

42. van der Windt GJ, Schouten M, Zeerleder S, Florquin S, van der Poll T. 2011; CD44 is protective during hyperoxia-induced lung injury. Am J Respir Cell Mol Biol. 44:377–83. DOI: 10.1165/rcmb.2010-0158OC. PMID: 20463290.

43. Knutson JR, Iida J, Fields GB, McCarthy JB. 1996; CD44/chondroitin sulfate proteoglycan and alpha 2 beta 1 integrin mediate human melanoma cell migration on type IV collagen and invasion of basement membranes. Mol Biol Cell. 7:383–96. DOI: 10.1091/mbc.7.3.383. PMID: 8868467. PMCID: PMC275891.

44. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. 1990; CD44 is the principal cell surface receptor for hyaluronate. Cell. 61:1303–13. DOI: 10.1016/0092-8674(90)90694-A. PMID: 1694723.

45. Weber GF, Ashkar S, Glimcher MJ, Cantor H. 1996; Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science. 271:509–12. DOI: 10.1126/science.271.5248.509. PMID: 8560266.

46. Faassen AE, Schrager JA, Klein DJ, Oegema TR, Couchman JR, McCarthy JB. 1992; A cell surface chondroitin sulfate proteoglycan, immunologically related to CD44, is involved in type I collagen-mediated melanoma cell motility and invasion. J Cell Biol. 116:521–31. DOI: 10.1083/jcb.116.2.521. PMID: 1730766. PMCID: PMC2289300.

47. Jalkanen M, Elenius K, Salmivirta M. 1992; Syndecan--a cell surface proteoglycan that selectively binds extracellular effector molecules. Adv Exp Med Biol. 313:79–85. DOI: 10.1007/978-1-4899-2444-5_8. PMID: 1279953.

48. Yu Q, Stamenkovic I. 1999; Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 13:35–48. DOI: 10.1101/gad.13.1.35. PMID: 9887098. PMCID: PMC316376.

49. Chen C, Zhao S, Karnad A, Freeman JW. 2018; The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol. 11:64. DOI: 10.1186/s13045-018-0605-5. PMID: 29747682. PMCID: PMC5946470.

50. Senbanjo LT, AlJohani H, Majumdar S, Chellaiah MA. 2019; Characterization of CD44 intracellular domain interaction with RUNX2 in PC3 human prostate cancer cells. Cell Commun Signal. 17:80. DOI: 10.1186/s12964-019-0395-6. PMID: 31331331. PMCID: PMC6647163. PMID: 4c0c380ca460428a986f61ba7e177b52.

51. Luo Y, Tan Y. 2016; Prognostic value of CD44 expression in patients with hepatocellular carcinoma: meta-analysis. Cancer Cell Int. 16:47. DOI: 10.1186/s12935-016-0325-2. PMID: 27330410. PMCID: PMC4912706.

52. Dhar D, Antonucci L, Nakagawa H, Kim JY, Glitzner E, Caruso S, Shalapour S, Yang L, Valasek MA, Lee S, Minnich K, Seki E, Tuckermann J, Sibilia M, Zucman-Rossi J, Karin M. 2018; Liver cancer initiation requires p53 inhibition by CD44-enhanced growth factor signaling. Cancer Cell. 33:1061–77.e6. DOI: 10.1016/j.ccell.2018.05.003. PMID: 29894692. PMCID: PMC6005359.

53. Fan Z, Xia H, Xu H, Ma J, Zhou S, Hou W, Tang Q, Gong Q, Nie Y, Bi F. 2018; Standard CD44 modulates YAP1 through a positive feedback loop in hepatocellular carcinoma. Biomed Pharmacother. 103:147–56. DOI: 10.1016/j.biopha.2018.03.042. PMID: 29649630.

54. Kopanja D, Pandey A, Kiefer M, Wang Z, Chandan N, Carr JR, Franks R, Yu DY, Guzman G, Maker A, Raychaudhuri P. 2015; Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. J Hepatol. 63:429–36. DOI: 10.1016/j.jhep.2015.03.023. PMID: 25828473. PMCID: PMC4508215.

55. Rani B, Malfettone A, Dituri F, Soukupova J, Lupo L, Mancarella S, Fabregat I, Giannelli G. 2018; Galunisertib suppresses the staminal phenotype in hepatocellular carcinoma by modulating CD44 expression. Cell Death Dis. 9:373. DOI: 10.1038/s41419-018-0384-5. PMID: 29515105. PMCID: PMC5841307.

56. Chen H, Li M, Sanchez E, Soof CM, Bujarski S, Ng N, Cao J, Hekmati T, Zahab B, Nosrati JD, Wen M, Wang CS, Tang G, Xu N, Spektor TM, Berenson JR. 2020; JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression. Br J Haematol. 188:283–94. DOI: 10.1111/bjh.16158. PMID: 31423579.

57. Martincuks A, Li PC, Zhao Q, Zhang C, Li YJ, Yu H, Rodriguez-Rodriguez L. 2020; CD44 in ovarian cancer progression and therapy resistance-a critical role for STAT3. Front Oncol. 10:589601. DOI: 10.3389/fonc.2020.589601. PMID: 33335857. PMCID: PMC7736609. PMID: 96062329de784f1daec48555a07d0af9.

58. Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R, Wu Z, Gönen M, Mulvey LA, Bessarabova MO, Huh SJ, Silver SJ, Kim SY, Park SY, Lee HE, Anderson KS, Richardson AL, Nikolskaya T, Nikolsky Y, Liu XS, Root DE, Hahn WC, Frank DA, Polyak K. 2011; The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24- stem cell-like breast cancer cells in human tumors. J Clin Invest. 121:2723–35. DOI: 10.1172/JCI44745. PMID: 21633165. PMCID: PMC3223826.

59. Hu K, Law JH, Fotovati A, Dunn SE. 2012; Small interfering RNA library screen identified polo-like kinase-1 (PLK1) as a potential therapeutic target for breast cancer that uniquely eliminates tumor-initiating cells. Breast Cancer Res. 14:R22. DOI: 10.1186/bcr3107. PMID: 22309939. PMCID: PMC3496140.

60. Funato K, Yamazumi Y, Oda T, Akiyama T. 2011; Tyrosine phosphatase PTPRD suppresses colon cancer cell migration in coordination with CD44. Exp Ther Med. 2:457–63. DOI: 10.3892/etm.2011.231. PMID: 22977525. PMCID: PMC3440690.

61. Huang X, Qin F, Meng Q, Dong M. 2020; Protein tyrosine phosphatase receptor type D (PTPRD)-mediated signaling pathways for the potential treatment of hepatocellular carcinoma: a narrative review. Ann Transl Med. 8:1192. DOI: 10.21037/atm-20-4733. PMID: 33241041. PMCID: PMC7576031.

62. Zhang H, Liu B, Cheng J, Ma H, Li Z, Xi Y. 2020; Identification of co-expressed genes associated with MLL rearrangement in pediatric acute lymphoblastic leukemia. Biosci Rep. 40:BSR20200514. DOI: 10.1042/BSR20200514. PMID: 32347296. PMCID: PMC7953500.

63. Fisher JN, Thanasopoulou A, Juge S, Tzankov A, Bagger FO, Mendez MA, Peters AHFM, Schwaller J. 2020; Transforming activities of the NUP98-KMT2A fusion gene associated with myelodysplasia and acute myeloid leukemia. Haematologica. 105:1857–67. DOI: 10.3324/haematol.2019.219188. PMID: 31558671. PMCID: PMC7327646.

64. Marques C, Unterkircher T, Kroon P, Oldrini B, Izzo A, Dramaretska Y, Ferrarese R, Kling E, Schnell O, Nelander S, Wagner EF, Bakiri L, Gargiulo G, Carro MS, Squatrito M. 2021; NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1. Elife. 10:e64846. DOI: 10.7554/eLife.64846. PMID: 34399888. PMCID: PMC8370767. PMID: 27a8334b7595495aa16d1f8e55366e1e.

65. Altevogt P, Sammar M, Hüser L, Kristiansen G. 2021; Novel insights into the function of CD24: a driving force in cancer. Int J Cancer. 148:546–59. DOI: 10.1002/ijc.33249. PMID: 32790899.

66. Fang X, Zheng P, Tang J, Liu Y. 2010; CD24: from A to Z. Cell Mol Immunol. 7:100–3. DOI: 10.1038/cmi.2009.119. PMID: 20154703. PMCID: PMC4001892.

67. Barkal AA, Brewer RE, Markovic M, Kowarsky M, Barkal SA, Zaro BW, Krishnan V, Hatakeyama J, Dorigo O, Barkal LJ, Weissman IL. 2019; CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature. 572:392–6. DOI: 10.1038/s41586-019-1456-0. PMID: 31367043. PMCID: PMC6697206.

68. Kristiansen G, Sammar M, Altevogt P. 2004; Tumour biological aspects of CD24, a mucin-like adhesion molecule. J Mol Histol. 35:255–62. DOI: 10.1023/B:HIJO.0000032357.16261.c5. PMID: 15339045.

69. Li D, Hu M, Liu Y, Ye P, Du P, Li CS, Cheng L, Liu P, Jiang J, Su L, Wang S, Zheng P, Liu Y. 2018; CD24-p53 axis suppresses diethylnitrosamine-induced hepatocellular carcinogenesis by sustaining intrahepatic macrophages. Cell Discov. 4:6. DOI: 10.1038/s41421-017-0007-9. PMID: 29423273. PMCID: PMC5799181.

70. Lim SC. 2005; CD24 and human carcinoma: tumor biological aspects. Biomed Pharmacother. 59(Suppl 2):S351–4. DOI: 10.1016/S0753-3322(05)80076-9. PMID: 16507407.

71. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. 2003; Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 100:3983–8. Erratum in: Proc Natl Acad Sci U S A 2003;100:6890. DOI: 10.1073/pnas.0530291100. PMID: 12629218. PMCID: PMC153034.

72. Liu H, Wang YJ, Bian L, Fang ZH, Zhang QY, Cheng JX. 2016; CD44+/CD24+ cervical cancer cells resist radiotherapy and exhibit properties of cancer stem cells. Eur Rev Med Pharmacol Sci. 20:1745–54. PMID: 27212166.

73. Zhang C, Li C, He F, Cai Y, Yang H. 2011; Identification of CD44+CD24+ gastric cancer stem cells. J Cancer Res Clin Oncol. 137:1679–86. DOI: 10.1007/s00432-011-1038-5. PMID: 21882047.

74. Wang M, Xiao J, Shen M, Yahong Y, Tian R, Zhu F, Jiang J, Du Z, Hu J, Liu W, Qin R. 2011; Isolation and characterization of tumorigenic extrahepatic cholangiocarcinoma cells with stem cell-like properties. Int J Cancer. 128:72–81. DOI: 10.1002/ijc.25317. PMID: 20232394.

75. Gao M, Bai H, Jethava Y, Wu Y, Zhu Y, Yang Y, Xia J, Cao H, Franqui-Machin R, Nadiminti K, Thomas GS, Salama ME, Altevogt P, Bishop G, Tomasson M, Janz S, Shi J, Chen L, Frech I, Tricot G, Zhan F. 2020; Identification and characterization of tumor-initiating cells in multiple myeloma. J Natl Cancer Inst. 112:507–15. DOI: 10.1093/jnci/djz159. PMID: 31406992. PMCID: PMC7225664.

76. Wang R, Li Y, Tsung A, Huang H, Du Q, Yang M, Deng M, Xiong S, Wang X, Zhang L, Geller DA, Cheng B, Billiar TR. 2018; iNOS promotes CD24+CD133+ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc Natl Acad Sci U S A. 115:E10127–36. DOI: 10.1073/pnas.1722100115. PMID: 30297396. PMCID: PMC6205478.

77. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. 2011; CD24+ liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 9:50–63. DOI: 10.1016/j.stem.2011.06.005. PMID: 21726833.

78. Ye J, Wu D, Shen J, Wu P, Ni C, Chen J, Zhao J, Zhang T, Wang X, Huang J. 2012; Enrichment of colorectal cancer stem cells through epithelial-mesenchymal transition via CDH1 knockdown. Mol Med Rep. 6:507–12. DOI: 10.3892/mmr.2012.938. PMID: 22684815.

79. Yuen VW, Wong CC. 2020; Hypoxia-inducible factors and innate immunity in liver cancer. J Clin Invest. 130:5052–62. DOI: 10.1172/JCI137553. PMID: 32750043. PMCID: PMC7524494.

80. Tiburcio PDB, Locke MC, Bhaskara S, Chandrasekharan MB, Huang LE. 2020; The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma. Transl Oncol. 13:100819. DOI: 10.1016/j.tranon.2020.100819. PMID: 32622311. PMCID: PMC7332530.

81. Haddock S, Alban TJ, Turcan Ş, Husic H, Rosiek E, Ma X, Wang Y, Bale T, Desrichard A, Makarov V, Monette S, Wu W, Gardner R, Manova K, Boire A, Chan TA. 2022; Phenotypic and molecular states of IDH1 mutation-induced CD24-positive glioma stem-like cells. Neoplasia. 28:100790. DOI: 10.1016/j.neo.2022.100790. PMID: 35398668. PMCID: PMC9014446.

82. Zhang W, Huang Q, Xiao W, Zhao Y, Pi J, Xu H, Zhao H, Xu J, Evans CE, Jin H. 2020; Advances in anti-tumor treatments targeting the CD47/SIRPα axis. Front Immunol. 11:18. DOI: 10.3389/fimmu.2020.00018. PMID: 32082311. PMCID: PMC7003246. PMID: ef3f21dd14244eebbf6c5526c1c2e363.

83. Soto-Pantoja DR, Kaur S, Roberts DD. 2015; CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit Rev Biochem Mol Biol. 50:212–30. DOI: 10.3109/10409238.2015.1014024. PMID: 25708195. PMCID: PMC4822708.

84. Brown EJ, Frazier WA. 2001; Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11:130–5. DOI: 10.1016/S0962-8924(00)01906-1. PMID: 11306274.

85. Jiang P, Lagenaur CF, Narayanan V. 1999; Integrin-associated protein is a ligand for the P84 neural adhesion molecule. J Biol Chem. 274:559–62. DOI: 10.1074/jbc.274.2.559. PMID: 9872987.

86. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, van Rooijen N, Weissman IL. 2009; CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 138:286–99. DOI: 10.1016/j.cell.2009.05.045. PMID: 19632179. PMCID: PMC2726837.

87. Lee TK, Cheung VC, Lu P, Lau EY, Ma S, Tang KH, Tong M, Lo J, Ng IO. 2014; Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology. 60:179–91. DOI: 10.1002/hep.27070. PMID: 24523067.

88. Li F, Lv B, Liu Y, Hua T, Han J, Sun C, Xu L, Zhang Z, Feng Z, Cai Y, Zou Y, Ke Y, Jiang X. 2017; Blocking the CD47-SIRPα axis by delivery of anti-CD47 antibody induces antitumor effects in glioma and glioma stem cells. Oncoimmunology. 7:e1391973. DOI: 10.1080/2162402X.2017.1391973. PMID: 29308321. PMCID: PMC5749673. PMID: 30958dc2d186440ba0fe0ce448fd8c60.

89. Cioffi M, Trabulo S, Hidalgo M, Costello E, Greenhalf W, Erkan M, Kleeff J, Sainz B Jr, Heeschen C. 2015; Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin Cancer Res. 21:2325–37. DOI: 10.1158/1078-0432.CCR-14-1399. PMID: 25717063.

90. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. 2012; The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 109:6662–7. DOI: 10.1073/pnas.1121623109. PMID: 22451913. PMCID: PMC3340046.

91. Chao MP, Weissman IL, Majeti R. 2012; The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 24:225–32. DOI: 10.1016/j.coi.2012.01.010. PMID: 22310103. PMCID: PMC3319521.

92. Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA, Finetti P, Van Egmond M, Matozaki T, Kraal G, Birnbaum D, van Elsas A, Kuijpers TW, Bertucci F, van den Berg TK. 2011; CD47-signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A. 108:18342–7. DOI: 10.1073/pnas.1106550108. PMID: 22042861. PMCID: PMC3215076.

93. Yu XY, Qiu WY, Long F, Yang XP, Zhang C, Xu L, Chang HY, Du P, Hou XJ, Yu YZ, Zeng DD, Wang S, Sun ZW. 2018; A novel fully human anti-CD47 antibody as a potential therapy for human neoplasms with good safety. Biochimie. 151:54–66. DOI: 10.1016/j.biochi.2018.05.019. PMID: 29864508.

94. Martinez-Torres AC, Quiney C, Attout T, Boullet H, Herbi L, Vela L, Barbier S, Chateau D, Chapiro E, Nguyen-Khac F, Davi F, Le Garff-Tavernier M, Moumné R, Sarfati M, Karoyan P, Merle-Béral H, Launay P, Susin SA. 2015; CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans. PLoS Med. 12:e1001796. DOI: 10.1371/journal.pmed.1001796. PMID: 25734483. PMCID: PMC4348493. PMID: 2b2543ff56164dc3bf8abd1cd6e551be.

95. Domínguez JM, Pérez-Chacón G, Guillén MJ, Muñoz-Alonso MJ, Somovilla-Crespo B, Cibrián D, Acosta-Iborra B, Adrados M, Muñoz-Calleja C, Cuevas C, Sánchez-Madrid F, Avilés P, Zapata JM. 2020; CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110. J Hematol Oncol. 13:32. DOI: 10.1186/s13045-020-00865-7. PMID: 32264921. PMCID: PMC7140356. PMID: 38476467c1d24e7b8130be99558bbb30.

96. Park SC, Nguyen NT, Eun JR, Zhang Y, Jung YJ, Tschudy-Seney B, Trotsyuk A, Lam A, Ramsamooj R, Zhang Y, Theise ND, Zern MA, Duan Y. 2015; Identification of cancer stem cell subpopulations of CD34+ PLC/PRF/5 that result in three types of human liver carcinomas. Stem Cells Dev. 24:1008–21. DOI: 10.1089/scd.2014.0405. PMID: 25519836. PMCID: PMC4390116.

97. Hashida H, Takabayashi A, Kanai M, Adachi M, Kondo K, Kohno N, Yamaoka Y, Miyake M. 2002; Aminopeptidase N is involved in cell motility and angiogenesis: its clinical significance in human colon cancer. Gastroenterology. 122:376–86. DOI: 10.1053/gast.2002.31095. PMID: 11832452.

98. Liu LL, Fu D, Ma Y, Shen XZ. 2011; The power and the promise of liver cancer stem cell markers. Stem Cells Dev. 20:2023–30. DOI: 10.1089/scd.2011.0012. PMID: 21651381.

99. Ikeda N, Nakajima Y, Tokuhara T, Hattori N, Sho M, Kanehiro H, Miyake M. 2003; Clinical significance of aminopeptidase N/CD13 expression in human pancreatic carcinoma. Clin Cancer Res. 9:1503–8. PMID: 12684426.

100. Zhang Q, Wang J, Zhang H, Zhao D, Zhang Z, Zhang S. 2015; Expression and clinical significance of aminopeptidase N/CD13 in non-small cell lung cancer. J Cancer Res Ther. 11:223–8. DOI: 10.4103/0973-1482.138007. PMID: 25879366.

101. Otsuki T, Nakashima T, Hamada H, Takayama Y, Akita S, Masuda T, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Miyata Y, Miyake M, Kohno N, Okada M, Hattori N. 2018; Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma. Eur Respir J. 51:1701610. DOI: 10.1183/13993003.01610-2017. PMID: 29519924.

102. Saida S, Watanabe K, Kato I, Fujino H, Umeda K, Okamoto S, Uemoto S, Hishiki T, Yoshida H, Tanaka S, Adachi S, Niwa A, Nakahata T, Heike T. 2015; Prognostic significance of aminopeptidase-N (CD13) in hepatoblastoma. Pediatr Int. 57:558–66. DOI: 10.1111/ped.12597. PMID: 25682862.

103. Kessler T, Baumeier A, Brand C, Grau M, Angenendt L, Harrach S, Stalmann U, Schmidt LH, Gosheger G, Hardes J, Andreou D, Dreischalück J, Lenz G, Wardelmann E, Mesters RM, Schwöppe C, Berdel WE, Hartmann W, Schliemann C. 2018; Aminopeptidase N (CD13): expression, prognostic impact, and use as therapeutic target for tissue factor induced tumor vascular infarction in soft tissue sarcoma. Transl Oncol. 11:1271–82. DOI: 10.1016/j.tranon.2018.08.004. PMID: 30125801. PMCID: PMC6113655.

104. 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. 120:3326–39. DOI: 10.1172/JCI42550. PMID: 20697159. PMCID: PMC2929722.

105. Kim HM, Haraguchi N, Ishii H, Ohkuma M, Okano M, Mimori K, Eguchi H, Yamamoto H, Nagano H, Sekimoto M, Doki Y, Mori M. 2012; Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Ann Surg Oncol. 19(Suppl 3):S539–48. DOI: 10.1245/s10434-011-2040-5. PMID: 21879266.

106. Nagano H, Ishii H, Marubashi S, Haraguchi N, Eguchi H, Doki Y, Mori M. 2012; Novel therapeutic target for cancer stem cells in hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 19:600–5. DOI: 10.1007/s00534-012-0543-5. PMID: 22892595.

107. Shao N, Cheng J, Huang H, Gong X, Lu Y, Idris M, Peng X, Ong BX, Zhang Q, Xu F, Liu C. 2021; GASC1 promotes hepatocellular carcinoma progression by inhibiting the degradation of ROCK2. Cell Death Dis. 12:253. DOI: 10.1038/s41419-021-03550-w. PMID: 33692332. PMCID: PMC7946911. PMID: 0e75b37488954e169275a5567d1511d4.

108. Cai J, Kehoe O, Smith GM, Hykin P, Boulton ME. 2008; The angiopoietin/Tie-2 system regulates pericyte survival and recruitment in diabetic retinopathy. Invest Ophthalmol Vis Sci. 49:2163–71. DOI: 10.1167/iovs.07-1206. PMID: 18436850.

109. Rege TA, Hagood JS. 2006; Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J. 20:1045–54. DOI: 10.1096/fj.05-5460rev. PMID: 16770003.

110. Sauzay C, Voutetakis K, Chatziioannou A, Chevet E, Avril T. 2019; CD90/Thy-1, a cancer-associated cell surface signaling molecule. Front Cell Dev Biol. 7:66. DOI: 10.3389/fcell.2019.00066. PMID: 31080802. PMCID: PMC6497726.

111. Lu JW, Chang JG, Yeh KT, Chen RM, Tsai JJ, Hu RM. 2011; Overexpression of Thy1/CD90 in human hepatocellular carcinoma is associated with HBV infection and poor prognosis. Acta Histochem. 113:833–8. DOI: 10.1016/j.acthis.2011.01.001. PMID: 21272924.

112. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, Chu PW, Lam CT, Poon RT, Fan ST. 2008; Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 13:153–66. DOI: 10.1016/j.ccr.2008.01.013. PMID: 18242515.

113. Yamashita T, Honda M, Nakamoto Y, Baba M, Nio K, Hara Y, Zeng SS, Hayashi T, Kondo M, Takatori H, Yamashita T, Mizukoshi E, Ikeda H, Zen Y, Takamura H, Wang XW, Kaneko S. 2013; Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma. Hepatology. 57:1484–97. DOI: 10.1002/hep.26168. PMID: 23174907. PMCID: PMC7180389.

114. Zhang K, Che S, Pan C, Su Z, Zheng S, Yang S, Zhang H, Li W, Wang W, Liu J. 2018; The SHH/Gli axis regulates CD90-mediated liver cancer stem cell function by activating the IL6/JAK2 pathway. J Cell Mol Med. 22:3679–90. DOI: 10.1111/jcmm.13651. PMID: 29722127. PMCID: PMC6010714.

115. Zhang K, Che S, Su Z, Zheng S, Zhang H, Yang S, Li W, Liu J. 2018; CD90 promotes cell migration, viability and sphere-forming ability of hepatocellular carcinoma cells. Int J Mol Med. 41:946–54. DOI: 10.3892/ijmm.2017.3314. PMCID: PMC5752240.

116. Naudin C, Hattabi A, Michelet F, Miri-Nezhad A, Benyoucef A, Pflumio F, Guillonneau F, Fichelson S, Vigon I, Dusanter-Fourt I, Lauret E. 2017; PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells. Blood. 129:2493–506. DOI: 10.1182/blood-2016-10-747436. PMID: 28232582. PMCID: PMC5429137.

117. Bui TM, Wiesolek HL, Sumagin R. 2020; ICAM-1: a master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis. J Leukoc Biol. 108:787–99. DOI: 10.1002/JLB.2MR0220-549R. PMID: 32182390. PMCID: PMC7977775.

118. Benedicto A, Romayor I, Arteta B. 2017; Role of liver ICAM-1 in metastasis. Oncol Lett. 14:3883–92. DOI: 10.3892/ol.2017.6700. PMID: 28943897. PMCID: PMC5604125.

119. Liu S, Li N, Yu X, Xiao X, Cheng K, Hu J, Wang J, Zhang D, Cheng S, Liu S. 2013; Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology. 144:1031–41.e10. DOI: 10.1053/j.gastro.2013.01.046. PMID: 23376424.

120. Badran BM, Wolinsky SM, Burny A, Willard-Gallo KE. 2002; Identification of three NFAT binding motifs in the 5'-upstream region of the human CD3gamma gene that differentially bind NFATc1, NFATc2, and NF-kappa B p50. J Biol Chem. 277:47136–48. DOI: 10.1074/jbc.M206330200. PMID: 12374807.

121. Xue J, Thippegowda PB, Hu G, Bachmaier K, Christman JW, Malik AB, Tiruppathi C. 2009; NF-kappaB regulates thrombin-induced ICAM-1 gene expression in cooperation with NFAT by binding to the intronic NF-kappaB site in the ICAM-1 gene. Physiol Genomics. 38:42–53. DOI: 10.1152/physiolgenomics.00012.2009. PMID: 19351910. PMCID: PMC2696150.

122. Bretz CA, Savage SR, Capozzi ME, Suarez S, Penn JS. 2015; NFAT isoforms play distinct roles in TNFα-induced retinal leukostasis. Sci Rep. 5:14963. DOI: 10.1038/srep14963. PMID: 26527057. PMCID: PMC4630625.

123. Chen E, Cen Y, Lu D, Luo W, Jiang H. 2018; IL-22 inactivates hepatic stellate cells via downregulation of the TGF-β1/Notch signaling pathway. Mol Med Rep. 17:5449–53. DOI: 10.3892/mmr.2018.8516. PMID: 29393435.

124. Baeuerle PA, Gires O. 2007; EpCAM (CD326) finding its role in cancer. Br J Cancer. 96:417–23. Erratum in: Br J Cancer 2007;96:1491. DOI: 10.1038/sj.bjc.6603494. PMID: 17211480. PMCID: PMC2360029.

125. Schmelzer E, Reid LM. 2008; EpCAM expression in normal, non-pathological tissues. Front Biosci. 13:3096–100. DOI: 10.2741/2911. PMID: 17981779.

126. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW. 2009; EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 136:1012–24. DOI: 10.1053/j.gastro.2008.12.004. PMID: 19150350. PMCID: PMC2828822.

127. Yamashita T, Budhu A, Forgues M, Wang XW. 2007; Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res. 67:10831–9. DOI: 10.1158/0008-5472.CAN-07-0908. PMID: 18006828.

128. Nio K, Yamashita T, Okada H, Kondo M, Hayashi T, Hara Y, Nomura Y, Zeng SS, Yoshida M, Hayashi T, Sunagozaka H, Oishi N, Honda M, Kaneko S. 2015; Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma. J Hepatol. 63:1164–72. DOI: 10.1016/j.jhep.2015.06.009. PMID: 26095183.

129. Yamashita T, Honda M, Nio K, Nakamoto Y, Yamashita T, Takamura H, Tani T, Zen Y, Kaneko S. 2010; Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation. Cancer Res. 70:4687–97. DOI: 10.1158/0008-5472.CAN-09-4210. PMID: 20484035.

130. Wang J, Dong M, Xu Z, Song X, Zhang S, Qiao Y, Che L, Gordan J, Hu K, Liu Y, Calvisi DF, Chen X. 2018; Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene. 37:3229–42. DOI: 10.1038/s41388-018-0188-1. PMID: 29545603. PMCID: PMC6002343.

131. Mao Y, Tang S, Yang L, Li K. 2018; Inhibition of the Notch signaling pathway reduces the differentiation of hepatic progenitor cells into cholangiocytes in biliary atresia. Cell Physiol Biochem. 49:1074–82. DOI: 10.1159/000493290. PMID: 30196281.

132. Minamide K, Sato T, Nakanishi Y, Ohno H, Kato T, Asano J, Ohteki T. 2020; IRF2 maintains the stemness of colonic stem cells by limiting physiological stress from interferon. Sci Rep. 10:14639. DOI: 10.1038/s41598-020-71633-3. PMID: 32901054. PMCID: PMC7479133.

133. Fan H, Zhang H, Pascuzzi PE, Andrisani O. 2016; Hepatitis B virus X protein induces EpCAM expression via active DNA demethylation directed by RelA in complex with EZH2 and TET2. Oncogene. 35:715–26. DOI: 10.1038/onc.2015.122. PMID: 25893293. PMCID: PMC4615262.

134. Zhi X, Lin L, Yang S, Bhuvaneshwar K, Wang H, Gusev Y, Lee MH, Kallakury B, Shivapurkar N, Cahn K, Tian X, Marshall JL, Byers SW, He AR. 2015; βII-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin. Hepatology. 61:598–612. DOI: 10.1002/hep.27558. PMID: 25307947. PMCID: PMC4327990.

135. Xu L, Lin W, Wen L, Li G. 2019; Lgr5 in cancer biology: functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy. Stem Cell Res Ther. 10:219. DOI: 10.1186/s13287-019-1288-8. PMID: 31358061. PMCID: PMC6664754. PMID: 670d7db485174705a80bbde6c5357ee6.

136. Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgård R. 2008; Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet. 40:1291–9. DOI: 10.1038/ng.239. PMID: 18849992.

137. Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H. 2010; Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 6:25–36. DOI: 10.1016/j.stem.2009.11.013. PMID: 20085740.

138. Plaks V, Brenot A, Lawson DA, Linnemann JR, Van Kappel EC, Wong KC, de Sauvage F, Klein OD, Werb Z. 2013; Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep. 3:70–8. DOI: 10.1016/j.celrep.2012.12.017. PMID: 23352663. PMCID: PMC3563842.

139. Ng A, Tan S, Singh G, Rizk P, Swathi Y, Tan TZ, Huang RY, Leushacke M, Barker N. 2014; Lgr5 marks stem/progenitor cells in ovary and tubal epithelia. Nat Cell Biol. 16:745–57. DOI: 10.1038/ncb3000. PMID: 24997521.

140. Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJ, van de Wetering M, Sojoodi M, Li VS, Schuijers J, Gracanin A, Ringnalda F, Begthel H, Hamer K, Mulder J, van Es JH, de Koning E, Vries RG, Heimberg H, Clevers H. 2013; Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 32:2708–21. DOI: 10.1038/emboj.2013.204. PMID: 24045232. PMCID: PMC3801438.

141. Leushacke M, Tan SH, Wong A, Swathi Y, Hajamohideen A, Tan LT, Goh J, Wong E, Denil SLIJ, Murakami K, Barker N. 2017; Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol. 19:774–86. DOI: 10.1038/ncb3541. PMID: 28581476.

142. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. 2007; Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 449:1003–7. DOI: 10.1038/nature06196. PMID: 17934449.

143. Effendi K, Yamazaki K, Fukuma M, Sakamoto M. 2014; Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) represents a typical Wnt/β-catenin pathway-activated hepatocellular carcinoma. Liver Cancer. 3:451–7. DOI: 10.1159/000343873. PMID: 26280006. PMCID: PMC4531428.

144. Lin Y, Fang ZP, Liu HJ, Wang LJ, Cheng Z, Tang N, Li T, Liu T, Han HX, Cao G, Liang L, Ding YQ, Zhou WJ. 2017; HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5+ liver stem cells. Nat Commun. 8:1175. DOI: 10.1038/s41467-017-01341-6. PMID: 29079780. PMCID: PMC5660090. PMID: cab654a367c941948d9cd8ac4d0be63a.

145. Lei ZJ, Wang J, Xiao HL, Guo Y, Wang T, Li Q, Liu L, Luo X, Fan LL, Lin L, Mao CY, Wang SN, Wei YL, Lan CH, Jiang J, Yang XJ, Liu PD, Chen DF, Wang B. 2015; Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of β-catenin signaling. Oncogene. 34:3188–98. Erratum in: Oncogene 2015;34:3214. DOI: 10.1038/onc.2015.129. PMID: 25893304.

146. Katoh M. 2018; Multi-layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β-catenin signaling activation (Review). Int J Mol Med. 42:713–25. DOI: 10.3892/ijmm.2018.3689. PMID: 29786110. PMCID: PMC6034925.

147. Lévy L, Wei Y, Labalette C, Wu Y, Renard CA, Buendia MA, Neuveut C. 2004; Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction. Mol Cell Biol. 24:3404–14. DOI: 10.1128/MCB.24.8.3404-3414.2004. PMID: 15060161. PMCID: PMC381622.

148. Weis B, Schmidt J, Maamar H, Raj A, Lin H, Tóth C, Riedmann K, Raddatz G, Seitz HK, Ho AD, Lyko F, Linhart HG. 2015; Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a. Oncogene. 34:1822–30. DOI: 10.1038/onc.2014.114. PMID: 24837369.

149. Taniguchi K, Moroishi T, de Jong PR, Krawczyk M, Grebbin BM, Luo H, Xu RH, Golob-Schwarzl N, Schweiger C, Wang K, Di Caro G, Feng Y, Fearon ER, Raz E, Kenner L, Farin HF, Guan KL, Haybaeck J, Datz C, Zhang K, Karin M. 2017; YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis. Proc Natl Acad Sci U S A. 114:1643–8. DOI: 10.1073/pnas.1620290114. PMID: 28130546. PMCID: PMC5320959.

150. Xie J, Li L, Deng S, Chen J, Gu Q, Su H, Wen L, Wang S, Lin C, Qi C, Zhang Q, Li J, He X, Li W, Wang L, Zheng L. 2020; Slit2/Robo1 mitigates DSS-induced ulcerative colitis by activating autophagy in intestinal stem cell. Int J Biol Sci. 16:1876–87. DOI: 10.7150/ijbs.42331. PMID: 32398956. PMCID: PMC7211176.

151. Rothenberg ME, Nusse Y, Kalisky T, Lee JJ, Dalerba P, Scheeren F, Lobo N, Kulkarni S, Sim S, Qian D, Beachy PA, Pasricha PJ, Quake SR, Clarke MF. 2012; Identification of a cKit+ colonic crypt base secretory cell that supports Lgr5+ stem cells in mice. Gastroenterology. 142:1195–205.e6. DOI: 10.1053/j.gastro.2012.02.006. PMID: 22333952. PMCID: PMC3911891.

152. Kawai T, Yasuchika K, Ishii T, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Mizumoto M, Hatano E, Uemoto S. 2015; Keratin 19, a cancer stem cell marker in human hepatocellular carcinoma. Clin Cancer Res. 21:3081–91. DOI: 10.1158/1078-0432.CCR-14-1936. PMID: 25820415.

153. Kawai T, Yasuchika K, Seo S, Higashi T, Ishii T, Miyauchi Y, Kojima H, Yamaoka R, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Nakamoto Y, Hatano E, Uemoto S. 2017; Identification of keratin 19-positive cancer stem cells associating human hepatocellular carcinoma using 18F-fluorodeoxyglucose positron emission tomography. Clin Cancer Res. 23:1450–60. DOI: 10.1158/1078-0432.CCR-16-0871. PMID: 27663597.

154. 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. 63:674–85. DOI: 10.1136/gutjnl-2012-304351. PMID: 23958557. PMCID: PMC3963546.

155. Fatourou E, Koskinas J, Karandrea D, Palaiologou M, Syminelaki T, Karanikolas M, Felekouras E, Antoniou E, Manesis EK, Delladetsima J, Tiniakos D. 2015; Keratin 19 protein expression is an independent predictor of survival in human hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 27:1094–102. DOI: 10.1097/MEG.0000000000000398. PMID: 26011233.

156. Kim H, Choi GH, Na DC, Ahn EY, Kim GI, Lee JE, Cho JY, Yoo JE, Choi JS, Park YN. 2011; Human hepatocellular carcinomas with "Stemness"-related marker expression: keratin 19 expression and a poor prognosis. Hepatology. 54:1707–17. DOI: 10.1002/hep.24559. PMID: 22045674.

157. Govaere O, Petz M, Wouters J, Vandewynckel YP, Scott EJ, Topal B, Nevens F, Verslype C, Anstee QM, Van Vlierberghe H, Mikulits W, Roskams T. 2017; The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma. Oncogene. 36:6605–16. DOI: 10.1038/onc.2017.260. PMID: 28783171. PMCID: PMC5702717.

158. Rhee H, Kim HY, Choi JH, Woo HG, Yoo JE, Nahm JH, Choi JS, Park YN. 2018; Keratin 19 expression in hepatocellular carcinoma is regulated by fibroblast-derived HGF via a MET-ERK1/2-AP1 and SP1 axis. Cancer Res. 78:1619–31. DOI: 10.1158/0008-5472.CAN-17-0988. PMID: 29363547.

159. Kuony A, Michon F. 2017; Epithelial markers aSMA, Krt14, and Krt19 unveil elements of murine lacrimal gland morphogenesis and maturation. Front Physiol. 8:739. DOI: 10.3389/fphys.2017.00739. PMID: 29033846. PMCID: PMC5627580.