Knockdown of ZEB1 reverses cancer stem cell properties in prostate cancer cells

Pérez,Gisella; López‑Moncada,Fernanda; Indo,Sebastián; Torres,María José; Castellón,Enrique A.; Contreras,Héctor R.

doi:10.3892/or.2021.8009

Knockdown of ZEB1 reverses cancer stem cell properties in prostate cancer cells

Authors:
- Gisella Pérez
- Fernanda López‑Moncada
- Sebastián Indo
- María José Torres
- Enrique A. Castellón
- Héctor R. Contreras
View Affiliations

Affiliations: Laboratory of Cellular and Molecular Oncology, Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, Laboratory of Endocrinology and Reproductive Biology, University of Chile Clinical Hospital, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, Department of Medical Technology, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
Published online on: March 10, 2021 https://doi.org/10.3892/or.2021.8009
Article Number: 58

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Prostate cancer (PCa) is the second most diagnosed type of cancer in men worldwide. Advanced PCa is resistant to conventional therapies and high recurrence has been associated with high rates of metastasis. Cancer stem cells (CSCs) have been proposed to be responsible for this, due to their ability of self‑renewal and differentiation into other cell types. Zinc finger E‑box‑binding homeobox 1 (ZEB1), a transcription factor involved in the regulation of epithelial‑mesenchymal transition (EMT), has been associated with the activation of several mechanisms that lead to resistance to treatment. As recent evidence has shown that CSCs may originate from non‑CSCs during EMT, it was hypothesized that knocking down ZEB1 expression in PCa cell lines could revert some properties associated with CSCs. Using lentiviraltransduction, ZEB1 expression was silenced in the PCa DU145 and LNCaP cell lines. The mRNA and protein expression levels of key canonical CSC markers (Krüppel‑like factor 4, SOX2, CD44 and CD133) were determined using reverse transcription‑quantitative PCR and western blot analysis, respectively. In addition, the colony forming ability of the ZEB1‑knockdown cells was evaluated, and the type of colonies formed (holoclones, paraclones and meroclones) was also characterized. Finally, the ability to form prostatospheres was evaluated in vitro. It was found that in ZEB1‑knockdown DU145 cells, the expression levels of CSC phenotype markers (CD44, CD133 and SOX2) were decreased compared with those in the control group. Furthermore, ZEB1‑knockdown cells exhibited a lower ability to form prostatospheres and to generate colonies. In conclusion, stable silencing of ZEB1 reversed CSC properties in PCa cell lines. Since ZEB1 is associated with malignancy, therapy resistance and a CSC phenotype in PCa cell lines, targeting ZEB1 may be a key factor to eradicate CSCs and improve the prognosis of patients with advanced PCa.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Fakhrejahani F, Madan RA and Dahut WL: Management options for biochemically recurrent prostate cancer. Curr Treat Options Oncol. 18:262017. View Article : Google Scholar : PubMed/NCBI
3	Wang K, Ruan H, Xu T, Liu L, Liu D, Yang H, Zhang X and Chen K: Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer. Onco Targets Ther. 11:3167–3178. 2018. View Article : Google Scholar : PubMed/NCBI
4	Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, Fossati N, Gross T, Henry AM, Joniau S, et al: EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent. Eur Urol. 71:618–629. 2017. View Article : Google Scholar : PubMed/NCBI
5	Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, Henry AM, Joniau S, Lam TB, Mason MD, et al: EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: Treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 71:630–642. 2017. View Article : Google Scholar : PubMed/NCBI
6	Chandrasekar T, Yang J, Gao A and Evans CP: Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 4:365–380. 2015.PubMed/NCBI
7	Yun EJ, Lo UG and Hsieh JT: The evolving landscape of prostate cancer stem cell: Therapeutic implications and future challenges. Asian J Urol. 3:203–210. 2016. View Article : Google Scholar : PubMed/NCBI
8	Chen X, Li Q, Liu X, Liu C, Liu R, Rycaj K, Zhang D, Liu B, Jeter C, Calhoun-Davis T, et al: Defining a population of stem-like human prostate cancer cells that can generate and propagate castration-resistant prostate cancer. Clin Cancer Res. 22:4505–4516. 2016. View Article : Google Scholar : PubMed/NCBI
9	Deng Q and Tang DG: Androgen receptor and prostate cancer stem cells: Biological mechanisms and clinical implications. Endocr Relat Cancer. 22:T209–T220. 2015. View Article : Google Scholar : PubMed/NCBI
10	Di Zazzo E, Galasso G, Giovannelli P, Di Donato M, Di Santi A, Cernera G, Rossi V, Abbondanza C, Moncharmont B, Sinisi AA, et al: Prostate cancer stem cells: The role of androgen and estrogen receptors. Oncotarget. 7:193–208. 2015. View Article : Google Scholar
11	Ojo D, Lin X, Wong N, Gu Y and Tang D: Prostate cancer stem-like cells contribute to the development of castration-resistant prostate cancer. Cancers (Basel). 7:2290–2308. 2015. View Article : Google Scholar : PubMed/NCBI
12	Peitzsch C, Tyutyunnykova A, Pantel K and Dubrovska A: Cancer stem cells: The root of tumor recurrence and metastases. Semin Cancer Biol. 44:10–24. 2017. View Article : Google Scholar : PubMed/NCBI
13	Tsao T, Beretov J, Ni J, Bai X, Bucci J, Graham P and Li Y: Cancer stem cells in prostate cancer radioresistance. Cancer Lett. 465:94–104. 2019. View Article : Google Scholar : PubMed/NCBI
14	Contreras HR, López-Moncada F and Castellón EA: Cancer stem cell and mesenchymal cell cooperative actions in metastasis progression and hormone resistance in prostate cancer: Potential role of androgen and gonadotropin-releasing hormone receptors. Int J Oncol. 56:1075–1082. 2020.PubMed/NCBI
15	Castellón EA, Valenzuela R, Lillo J, Castillo V, Contreras HR, Gallegos I, Mercado A and Huidobro C: Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis. Biol Res. 45:294–305. 2012. View Article : Google Scholar
16	Castillo V, Valenzuela R, Huidobro C, Contreras HR and Castellon EA: Functional characteristics of cancer stem cells and their role in drug resistance of prostate cancer. Int J Oncol. 45:985–994. 2014. View Article : Google Scholar : PubMed/NCBI
17	Carnero A, Garcia-Mayea Y, Mir C, Lorente J, Rubio IT and LLeonart ME: The cancer stem-cell signaling network and resistance to therapy. Cancer Treat Rev. 49:25–36. 2016. View Article : Google Scholar : PubMed/NCBI
18	Najafi M, Mortezaee K and Majidpoor J: Cancer stem cell (CSC) resistance drivers. Life Sci. 234:1167812019. View Article : Google Scholar : PubMed/NCBI
19	Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H and Skvortsova II: Therapy resistance mediated by cancer stem cells. Semin Cancer Biol. 53:156–167. 2018. View Article : Google Scholar : PubMed/NCBI
20	Mitra A, Mishra L and Li S: EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget. 6:10699–10710. 2015. View Article : Google Scholar
21	Leão R, Domingos C, Figueiredo A, Hamilton R, Tabori U and Castelo-Branco P: Cancer stem cells in prostate cancer: Implications for targeted therapy. Urol Int. 99:125–136. 2017. View Article : Google Scholar : PubMed/NCBI
22	Packer JR and Maitland NJ: The molecular and cellular origin of human prostate cancer. Biochim Biophys Acta. 1863:1238–1260. 2016. View Article : Google Scholar : PubMed/NCBI
23	Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S, Chen D, Seo K, Modrusan Z, Gao WQ, et al: Androgen deprivation causes epithelial-mesenchymal transition in the prostate: Implications for androgen-deprivation therapy. Cancer Res. 72:527–36. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kuşoğlu A and Biray Avcı Ç: Cancer stem cells: A brief review of the current status. Gene. 681:80–85. 2019. View Article : Google Scholar : PubMed/NCBI
25	Adamowicz J, Pakravan K, Bakhshinejad B, Drewa T and Babashah S: Prostate cancer stem cells: From theory to practice. Scand J Urol. 51:95–106. 2017. View Article : Google Scholar : PubMed/NCBI
26	Lan L, Luo Y, Cui D, Shi BY, Deng W, Huo LL, Chen HL, Zhang GY and Deng LL: Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells. Int J Oncol. 43:113–120. 2013. View Article : Google Scholar : PubMed/NCBI
27	Eun K, Ham SW and Kim H: Cancer stem cell heterogeneity: Origin and new perspectives on CSC targeting. BMB Rep. 50:117–125. 2017. View Article : Google Scholar : PubMed/NCBI
28	Nieto MA, Huang RYYJ, Jackson RAA and Thiery JPP: EMT: 2016. Cell. 166:21–45. 2016. View Article : Google Scholar : PubMed/NCBI
29	Gonzalez DM and Medici D: Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 7:re82014. View Article : Google Scholar : PubMed/NCBI
30	Zhang J, Tian XJ and Xing J: Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks. J Clin Med. 5:412016. View Article : Google Scholar
31	Sánchez-Tilló E, Liu Y, De Barrios O, Siles L, Fanlo L, Cuatrecasas M, Darling DS, Dean DC, Castells A and Postigo A: EMT-activating transcription factors in cancer: Beyond EMT and tumor invasiveness. Cell Mol Life Sci. 69:3429–3456. 2012. View Article : Google Scholar : PubMed/NCBI
32	Goossens S, Vandamme N, Van Vlierberghe P and Berx G: EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET. Biochim Biophys Acta Rev Cancer. 1868:584–591. 2017. View Article : Google Scholar : PubMed/NCBI
33	Zhang P, Sun Y and Ma L: ZEB1: At the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle. 14:481–487. 2015. View Article : Google Scholar : PubMed/NCBI
34	Lazarova D and Bordonaro M: ZEB1 mediates drug resistance and EMT in p300-deficient CRC. J Cancer. 8:1453–1459. 2017. View Article : Google Scholar : PubMed/NCBI
35	Zhang P, Wei Y, Wang L, Debeb BG, Yuan Y, Zhang J, Yuan J, Wang M, Chen D, Sun Y, et al: ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat Cell Biol. 16:864–875. 2014. View Article : Google Scholar : PubMed/NCBI
36	Guo C, Ma J, Deng G, Qu Y, Yin L, Li Y, Han Y, Cai C, Shen H and Zeng S: ZEB1 promotes oxaliplatin resistance through the induction of epithelial-mesenchymal transition in colon cancer cells. J Cancer. 8:3555–3566. 2017. View Article : Google Scholar : PubMed/NCBI
37	Orellana-serradell O, Herrera D, Castellón EA and Contreras HR: The transcription factor ZEB1 promotes chemoresistance in prostate cancer cell lines. Asian J Androl. 21:460–467. 2019. View Article : Google Scholar : PubMed/NCBI
38	Orellana-Serradell O, Herrera D, Castellón EA and Contreras HR: The transcription factor ZEB1 promotes an aggressive phenotype in prostate cancer cell lines. Asian J Androl. 20:294–299. 2018. View Article : Google Scholar : PubMed/NCBI
39	Farfán N, Ocarez N, Castellón EA, Mejía N, de Herreros AG and Contreras HR: The transcriptional factor ZEB1 represses Syndecan 1 expression in prostate cancer. Sci Rep. 8:114672018. View Article : Google Scholar : PubMed/NCBI
40	Stone KR, Mickey DD, Wunderli H, Mickey GH and Paulson DF: Isolation of a human prostate carcinoma cell line (DU 145). Int J Cancer. 21:274–281. 1978. View Article : Google Scholar : PubMed/NCBI
41	Horoszewicz JS, Leong SS, Kawinski E, Karr JP, Rosenthal H, Chu TM, Mirand EA and Murphy GP: LNCaP model of human prostatic carcinoma. Cancer Res. 43:1809–1818. 1983.PubMed/NCBI
42	Krasnov GS, Kudryavtseva AV, Snezhkina AV, Lakunina VA, Beniaminov AD, Melnikova NV and Dmitriev AA: Pan-cancer analysis of TCGA data revealed promising reference genes for qPCR normalization. Front Genet. 10:972019. View Article : Google Scholar : PubMed/NCBI
43	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
44	Barrandon Y and Green H: Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA. 84:2302–2306. 1987. View Article : Google Scholar : PubMed/NCBI
45	Acikgoz E, Guven U, Duzagac F, Uslu R, Kara M, Soner BC and Oktem G: Enhanced G2/M arrest, caspase related apoptosis and reduced E-cadherin dependent intercellular adhesion by trabectedin in prostate cancer stem cells. PLoS One. 10:e01410902015. View Article : Google Scholar : PubMed/NCBI
46	Wang S: Anchorage-independent growth of prostate cancer stem cells. Methods Mol Biol. 568:151–160. 2009. View Article : Google Scholar : PubMed/NCBI
47	Sobel RE and Sadar MD: Cell lines used in prostate cancer research: A compendium of old and new lines-Part 1. J Urol. 173:342–359. 2005. View Article : Google Scholar : PubMed/NCBI
48	Yu Z, Pestellc TG, Lisantic MP and Pestell RG: Cancer Stem Cells. Int J Biochem Cell Biol. 44:2144–2151. 2012. View Article : Google Scholar : PubMed/NCBI
49	Johnston MD, Maini PK, Jonathan Chapman S, Edwards CM and Bodmer WF: On the proportion of cancer stem cells in a tumour. J Theor Biol. 266:708–711. 2010. View Article : Google Scholar : PubMed/NCBI
50	Collins AT, Berry PA, Hyde C, Stower MJ and Maitland NJ: Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65:10946–10951. 2005. View Article : Google Scholar : PubMed/NCBI
51	Ajani JA, Song S, Hochster HS and Steinberg IB: Cancer stem cells: The promise and the potential. Semin Oncol. 42 (Suppl 1):S3–S17. 2015. View Article : Google Scholar : PubMed/NCBI
52	Jolly MK and Celià-Terrassa T: Dynamics of phenotypic heterogeneity during EMT and stemness in cancer progression. J Clin Med. 8:15422019. View Article : Google Scholar
53	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
54	Hanrahan K, O'Neill A, Prencipe M, Bugler J, Murphy L, Fabre A, Puhr M, Culig Z, Murphy K and Watson RW: The role of epithelial-mesenchymal transition drivers ZEB1 and ZEB2 in mediating docetaxel-resistant prostate cancer. Mol Oncol. 11:251–265. 2017. View Article : Google Scholar : PubMed/NCBI
55	Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O, Boerries M, Busch H, Boettcher M, Mougiakakos D, Reichardt W, Bronsert P, et al: The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 19:518–529. 2017. View Article : Google Scholar : PubMed/NCBI
56	Zhang S and Cui W: Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J Stem Cells. 6:305–311. 2014. View Article : Google Scholar : PubMed/NCBI
57	Adachi K, Suemori H, Yasuda SY, Nakatsuji N and Kawase E: Role of SOX2 in maintaining pluripotency of human embryonic stem cells. Genes Cells. 15:455–470. 2010.PubMed/NCBI
58	Ghaleb AM and Yang VW: Krüppel-like factor 4 (KLF4): What we currently know. Gene. 611:27–137. 2017. View Article : Google Scholar : PubMed/NCBI
59	Zhang P, Andrianakos R, Yang Y, Liu C and Lu W: Kruppel-like factor 4 (Klf4) prevents embryonic stem (ES) cell differentiation by regulating Nanog gene expression. J Biol Chem. 285:9180–9189. 2010. View Article : Google Scholar : PubMed/NCBI
60	An Z, Liu P, Zheng J, Si C, Li T, Chen Y, Ma T, Zhang MQ, Zhou Q and Ding S: Sox2 and Klf4 as the functional core in pluripotency induction without exogenous Oct4. Cell Rep. 29:1986–2000,e8. 2019. View Article : Google Scholar : PubMed/NCBI
61	Mamun MA, Mannoor K, Cao J, Qadri F and Song X: SOX2 in cancer stemness: Tumor malignancy and therapeutic potentials. J Mol Cell Biol. 12:85–98. 2020. View Article : Google Scholar : PubMed/NCBI
62	Russo MV, Esposito S, Tupone MG, Manzoli L, Airoldi I, Pompa P, Cindolo L, Schips L, Sorrentino C and Di Carlo E: SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis. Oncotarget. 7:12372–12385. 2016. View Article : Google Scholar : PubMed/NCBI
63	Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, Wongvipat J, Ku SY, Gao D, Cao Z, et al: SOX2 promotes lineage plasticity and antiandrogen resistance in TP53-and RB1-deficient prostate cancer. Science. 355:84–88. 2017. View Article : Google Scholar : PubMed/NCBI
64	Liu X, Qiao B, Zhao T, Hu F, Lam AK and Tao Q: Sox2 promotes tumor aggressiveness and epithelial-mesenchymal transition in tongue squamous cell carcinoma. Int J Mol Med. 42:1418–1426. 2018.PubMed/NCBI
65	Gao H, Teng C, Huang W, Peng J and Wang C: SOX2 promotes the epithelial to mesenchymal transition of esophageal squamous cells by modulating slug expression through the activation of STAT3/HIF-α signaling. Int J Mol Sci. 16:21643–21657. 2015. View Article : Google Scholar : PubMed/NCBI
66	Herreros-Villanueva M, Zhang JS, Koenig A, Abel EV, Smyrk TC, Bamlet WR, de Narvajas AA, Gomez TS, Simeone DM, Bujanda L, et al: SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells. Oncogenesis. 2:e612013. View Article : Google Scholar : PubMed/NCBI
67	Srinivasan D, Senbanjo L, Majumdar S, Franklin RB and Chellaiah MA: Androgen receptor expression reduces stemness characteristics of prostate cancer cells (PC3) by repression of CD44 and SOX2. J Cell Biochem. 120:2413–2428. 2019. View Article : Google Scholar
68	Zhou W, Lv R, Qi W, Wu D, Xu Y, Liu W, Mou Y and Wang L: Snail contributes to the maintenance of stem cell-like phenotype cells in human pancreatic cancer. PLoS One. 9:e874092014. View Article : Google Scholar : PubMed/NCBI
69	Deep G, Jain AK, Ramteke A, Ting H, Vijendra KC, Gangar SC, Agarwal C and Agarwal R: SNAI1 is critical for the aggressiveness of prostate cancer cells with low E-cadherin. Mol Cancer. 13:372014. View Article : Google Scholar : PubMed/NCBI
70	Celià-terrassa T, Meca-cortés Ó, Mateo F, Martínez de Paz A, Rubio N, Arnal-Estapé A, Ell BJ, Bermudo R, Díaz A, Guerra-Rebollo M, et al: Epithelial-mesenchymal transition can suppress major attributes of human epithelial. J Clin Invest. 122:1849–1868. 2012. View Article : Google Scholar : PubMed/NCBI
71	Anose BM and Sanders MM: Androgen receptor regulates transcription of the ZEB1 transcription factor. Int J Endocrinol. 2011:9039182011. View Article : Google Scholar : PubMed/NCBI
72	Mooney SM, Parsana P, Hernandez JR, Liu X, Verdone JE, Torga G, Harberg CA and Pienta KJ: The presence of androgen receptor elements regulates ZEB1 expression in the absence of androgen receptor. J Cell Biochem. 116:115–23. 2015. View Article : Google Scholar : PubMed/NCBI
73	Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, D'Alessio AC, Young RA and Weinberg RA: Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 154:61–74. 2013. View Article : Google Scholar : PubMed/NCBI
74	Zhou C, Jiang H, Zhang Z, Zhang G, Wang H, Zhang Q, Sun P, Xiang R and Yang S: ZEB1 confers stem cell-like properties in breast cancer by targeting neurogenin-3. Oncotarget. 8:54388–54401. 2017. View Article : Google Scholar : PubMed/NCBI
75	Yu Z and Pestell RG: MicroRNAs and Cancer Stem Cells. MicroRNAs in Cancer Translational Research. William C.S.C: Springer; pp. 373–398. 2011, View Article : Google Scholar
76	Brabletz S, Bajdak K, Meidhof S, Burk U, Niedermann G, Firat E, Wellner U, Dimmler A, Faller G, Schubert J and Brabletz T: The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J. 30:770–782. 2011. View Article : Google Scholar : PubMed/NCBI
77	Tan L, Sui X, Deng H and Ding M: Holoclone forming cells from pancreatic cancer cells enrich tumor initiating cells and represent a novel model for study of cancer stem cells. PLoS One. 6:e233832011. View Article : Google Scholar : PubMed/NCBI
78	Zhang L, Jiao M, Li L, Wu D, Wu K, Li X, Zhu G, Dang Q, Wang X, Hsieh JT and He D: Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties. J Cancer Res Clin Oncol. 138:675–686. 2012. View Article : Google Scholar : PubMed/NCBI
79	Knaack H, Lenk L, Philipp LM, Miarka L, Rahn S, Viol F, Hauser C, Egberts JH, Gundlach JP, Will O, et al: Liver metastasis of pancreatic cancer: The hepatic microenvironment impacts differentiation and self-renewal capacity of pancreatic ductal epithelial cells. Oncotarget. 9:31771–31786. 2018. View Article : Google Scholar : PubMed/NCBI
80	Sohn HM, Kim B, Park M, Ko YJ, Moon YH, Sun JM, Jeong BC, Kim YW and Lim W: Effect of CD133 overexpression on bone metastasis in prostate cancer cell line LNCaP. Oncol Lett. 18:1189–1198. 2019.PubMed/NCBI
81	Bisson I and Prowse DM: WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 19:683–697. 2009. View Article : Google Scholar : PubMed/NCBI
82	Chen B, Zhu Z, Li L, Ye W, Zeng J, Gao J, Wang S, Zhang L and Huang Z: Effect of overexpression of oct4 and sox2 genes on the biological and oncological characteristics of gastric cancer cells. Onco Targets Ther. 12:4667–4682. 2019. View Article : Google Scholar : PubMed/NCBI
83	Kanwal R, Shukla S, Walker E and Gupta S: Acquisition of tumorigenic potential and therapeutic resistance in CD133+ subpopulation of prostate cancer cells exhibiting stem-cell like characteristics. Cancer Lett. 430:25–33. 2018. View Article : Google Scholar : PubMed/NCBI
84	Hoofd C, Wang X, Lam S, Jenkins C, Wood B, Giambra V and Weng AP: CD44 promotes chemoresistance in T-ALL by increased drug efflux. Exp Hematol. 44:166–171.e17. 2016. View Article : Google Scholar : PubMed/NCBI