臺灣博碩士論文加值系統

外源性的多能性因子引入可用於與重編程癌細胞相關之癌症疾病模型開發。微小RNA（miRNA）是透過各種機制（包括上皮 - 間質轉化（EMT）和間充質 - 上皮轉換（MET）過程）對細胞重編程和癌症轉移相關重要之基因表現的負調控物。然而，目前缺乏關於miRNA在誘導多能性癌（iPC）細胞中調控EMT / MET過程中之作用的相關研究。先前在我們的實驗室中通過Yamanaka因子的逆轉錄病毒轉導從兩個結腸直腸癌（CRC）細胞系產生的四個iPC克隆進行全基因組miRNA分析和生物訊息學調查。 CRC-iPCs在癌症和多能胚胎幹細胞的miRNA譜中具有相似性，但不表現一些已知的重編程miRNA，表明不完全重編程。預測鑑定的一百二十個差異表達的miRNA通過PI3K-Akt和TGF-β訊息傳導途徑調節EMT / MET過程。 EMT基因屬於SMAD家族成空員4（SMAD4）和Snail（SNAI1）以及MET基因，且在熒光素酶測定中驗證E-鈣粘蛋白（CDH1）和occludin（OCLN）均被miR-362-5p / -3p下調控。在西方墨點法分析中，在CRC-iPC克隆中觀察到矛盾的EMT / MET蛋白表現，表示可能通過部分重編程引發的上皮/間充質（E / M）雜合表型。 EMT / MET基因表達在iPCs後通常是可逆的，表明表觀遺傳調節。 miR-362-5p / -3p的過表現模擬下調控了除SNAI1以外的EMT和MET蛋白，與E / M雜合表型一致。相反，在CRC-iPCs中下調控的miR-362-3p / -5p的抑制增強了MET，這促進了重編程的早期階段。 顯著miR-362-3p / -5p的過表現增強細胞遷移和侵襲。總之，CRC-iPC的部分重編程可能引發E / M雜合表型。還提供了構想以顯示miR-362-5p / -3p與透過鎖定EMT / MET基因調節細胞遷移，侵襲和CRC重編程的訊息傳導之間的相互作用。

Exogenous introduction of pluripotency factors may be used to reprogramme cancer cells for use in the development of cancer disease models. MicroRNAs (miRNAs) are negative regulators of gene expression important for cellular reprogramming and cancer metastasis through various mechanisms, including the epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) processes. However, studies on the roles of miRNAs in regulating the EMT/MET processes in induced pluripotent cancer (iPC) cells are lacking. Four iPC clones previously generated in our laboratory from two colorectal cancer (CRC) cell lines by retroviral transduction of the Yamanaka factors were subjected to genome-wide miRNA profiling and bioinformatics interrogation. The CRC-iPCs shared similarities in the miRNA profiles of both cancer and pluripotent embryonic stem cells, but did not express some known reprogramming miRNAs, suggesting incomplete reprogramming. The hundred-and-two differentially-expressed miRNAs identified were predicted to regulate the EMT/MET processes through the PI3K-Akt and TGF-β signalling pathways. The EMT genes, SMAD family member 4 (SMAD4) and Snail (SNAI1), and the MET genes, E-cadherin (CDH1) and occludin (OCLN), are all targeted by the down-regulated miR-362-5p/-3p, as validated in luciferase assays. On western blot analysis, contradictory EMT/MET protein expression was observed in the CRC-iPC clones, suggesting an epithelial/mesenchymal (E/M) hybrid phenotype possibly elicited by partial reprogramming. The EMT/MET gene expression was generally reversible in post-iPCs, indicating the epigenetic regulation. Overexpression of miR-362-5p/-3p mimics down-regulated both EMT and MET proteins, except SNAI1, consistent with an E/M hybrid phenotype. On the contrary, inhibition of miR-362-3p/-5p, as were down-regulated in CRC-iPCs, enhanced MET, which facilitates the early stage of reprogramming. Overexpression of miR-362-3p/-5p significantly enhanced cell migration and invasion. Taken together, partial reprogramming of CRC-iPCs might have elicited an E/M hybrid phenotype. Schemes are also presented to show the interplay between miR-362-5p/-3p and signalling in regulating cellular migration, invasion and CRC reprogramming via targeting EMT/MET genes.

CONTENTS
ACKNOWLEDGEMENTS……………………………………………………………i
CHINESE ABSTRACT………………………………………………………………iii
ABSTRACT………………………………………………………………………iv
CONTENTS………………………………………………………………………vi
LIST OF FIGURES…………………………………………………………………x
LIST OF TABLES……………………………………………………………………xii
LIST OF ABBREVIATIONS ……………………………………………………xii

CHAPTER 1. INTRODUCTION…………………………………………………1

CHAPTER 2. LITERATURE REVIEW…………………………………………5
2.1 Colorectal Cancer (CRC)………………………………………………………5
2.1.1 Risk Factors of Colorectal Cancer…………………………………5
2.1.2 Molecular Basis of Colorectal Cancer……………………………6
2.1.3 Current Models of CRC and Limitations…………………………8
2.2 Induced Pluripotency in Cancers………………………………………………9
2.2.1 Induced Pluripotent Cancer Cells (iPCs)……………………………...9
2.2.2 Application of iPCs in Disease Modelling…………………………...11
2.3 Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Epithelial Transition (MET)……………………………………………………………12
2.3.1 Molecular Mechanism of EMT/MET Signalling Pathway…………14
2.3.2 Roles of EMT and MET in Cancer Development and Metastasis…15
2.3.3 Roles of EMT and MET in Somatic and Cancer Cells Reprogramming……………………………………………………18
2.4 MicroRNAs (miRNAs)……………………………………………………19
2.4.1 Biogenesis and Function of miRNAs………………………………20
2.4.2 Roles of miRNAs in Pluripotency Maintenance and Self-Renewal23
24.2.1 MiRNA-Mediated Reprogramming of Somatic and Cancer cells…25
2.4.3 Roles of miRNAs in Tumourigenesis………………………………27
2.4.3.1 Roles of miRNAs in Regulating EMT and MET in Cancer Metastasis………………………………………………….28

CHAPTER 3.METHODOLOGY………………………………………………32
3.1 Cell Culture and Maintenance………………………………………………32
3.1.1 Preparation of Cell Culture Media…………………………………32
3.1.2 Cell Revival from Liquid Nitrogen Frozen Stock……………………33
3.1.3 Cell Culture Maintenance and Sub-culturing………………………...33
3.1.4 Cryopreservation of Cell Lines………………………………………35
3.2 Establishment of Stable Cell Lines with Selected miRNAs Knockdown……………………………………………………………35
3.2.1 Production of Lentiviral Vectors in 293FT Cells……………………35
3.2.2 Transduction of Lentiviral Vectors in HCT-15 cells………………36
3.3 Genome-wide Analysis of miRNA Expression……………………………37
3.3.1 MiRNA Microarray Analysis and Target Gene Prediction…………37
3.3.2 Gene Ontology and KEGG Pathway Analysis………………………38
3.3.3 Identification of Differentially-Expressed miRNAs Targeting at EMT/MET-Related Genes……………………………………………38
3.4 RNA Isolation by TRIZOL…………………………………………………38
3.4.1 cDNA Synthesis by Reverse Transcription…………………………..39
3.5 Quantification and Validation of the miRNA Expression Levels…………40
3.5.1 MicroRNA (miRNA) Primers for qRT-PCR………………………40
3.5.2 Polyadenylated-Reverse Transcription of miRNAs…………………40
3.5.3 MicroRNA Quantification by qRT-PCR……………………………42
3.6 Western Blot Analysis of Protein Expression………………………………45
3.6.1 Buffers and Reagents Preparation……………………………………45
3.6.2 Preparation of Cell Lysates…………………………………………..45
3.6.3 Preparation of Standard Curve and Quantification of Protein by Bradford Protein Assay……………………………………………….47
3.6.4 Separation of Protein by Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE)………………………………………47
3.6.5 Wet Transfer of Protein to PVDF Membrane………………………51
3.6.6 Membrane Blocking…………………………………………………53
3.6.7 Primary and Secondary Antibody Staining…………………………53
3.6.8 Chemiluminescence Detection………………………………………54
3.6.9 Stripping and Reprobing of Membrane………………………………54
3.7 Ectopic expression of miRNAs………………………………………………55
3.7.1 Transient Transfection of miRNA Mimics…………………………55
3.7.2 Co-transfection of miRNA Mimics and Plasmid Vectors containing 3’UTR Regions of Putative Target Genes……………………………55
3.8 Validation of MiRNA Targeted Transcripts by Luciferase Assays…………56
3.8.1 Construction of PmirGLO Plasmids containing 3’UTR of Putative Target Genes…………………………………………………………56
3.8.2 Cloning of PmirGLO Plasmids containing 3’UTR of Putative Target Genes and Plasmid Extraction.………………………………………58
3.8.3 Culture of Transformed Colonies and Plasmid DNA Extraction……59
3.8.4 Dual Luciferase Reporter Assays……………………………………60
3.9 Cell Migration and Invasion Assays…………………………………………61
3.9.1 Wound Healing Assay………………………………………………61
3.9.2 Transwell Migration Assay…………………………………………61
3.9.3 Transwell Invasion Assay……………………………………………62
3.10 Statistical Analysis……………………………………………………………63


CHAPTER 4.RESULTS……………………………………………………………64
4.1 Study Design of Part 1………………………………………………………64
4.2 Genome-wide miRNA Profiling of Colorectal Cancer Induced-Pluripotent Cancer Cells (CRC-iPCs) Showed Similarities of Both Cancer and Pluripotent Embryonic Stem Cell (ESC)……66
4.3 Validation of microRNA Expression in CRC-iPCs…………………………72
4.4 Up- and Down-regulated miRNAs Predicted to Suppress Apoptosis and Modulate Cell Migration……………………………………………………74
4.5 Differentially expressed MiRNAs are Predicted to Target EMT/MET-related Pathways in Reprogrammed CRC………………………………………78
4.6 Predicted Activation of miRNAs Targeting the TGF-β and PI3K-AKT Signalling Pathways to Regulate the EMT/MET Processes in CRC-iPCs…81
4.7 Differentially-expressed miRNAs Validated Targeting at EMT/MET Genes in CRC-iPCs………………………………………………………………85
4.8 Epithelial/Mesenchymal (E/M) Hybrid Phenotype…………………………88
4.9 Bioinformatics Prediction of miR-362 Involvement in Cell Migration and Invasion……………………………………………………………………91
4.10 Study design of Part II……………………………………………………93
4.11Down-regulated miR-362 Expression on Cancer and Somatic Cell Reprogramming…………………………………………………………95
4.12 miR-362-5p/-3p Overexpression Promotes Epithelial/Mesenchymal (E/M) Hybrid State………………………………………………………………98
4.13 miR-362-5p/-3p Knockdown Promotes MET Activation………………102
4.14 Direct miR-362 Targeting of EMT/MET Genes…………………………105
4.15 miR-362-3p/5p Promotes Cell Migration and Invasion in vitro…………110

CHAPTER 5. DISCUSSION ………………………………………………………114
5.1 Partial Reprogramming Status of CRC-iPCs……………………………114
5.2 Role of EMT/MET in Regulation of the Reprogramming Process………116
5.3 Association of Stemness with Epithelial/Mesenchymal (E/M) Hybrid Phenotype…………………………………………………………………117
5.4 MiR-362-5p/-3p Promotes an E/M Hybrid Phenotype and Cellular Migration and Invasion……………………………………………………119
5.5 Down-regulation of MiR-362-5p/-3p Activates MET, Which is Required For Initial Stage of Reprogramming in CRC-iPCs…………………………….122
CHAPTER 6. CONCLUSIONS……………………………………………………125
6.1 Summary of Main Findings…………………………………………125
6.2 Conclusions…………………………………………………………126
6.3 Limitation and Future Studies………………………………………127
REFERENCES……………………………………………………………………128
APPENDICES………………………………………………………………………144



LIST OF FIGURES

Figure 2.1 Morphological changes involved in EMT regulation……………………13
Figure 2.2 Regulation of EMT and the reversed process, MET in cancer metastasis………………………………………………17
Figure 2.3 Biogenesis process of microRNAs………………………………………22
Figure 2.4 MiRNA-mediated regulation of epithelial mesenchymal transition (EMT) in colorectal cancer…………………………………………………………31
Figure 3.1 Plotting of Standard Curve of BSA…………………………………………49
Figure 3.2 Schematic arrangement of transfer sandwich………………………………52
Figure 4.1 Study design of Part I of the study…………………………………………65
Figure 4.2 Volcano plot of differentially expressed miRNAs of parental CRC and CRC-iPC clones……………………………………………………………67
Figure 4.3 Hierarchical clustering analysis of differentially expressed miRNAs of the parental CRC, CRC-derived iPC clones and embryonic stem cells (ESCs)………………………………………………………70
Figure 4.4 Validation of differentially-expressed miRNAs by quantitative real-time PCR………………………………………………………………………73
Figure 4.5 Gene Ontology (GO) analyses of the predicted genes targeted by the 52 up-regulated miRNAs…………………………………………………76
Figure 4.6 Gene Ontology (GO) analyses of the predicted genes targeted by the 50 down-regulated miRNAs…………………………………………………77
Figure 4.7 Top 10 KEGG pathways of predicted genes targeted by differentially expressed miRNAs……………………………………………………79
Figure 4.8 Predicted miRNA-mRNA interactions in the TGF-β signalling pathway…………………………………………………………………83
Figure 4.9 Predicted miRNA-mRNA interactions in the PI3K-AKT signalling pathway…………………………………………………………………84
Figure 4.10 Expression of the predicted miRNAs targeting SNAI1 and CDH1 genes in the CRC-iPC clones…………………………………………87
Figure 4.11 Quantification of changes of EMT and MET protein levels from three independent experiments………………………………………………90
Figure 4.12 Study design of Part II of this work……………………………………94
Figure 4.13 Endogenous expressions of miR-362-5p/-3p in various cell lines………97
Figure 4.14 Overexpression of miR-362-5p/-3p in MCF-7 cells……………………100
Figure 4.15 Effects of miR-362-5p/-3p overexpression on EMT/MET-related target genes at protein level………………………………………101
Figure 4.16 Stable knockdown of miR-362-5p/-3p in HCT-15 cells………………103
Figure 4.17 Effects of miR-362-5p/-3p knockdown on protein levels of EMT/MET-related target genes………………………………………………104
Figure 4.18 Construction of luciferase plasmids containing miR-362-3p/5p binding sites in the 3’UTR of MET/EMT target genes based on prediction logarithms……………………………………………106
Figure 4.19 Validation of miR-362-5p/-3p directs targeting of OCLN in luciferase assays……………………………………………………107
Figure 4.20 Validations of miR-362-5p/-3p direct targeting CDH1 and SNAI1, respectively, in luciferase assays………………………108
Figure 4.21 Validation of miR-362-5p/-3p direct targeting SMAD4 in luciferase assays………………………………………………………109
Figure 4.22 Effects of miR-362-5p/3p overexpression on cellular migration………111
Figure 4.23 Ectopic expression of miR-362-5p/-3p increases cellular migration ability………………………………………………………112
Figure 4.24 MiR-362-5p/-3p overexpression enhances cellular invasion…………...113
Figure 5.1 A proposed scheme of miR-362-5p/-3p overexpression in the regulation of cellular migration and invasion………………………121
Figure 5.2 A proposed scheme of miR-362-5p/-3p involvement in the regulation of colorectal cancer cell reprogramming……………………124


LIST OF TABLES

Table 3.1 Sources and culture of cell lines used……………………………………34
Table 3.2 miRNA primer sequences for qRT-PCR…………………………………41
Table 3.3 MicroRNA cDNA synthesis mix…………………………………………43
Table 3.4 miRNA qRT-PCR reaction mixture………………………………………44
Table 3.5 Buffers and reagents prepared for western blot analysis…………………46
Table 3.6 Preparation of standard curve……………………………………………48
Table 3.7 Primers with restriction sites used for cloning of luciferase constructs…57
Table 4.1 Top ten differentially up- or down-regulated miRNAs in reprogrammed CRC-iPCs………………………………………………………………71
Table 4.2 Top 10 predicted KEGG pathways and genes targeted by the differentially expressed miRNAs in CRC-iPC……………………………………80
Table 4.3 Differentially expressed miRNAs in the CRC-iPC clones target selected mesenchymal and epithelial genes………………………………………86
Table 4.4 Down-regulated miRNAs mapping at the XP11.23 chromosomal locus were differentially expressed in CRC-iPCs………………………………92

References
1. VeettilSK, LimKG, ChaiyakunaprukN, ChingSM, Abu HassanMR. Colorectal cancer in Malaysia: Its burden and implications for a multiethnic country. Asian J Surg. 2017; 40(6):481–9.
2. DeRosaM, PaceU, RegaD, CostabileV, DuraturoF, IzzoP, et al. Genetics, diagnosis and management of colorectal cancer (Review). Oncol Rep. 2015;34(3):1087–96.
3. HaggarFA, BousheyRP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22(4):191–7.
4. VuT, DattaPK. Regulation of EMT in colorectal cancer: A culprit in metastasis. Cancers (Basel). 2017;9(12):1–22.
5. TsaiJH, YangJ. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013; 27(20):2192–206.
6. LiuX, FanD. The epithelial-mesenchymal transition and cancer stem cells: functional and mechanistic links. Curr Pharm Des. 2015; 21(10):1279–91.
7. LiX, PeiD, ZhengH. Transitions between epithelial and mesenchymal states during cell fate conversions. Protein Cell. 2014;5(8):580–91.
8. ShimonoY, ZabalaM, ChoRW, LoboN, DalerbaP, QianD, et al. Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells. Cell. 2009;138(3):592–603.
9. SubramanyamD, LamouilleS, RobertJL, LiuJY, BucayN, DerynckR, et al. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol. 2011;29(5):443–8.
10. TakahashiK, YamanakaS. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006;126(4):663–76.
11. TakahashiK, OkitaK, NakagawaM, YamanakaS. Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc. 2007;2(12):3081–9.
12. CamaraDAD, MambelliLI, PorcacchiaAS, KerkisI. Advances and challenges on cancer cells reprogramming using induced pluripotent stem cells technologies. J Cancer. 2016;7(15):2296–303.
13. MiyoshiN, IshiiH, NagaiK -i., HoshinoH, MimoriK, TanakaF, et al. Defined factors induce reprogramming of gastrointestinal cancer cells. Proc Natl Acad Sci. 2010;107(1):40–5.
14. ZhangX, CruzFD, TerryM, RemottiF, MatushanskyI. Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Oncogene. 2013;32(18):2249–60.
15. MiyazakiS, YamamotoH, MiyoshiN, WuX, OgawaH, UemuraM, et al. A Cancer Reprogramming Method Using MicroRNAs as a Novel Therapeutic Approach against Colon Cancer: Research for Reprogramming of Cancer Cells by MicroRNAs. Ann Surg Oncol. 2015;22 (3):1394-401.
16. TakaishiM, TarutaniM, TakedaJ, SanoS. Mesenchymal to Epithelial Transition Induced by Reprogramming Factors Attenuates the Malignancy of Cancer Cells. ColemanWB, editor. PLoS One. 2016;11(6)
17.HiewMSY, ChengHP, HuangCJ, ChongKY, CheongSK, ChooKB, et al. Incomplete cellular reprogramming of colorectal cancer cells elicits an epithelial/mesenchymal hybrid phenotype. J Biomed Sci. 2018;25(1):1–13.
18. IzgiK, CanatanH, IskenderB. Current status in cancer cell reprogramming and its clinical implications. J Cancer Res Clin Oncol. 2017;143(3):371–83.
19. LiR, LiangJ, NiS, ZhouT, QingX, LiH, et al. A mesenchymal-to-Epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010;7(1):51–63.
20. Samavarchi-TehraniP, GolipourA, DavidL, SungH-K, BeyerTA, DattiA, et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell. 2010; 7(1):64–77.
21. Anokye-DansoF, TrivediCM, JuhrD, GuptaM, CuiZ, TianY, et al. Highly Efficient miRNA-Mediated Reprogramming of Mouse and Human Somatic Cells to Pluripotency. Cell Stem Cell. 2011;8(4):376–88.
22. WangW, YangJ, LiuH, LuD, ChenX, ZenonosZ, et al. Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc Natl Acad Sci. 2011;108(45):18283–8.
23. FerlayJ, ShinH-R, BrayF, FormanD, MathersC, ParkinDM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.
24. RaskovH, PommergaardH-C, BurcharthJ, RosenbergJ. Colorectal carcinogenesis--update and perspectives. World J Gastroenterol. 2014 20(48):18151–64.
25. PourhoseingholiMA. Increased burden of colorectal cancer in Asia. World J Gastrointest Oncol.2012;4(4):68–70.
26. Granados-RomeroJJ, Valderrama-TrevinoAI, Contreras-FloresEH, Barrera-MeraB, Herrera EnriquezM, Uriarte-RuizK, et al. Colorectal cancer: a review. Int J Res Med Sci. 2017;5(11):4667.
27. BrosensLAA, OfferhausGJA, GiardielloFM. Hereditary Colorectal Cancer: Genetics and Screening. Surg Clin North Am. 2015;95(5):1067–80.
28. TariqK, GhiasK. Colorectal cancer carcinogenesis: a review of mechanisms. Cancer Biol Med. 2016;13(1):120–35.
29. NajdiR, HolcombeR, WatermanM. Wnt signaling and colon carcinogenesis: Beyond APC. J Carcinog [Internet]. 2011;10(1):5.
30. ColussiD, BrandiG, BazzoliF, RicciardielloL. Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention. Int J Mol Sci. 2013;14(8):16365–85.
31. MacDonaldBT, TamaiK, HeX. Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases. Dev Cell. 2009;17(1):9–26.
32. Al-SohailyS, BiankinA, LeongR, Kohonen-CorishM, WarusavitarneJ. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012;27(9):1423–31.
33. LiX-L, ZhouJ, ChenZ-R, ChngW-J. P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation. World J Gastroenterol.2015 21(1):84–93.
34. CaoH, XuE, LiuH, WanL, LaiM. Epithelial-mesenchymal transition in colorectal cancer metastasis: A system review. Pathol Res Pract. 2015;211(8):557–69.
35. BellamN, PascheB. TGF-β Signaling Alterations and Colon Cancer. In: Cancer treatment and research. 2010. p. 85–103.
36. FreemanTJ, SmithJJ, ChenX, WashingtonMK, RolandJT, MeansAL, et al. Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of β-catenin. Gastroenterology. 2012;142(3):562–571.
37. ZhaoS, VenkatasubbaraoK, LazorJW, SperryJ, JinC, CaoL, et al. Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res. 2008;68(11):4221–8.
38. XiongH, HongJ, DuW, LinY, RenL, WangY, et al. Roles of STAT3 and ZEB1 Proteins in E-cadherin Down-regulation and Human Colorectal Cancer Epithelial-Mesenchymal Transition. J Biol Chem. 2012;287(8):5819–32.
39. MolinariF, FrattiniM. Functions and Regulation of the PTEN Gene in Colorectal Cancer. Front Oncol. 2014; 3:326.
40. SumanS, KurisettyV, DasTP, VadodkarA, RamosG, LakshmanaswamyR, et al. Activation of AKT signaling promotes epithelial-mesenchymal transition and tumor growth in colorectal cancer cells. Mol Carcinog. 2014;53(1):151–60.
41. GulhatiP, BowenKA, LiuJ, StevensPD, RychahouPG, ChenM, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011;71(9):3246–56.
42. CalonA, EspinetE, Palomo-PonceS, TaurielloDVF, IglesiasM, CespedesMV, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22(5):571–84.
43. BrennerH, KloorM, PoxCP. Colorectal cancer. Lancet. 2014;383(9927):1490–502.
44. KolaI, LandisJ. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711–6.
45. GarnettMJ, McDermottU. The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response. Curr Opin Genet Dev. 2014;24:114–9.
46. McIntyreRE, BuczackiSJA, ArendsMJ, AdamsDJ. Mouse models of colorectal cancer as preclinical models. BioEssays. 2015;37(8):909–20.
47. GolovkoD, KedrinD, YilmazOH, RoperJ. Colorectal cancer models for novel drug discovery. Expert Opin Drug Discov. 2015;10(11):1217–29.
48. KatsiampouraA, RaghavK, JiangZ-Q, MenterDG, VarkarisA, MorelliMP, et al. Modeling of Patient-Derived Xenografts in Colorectal Cancer. Mol Cancer Ther. 2017;16(7):1435–42.
49. EvansJP, SuttonPA, WiniarskiBK, FenwickSW, MalikHZ, VimalachandranD, et al. From mice to men: Murine models of colorectal cancer for use in translational research. Crit Rev Oncol Hematol. 2016; 98:94–105.
50. SzaboV, BugyikE, DezsoK, EckerN, NagyP, TimarJ, et al. Mechanism of tumour vascularization in experimental lung metastases. J Pathol. 2015;235(3):384–96.
51. LinS, ChangDC, Chang-linS, LinC, WuDTS, ChenDT, et al. Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. 2008;2115–24.
52. CaretteJE, PruszakJ, VaradarajanM, BlomenV a, GokhaleS, CamargoFD, et al. Brief report Generation of iPSCs from cultured human malignant cells. Blood. 2010;115(20):4039–42.
53. ZhuD, KongCSL, GingoldJA, ZhaoR, LeeD-F. Induced Pluripotent Stem Cells and Induced Pluripotent Cancer Cells in Cancer Disease Modeling. Adv Exp Med Biol.2018;1–15.
54. YamanakaS. Elite and stochastic models for induced pluripotent stem cell generation. Nature. 2009; 460(7251):49–52.
55. Ramos-MejiaV, FragaMF, MenendezP. IPSCs from cancer cells: Challenges and opportunities. Trends Mol Med. 2012;18(5):245–7.
56. MathieuJ, ZhangZ, ZhouW, WangAJ, HeddlestonJM, PinnaCMA, et al. HIF induces human embryonic stem cell markers in cancer cells. Cancer Res. 2011;71(13):4640–52.
57. MohyeldinA, Garzon-MuvdiT, Quinones-HinojosaA. Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche. Cell Stem Cell. 2010;7(2):150–61.
58. LinC-P, ChoiYJ, HicksGG, HeL. The emerging functions of the p53-miRNA network in stem cell biology. Cell Cycle. 2012; 11(11):2063–72.
59. BernhardtM, NovakD, AssenovY, OroujiE, KnappeN, WeinaK, et al. Melanoma-Derived iPCCs Show Differential Tumorigenicity and Therapy Response. Stem Cell Reports. 2017;8(5):1379–91.
60. KumanoK, AraiS, HosoiM, TaokaK, TakayamaN, OtsuM, et al. Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples. Blood. 2012;119(26):6234–42.
61. ChoongPF, TehHX, TeohHK, OngHK, ChooKB, SugiiS, et al. Heterogeneity of osteosarcoma cell lines led to variable responses in reprogramming. Int J Med Sci. 2014;11(11):1154–60.
62. KimJ, HoffmanJP, AlpaughRK, RhimAD, ReichertM, StangerBZ, et al. An iPSC Line from Human Pancreatic Ductal Adenocarcinoma Undergoes Early to Invasive Stages of Pancreatic Cancer Progression. Cell Rep. 2013;3(6):2088–99.
63. StrickerS, PollardS. Reprogramming cancer cells to pluripotency: an experimental tool for exploring cancer epigenetics. Epigenetics. 2014;9(6):798–802.
64. ThieryJP, AcloqueH, HuangRYJ, NietoMA. Epithelial-Mesenchymal Transitions in Development and Disease. Cell. 2009;139(5):871–90.
65. ChenJ, HanQ, PeiD. EMT and MET as paradigms for cell fate switching. J Mol Cell Biol. 2012;4(2):66–9.
66. KalluriR, WeinbergR a. Review series The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.
67. CraeneBDe, BerxG. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.
68. LamouilleS, XuJ, DerynckR. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.
69. ChapmanHA. Epithelial-Mesenchymal Interactions in Pulmonary Fibrosis. Annu Rev Physiol. 2011;73(1):413–35.
70. ZhengH, KangY. Multilayer control of the EMT master regulators. Oncogene. 2014;33(14):1755–63.
71. NeureiterD. Epigenetic control of epithelial-mesenchymal-transition in human cancer (Review). Mol Clin Oncol. 2012;3–11.
72. ZhangJ, TianX-J, XingJ. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks. J Clin Med. 2016;5(4):41.
73. FanF, SamuelS, EvansKW, LuJ, XiaL, ZhouY, et al. Overexpression of Snail induces epithelial-mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Med. 2012;1(1):5–16.
74. WangY, ZhouBP. Epithelial-mesenchymal Transition---A Hallmark of Breast Cancer Metastasis. Cancer Hallm. 2013;1(1):38–49.
75. SkovieroviH, OkajekoviT, StrnidelJ, VidomanoviE, HalaoviE. Molecular regulation of epithelial-to-mesenchymal transition in tumorigenesis (Review). Int J Mol Med. 2017; 41(3):1187–200.
76. ThieryJP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54.
77. BrabletzT. To differentiate or not — routes towards metastasis. Nat Rev Cancer. 2012;12(6):425–36.
78. MejlvangJ, KriajevskaM, VandewalleC, ChernovaT, SayanAE, BerxG, et al. Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. MargolisB, editor. Mol Biol Cell. 2007;18(11):4615–24.
79. OcanaOH, CorcolesR, FabraA, Moreno-BuenoG, AcloqueH, VegaS, et al. Metastatic Colonization Requires the Repression of the Epithelial-Mesenchymal Transition Inducer Prrx1. Cancer Cell. 2012;22(6):709–24.
80. TsaiJH, DonaherJL, MurphyDA, ChauS, YangJ. Spatiotemporal Regulation of Epithelial-Mesenchymal Transition Is Essential for Squamous Cell Carcinoma Metastasis. Cancer Cell. 2012;22(6):725–36.
81. JollyMK. Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis. Front Oncol. 2015;5:1–19.
82. SaitohM. Involvement of partial EMT in cancer progression. J Biochem. 2018;164(4):257–64.
83. AcetoN, BardiaA, MiyamotoDT, DonaldsonMC, WittnerBS, SpencerJA, et al. Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis. Cell. 2014;158(5):1110–22.
84. JoosseSA, GorgesTM, PantelK. Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med. 2015;7(1):1–11.
85. HouJ-M, KrebsMG, LancashireL, SloaneR, BackenA, SwainRK, et al. Clinical Significance and Molecular Characteristics of Circulating Tumor Cells and Circulating Tumor Microemboli in Patients With Small-Cell Lung Cancer. J Clin Oncol. 2012;30(5):525–32.
86. HawkinsK, JoyS, McKayT. Cell signalling pathways underlying induced pluripotent stem cell reprogramming. World J Stem Cells. 2014;6(5):620.
87. MaheraliN, HochedlingerK. Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr Biol. 2009;19(20):1718–23.
88. ChenJ, LiuJ, YangJ, ChenY, ChenJ, NiS, et al. BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone. Cell Res. 2011;21(1):205–12.
89. UnternaehrerJJ, ZhaoR, KimK, CesanaM, PowersJT, RatanasirintrawootS, et al. The epithelial-mesenchymal transition factor SNAIL paradoxically enhances reprogramming. Stem Cell Reports. 2014;3(5):691–8.
90. LiuX, SunH, QiJ, WangL, HeS, LiuJ, et al. Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat Cell Biol. 2013;15(7):829–38.
91. BartelDP. MicroRNAs: Target Recognition and Regulatory Functions. Cell. 2009;136(2):215–33.
92. TetreaultN, DeGuireV. MiRNAs: Their discovery, biogenesis and mechanism of action. Clin Biochem. 2013;46(10–11):842–5.
93. WangY, LuoJ, ZhangH, LuJ. microRNAs in the Same Clusters Evolve to Coordinately Regulate Functionally Related Genes. Mol Biol Evol. 2016 ;33(9):2232–47.
94. Andres-LeonE, CasesI, AlonsoS, RojasAM. Novel miRNA-mRNA interactions conserved in essential cancer pathways. Sci Rep. 2017;7(1):46101.
95. MacFarlaneLA, R. MurphyP. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010;11(7):537–61.
96. KimYK, KimVN. Processing of intronic microRNAs. EMBO J. 2007;26(3):775–83.
97. RamalingamP, PalanichamyJK, SinghA, DasP, BhagatM, KassabMA, et al. Biogenesis of intronic miRNAs located in clusters by independent transcription and alternative splicing. RNA. 2014;20(1):76–87.
98. LeeY, KimM, HanJ, YeomK-H, LeeS, BaekSH, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004;23(20):4051–60.
99. LeeY, AhnC, HanJ, ChoiH, KimJ, YimJ, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425(6956):415–9.
100. GregoryRI, YanK-P, AmuthanG, ChendrimadaT, DoratotajB, CoochN, et al. The Microprocessor complex mediates the genesis of microRNAs. Nature. 2004;432(7014):235–40.
101. LundE, GuttingerS, CaladoA, DahlbergJE, KutayU. Nuclear Export of MicroRNA Precursors. Science. 2004;303(5654):95–8.
102. HutvagnerG, McLachlanJ, PasquinelliAE, BalintE, TuschlT, ZamorePD. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science. 2001;293(5531):834–8.
103. ManiatakiE, MourelatosZ. A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005;19(24):2979–90.
104. MallannaSK, RizzinoA. Emerging roles of microRNAs in the control of embryonic stem cells and the generation of induced pluripotent stem cells. Dev Biol. 2010;344(1):16–25.
105. WinterJ, JungS, KellerS, GregoryRI, DiederichsS. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol [Internet]. 2009;11(3):228–34.
106. ChooKB, SoonYL, NguyenPNN, HiewMSY, HuangC-J. MicroRNA-5p and -3p co-expression and cross-targeting in colon cancer cells. J Biomed Sci. 2014;21(1):95.
107. Griffiths-JonesS, GrocockRJ, vanDongenS, BatemanA, EnrightAJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34:140-4.
108. LuningschrorP, HauserS, KaltschmidtB, KaltschmidtC. MicroRNAs in pluripotency, reprogramming and cell fate induction. Biochim Biophys Acta - Mol Cell Res. 2013;1833(8):1894–903.
109. MarsonA, LevineSS, ColeMF, FramptonGM, BrambrinkT, JohnstoneS, et al. Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells. Cell. 2008;134(3):521–33.
110. WangY, BaskervilleS, ShenoyA, BabiarzJE, BaehnerL, BlellochR. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet. 2008;40(12):1478–83.
111. WangY, MeltonC, LiY-P, ShenoyA, ZhangX-X, SubramanyamD, et al. miR-294/miR-302 promotes proliferation, suppresses G1-S restriction point, and inhibits ESC differentiation through separable mechanisms. Cell Rep. 2013;4(1):99–109.
112. LinS-L, ChangDC, LinC-H, YingS-Y, LeuD, WuDTS. Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Res [Internet]. 2011 Feb [cited 2018 Sep 20];39(3):1054–65.
113. Anokye-DansoF, SnitowM, MorriseyEE. How microRNAs facilitate reprogramming to pluripotency. J Cell Sci. 2012;125(18):4179–787.
114. Shyh-ChangN, DaleyGQ. Lin28: primal regulator of growth and metabolism in stem cells. Cell Stem Cell. 2013;12(4):395–406.
115. MeltonC, JudsonRL, BlellochR. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature. 2010;463(7281):621–6.
116. TayYM-S, TamW-L, AngY-S, GaughwinPM, YangH, WangW, et al. MicroRNA-134 modulates the differentiation of mouse embryonic stem cells, where it causes post-transcriptional attenuation of Nanog and LRH1. Stem Cells. 2008;26(1):17–29.
117. TayY, ZhangJ, ThomsonAM, LimB, RigoutsosI. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature. 2008;455(7216):1124–8.
118. ThorntonJE, GregoryRI. How does Lin28 let-7 control development and disease? Trends Cell Biol. 2012;22(9):474–82.
119. LinSL, ChangDC, Chang-LinS, LinCH, WuDTS, ChenDT, et al. Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA. 2008;14(10):2115–24.
120. JudsonRL, BabiarzJE, VenereM, BlellochR. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol. 2009;27(5):459–61.
121 MiyoshiN, IshiiH, NaganoH, HaraguchiN, DewiDL, KanoY, et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell. 2011;8(6):633–8.
122. KogaC, KobayashiS, NaganoH, TomimaruY, HamaN, WadaH, et al. Reprogramming using microRNA-302 improves drug sensitivity in hepatocellular carcinoma cells. Ann Surg Oncol. 2014; 21(4):591-600.
123. LipchinaI, ElkabetzY, HafnerM, SheridanR, MihailovicA, TuschlT, et al. Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response. Genes Dev. 2011;25(20):2173–86.
124.WangG, GuoX, HongW, LiuQ, WeiT, LuC, et al. Critical regulation of miR-200 / ZEB2 pathway in Oct4 / Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation. Proc Natl Acad Sci U S A. 2013;110(8):2858–63.
125. TianY, ZhangY, HurdL, HannenhalliS, LiuF, LuMM, et al. Regulation of lung endoderm progenitor cell behavior by miR302/367. Development. 2011;138(7):1235–45.
126. SpikeBT, WahlGM. p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome. Genes Cancer. 2011;2(4):404–19.
127. YeD, WangG, LiuY, HuangW, WuM, ZhuS, et al. MiR-138 Promotes Induced Pluripotent Stem Cell Generation Through the Regulation of the p53 Signaling. Stem Cells. 2012;30(8):1645–54.
128. ChoiYJ, LinC-P, HoJJ, HeX, OkadaN, BuP, et al. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol. 2011;13(11):1353–60.
129. HuK. All roads lead to induced pluripotent stem cells: the technologies of iPSC generation. Stem Cells Dev. 2014;23(12):1285–300.
130. MendellJT, OlsonEN. MicroRNAs in Stress Signaling and Human Disease. Cell. 2012;148(6):1172–87.
131. JanssonMD, LundAH. MicroRNA and cancer. Mol Oncol. 2012 ;6(6):590–610.
132. FengYH, TsaoC-J. Emerging role of microRNA-21 in cancer. Biomed reports. 2016;5(4):395–402.
133. WangR, MaJ, WuQ, XiaJ, MieleL, SarkarFH, et al. Functional role of miR-34 family in human cancer. Curr Drug Targets. 2013;14(10):1185–91.
134. LiJ-M, ZhaoR-H, LiS-T, XieC-X, JiangH-H, DingW-J, et al. Down-regulation of fecal miR-143 and miR-145 as potential markers for colorectal cancer. Saudi Med J. 2012;33(1):24–9.
135. DongY, WuWKK, WuCW, SungJJY, YuJ, NgSSM. MicroRNA dysregulation in colorectal cancer: a clinical perspective. Br J Cancer. 2011;104(6):893–8.
136. RenA, DongY, TsoiH, YuJ. Detection of miRNA as Non-Invasive Biomarkers of Colorectal Cancer. Int J Mol Sci. 2015;16(2):2810–23.
137. BaumannV, WinklerJ. miRNA-based therapies: strategies and delivery platforms for oligonucleotide and non-oligonucleotide agents. Future Med Chem. 2014;6(17):1967–84.
138. YilmazM, ChristoforiG. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28(1–2):15–33.
139. HeerbothS, HousmanG, LearyM, LongacreM, BylerS, LapinskaK, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4(1):6.
140. ChiY, ZhouD. MicroRNAs in colorectal carcinoma - from pathogenesis to therapy. J Exp Clin Cancer Res. 2016;35(1):43.
141. KorpalM, LeeES, HuG, KangY. The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2. J Biol Chem. 2008;283(22):14910–4.
142. ParkS-M, GaurAB, LengyelE, PeterME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22(7):894–907.
143. ChenML, LiangLSen, WangXK. miR-200c inhibits invasion and migration in human colon cancer cells SW480/620 by targeting ZEB1. Clin Exp Metastasis. 2012;29(5):457–69.
144. GengL, ChaudhuriA, TalmonG, WisecarverJL, AreC, BrattainM, et al. MicroRNA-192 suppresses liver metastasis of colon cancer. Oncogene. 2014;33(46):5332–40.
145. SunZ, ZhangZ, LiuZ, QiuB, LiuK, DongG. MicroRNA-335 inhibits invasion and metastasis of colorectal cancer by targeting ZEB2. Med Oncol. 2014;31(6):982.
146. ZhengY-B, LuoH-P, ShiQ, HaoZ-N, DingY, WangQ-S, et al. miR-132 inhibits colorectal cancer invasion and metastasis via directly targeting ZEB2. World J Gastroenterol. 2014 ;20(21):6515–22.
147. HillL, BrowneG, TulchinskyE. ZEB/miR-200 feedback loop: at the crossroads of signal transduction in cancer. Int J cancer. 2013;132(4):745–54.
148. LuM, JollyMK, LevineH, OnuchicJN, Ben-JacobE. MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination. Proc Natl Acad Sci U S A. 2013;110(45):18144–9.
149. SunY, ShenS, LiuX, TangH, WangZ, YuZ, et al. miR-429 inhibits cells growth and invasion and regulates EMT-related marker genes by targeting Onecut2 in colorectal carcinoma. Mol Cell Biochem. 2014;390(1–2):19–30.
150. RokavecM, OnerMG, LiH, JackstadtR, JiangL, LodyginD, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124(4):1853–67.
151. WangB, LiW, LiuH, YangL, LiaoQ, CuiS, et al. miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition. Cell Death Dis. 2014;5(7):1335.
152. ZhangJX, MaiSJ, HuangXX, WangFW, LiaoYJ, LinMC, et al. MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of β-catenin signaling. Ann Oncol. 2014;25(11):2196–204.
153. TangW, ZhuY, GaoJ, FuJ, LiuC, LiuY, et al. MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4. Br J Cancer. 2014;110(2):450–8.
154. PfaffN, FiedlerJ, HolzmannA, SchambachA, MoritzT, CantzT, et al. MiRNA screening reveals a new miRNA family stimulating iPS cell generation via regulation of Meox2. EMBO Rep. 2011;12(11):1153–9.
155. NguyenPNN, ChooKB, HuangCJ, SugiiS, CheongSK, KamarulT. MIR-524-5p of the primate-specific C19MC miRNA cluster targets TP53IPN1-and EMT-Associated genes to regulate cellular reprogramming. Stem Cell Res Ther. 2017;8(1):1–15.
156. LiM, HeL. microRNAs as novel regulators of stem cell pluripotency and somatic cell reprogramming. Bioessays. 2012;34(8):670–80.
157. GiordaR, BonagliaMC, BeriS, FicheraM, NovaraF, MaginiP, et al. Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females. Am J Hum Genet. 2009;8(3):394–400.
158. WolczykD, Zaremba-CzogallaM, Hryniewicz-JankowskaA, TabolaR, GrabowskiK, SikorskiAF, et al. TNF-α promotes breast cancer cell migration and enhances the concentration of membrane-associated proteases in lipid rafts. Cell Oncol. 2016;39(4):353–63.
159. ZhaoP, ZhangZ. TNF-α promotes colon cancer cell migration and invasion by upregulating TROP-2. Oncol Lett. 2018;15(3):3820–7.
160. WuY, ZhouBP. TNF-α/NFκ-B/Snail pathway in cancer cell migration and invasion. Br J Cancer. 2010;102(4):639–44.
161. LiuG, ZhuJ, YuM, CaiC, ZhouY, YuM, et al. Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients. J Transl Med. 2015;13(1):1–10.
162. NeganovaI, ShmelevaE, MunkleyJ, ChichagovaV, AnyfantisG, AndersonR, et al. JNK/SAPK Signaling Is Essential for Efficient Reprogramming of Human Fibroblasts to Induced Pluripotent Stem Cells. Stem Cells. 2016;34(5):1198–212.
163. XuW, YangZ, LuN. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 2015;9(4):317–24.
164. HardyKM, BoothBW, HendrixMJC. Erb/EFG Signaling and EMT in mammary development and breast cancer. J Mammary Gland Biol Neoplasia. 2010;15(2):191–9.
165. LuKV, ChangJP, ParachoniakCA, PandikaMM, AghiMK, MeyronetD, et al. VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex. Cancer Cell. 2012;22(1):21–35.
166. XuW, YangZ, LuN. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 2015;9(4):317–24.
167. DavidL, PoloJM. Phases of reprogramming. Stem Cell Res. 2014;12(3):754–61.
168. LuKV, ChangJP, ParachoniakCA, PandikaMM, AghiK, MeyronetD, et al. NIH Public Access. 2014;22(1):21–35.
169. YuJSL, CuiW. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 2016;143(17):3050–60.
170. EngelmanJA. Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.
171. KalimuthuS, Se-KwonK. Cell survival and apoptosis signaling as therapeutic target for cancer: Marine bioactive compounds. Int J Mol Sci. 2013;14(2):2334–54.
172. DownwardJ. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004;15(2):177–82.
173. LeeYJ, HanHJ. Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3β, Snail1, and β-catenin in renal proximal tubule cells. Am J Physiol Physiol. 2010;298(5):1263–75.
174. MiyazokoK. Transforming growth factor-β signaling in epithelial-mesenchymal transition and progression of cancer. Proc Japan Acad Ser B. 2009;85(8):314–23.
175. LiH, BatthIS, QuX, XuL, SongN, WangR, et al. IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: Overview and new insights. Mol Cancer. 2017;16(1):1–15.
176. MatosML, LapyckyjL, RossoM, BessoMJ, MencucciMV, BriggilerCIM, et al. Identification of a Novel Human E-Cadherin Splice Variant and Assessment of Its Effects Upon EMT-Related Events. J Cell Physiol. 2017;232(6):1368–86.
177. GargM. Urothelial cancer stem cells and epithelial plasticity: current concepts and therapeutic implications in bladder cancer. Cancer Metastasis Rev. 2015;34(4):691–701.
178. LobodaA, NebozhynMV., WattersJW, BuserCA, ShawPM, HuangPS, et al. EMT is the dominant program in human colon cancer. BMC Med Genomics. 2011;4(1):9.
179. ChangYY, KuoWH, HungJH, LeeCY, LeeYH, ChangYC, et al. Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing. Mol Cancer. 2015;14(1):1–13.
180. ZhangH, QiS, ZhangT, WangA, LiuR, GuoJ, et al. miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression. Oncotarget. 2015;6(8):6092–104.
181. FortunatoO, BoeriM, MoroM, VerriC, MensahM, ConteD, et al. Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction. Cell Death Dis. 2014;5(12):1564-9.
182. XuX, ZhangY, LiuZ, ZhangX, JiaJ. miRNA-532-5p functions as an oncogenic microRNA in human gastric cancer by directly targeting RUNX3. J Cell Mol Med. 2016;20(1):95–103.
183. JiangC, LongJ, LiuB, XuM, WangW, XieX, et al. miR-500a-3p promotes cancer stem cells properties via STAT3 pathway in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2017;36(1):99.
184. NiF, GuiZ, GuoQ, HuZ, WangX, ChenD, et al. Downregulation of miR-362-5p inhibits proliferation, migration and invasion of human breast cancer MCF7 cells. Oncol Lett. 2016;11(2):1155–60.
185. NiF, ZhaoH, CuiH, WuZ, ChenL, HuZ, et al. MicroRNA-362-5p promotes tumor growth and metastasis by targeting CYLD in hepatocellular carcinoma. Cancer Lett. 2015;356(2):809–18.
186. LuoD, ZhangZ, ZhangZ, LiJ-Y, CuiJ, ShiW-P, et al. Aberrant Expression of miR-362 Promotes Lung Cancer Metastasis through Downregulation of Sema3A. J Immunol Res. 2018;2018:1–10.
187. ChiY, CuiJ, WangY, DuW, ChenF, LiZ, et al. Interferon alters the microRNA profile of umbilical cord derived mesenchymal stem cells. Mol Med Rep. 2016;14(5):4187–97.
188. GestC, JoimelU, HuangL, PritchardLL, PetitA, DulongC, et al. Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: Differences in MDA-MB-231 and MCF-7 breast cancer cell lines. BMC Cancer. 2013;13.
189. WangXH, LiuW, FanDX, HuWT, LiMQ, ZhuXY, et al. IL-33 restricts invasion and adhesion of trophoblast cell line JEG3 by downregulation of integrin α4β1 and CD62L. Mol Med Rep. 2017;16(4):3887–93.
190. EhrigK, KilincMO, ChenNG, StritzkerJ, BuckelL, ZhangQ, et al. Growth inhibition of different human colorectal cancer xenografts after a single intravenous injection of oncolytic vaccinia virus GLV-1h68. J Transl Med. 2013;11(1):1.
191. WangW, YangJ, LiuH, LuD, ChenX, ZenonosZ, et al. Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc Natl Acad Sci U S A. 2011;108(45):18283–8.
192. CamaraDAD, PorcacchiaAS, CostaAS, AzevedoRA, KerkisI. Murine melanoma cells incomplete reprogramming using non-viral vector. Cell Prolif. 2017;50(4):1–10.
193. KuoC-H, YingS-Y. Advances in microRNA-mediated reprogramming technology. Stem Cells Int. 2012;2012:823709.
194. NelakantiRV, KooremanNG, WuJC. Teratoma formation: a tool for monitoring pluripotency in stem cell research. Curr Protoc Stem Cell Biol. 2015;32:8-17.
195. OshimaN, YamadaY, NagayamaS, KawadaK, HasegawaS, OkabeH, et al. Induction of Cancer Stem Cell Properties in Colon Cancer Cells by Defined Factors. SinghSR, editor. PLoS One. 2014;9(7):101735.
196. IslamSMR, SuenagaY, TakatoriA, UedaY, KanekoY, KawanaH, et al. Sendai virus-mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells. Cancer Sci. 2015;106(10):1351–61.
197. LaiJ, KongCM, MahalingamD, XieX, WangX. Elite model for the generation of induced pluripotent cancer cells (iPCs). JohnsonR, editor. PLoS One. 2013;8(2):56702.
198. RedmerT, DieckeS, GrigoryanT, Quiroga-NegreiraA, BirchmeierW, BesserD. E-cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming. EMBO Rep. 201;12(7):720–6.
199. BalzanoF, CrucianiS, BasoliV, SantanielloS, FacchinF, VenturaC, et al. MiR200 and MiR302: Two big families influencing stem cell behavior. Molecules. 2018;23(2).
200. KongQ, XieB, LiJ, HuanY, HuangT, WeiR, et al. Identification and characterization of an oocyte factor required for porcine nuclear reprogramming. J Biol Chem. 2014;289(10):6960–8.
201. NietoMA, HuangRY-J, JacksonRA, ThieryJP. EMT: 2016. Cell. 2016;166(1):21–45.
202. ForteE, ChimentiI, RosaP, AngeliniF, PaganoF, CalogeroA, et al. EMT/MET at the crossroad of stemness, regeneration and oncogenesis: The Ying-Yang equilibrium recapitulated in cell spheroids. Cancers (Basel). 2017;9(8):1–15.
203. JollyMK, JiaD, BoaretoM, ManiSA, PientaKJ, Ben-JacobE, et al. Coupling the modules of EMT and stemness: A tunable “stemness window” model. Oncotarget. 2015;6(28):25161–74.
204. StraussR, LiZ-Y, LiuY, BeyerI, PerssonJ, SovaP, et al. Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. GullbergD, editor. PLoS One. 2011;6(1):16186.
205. Grosse-WildeA, Fouquier d’HerouelA, McIntoshE, ErtaylanG, SkupinA, KuestnerRE, et al. Stemness of the hybrid Epithelial/Mesenchymal State in Breast Cancer and Its Association with Poor Survival. Ben-JacobE, editor. PLoS One. 2015;10(5):126522.
206. RuscettiM, QuachB, DadashianEL, MulhollandDJ, WuH. Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells during Prostate Cancer Metastasis. Cancer Res. 2015;75(13):2749–59.
207. JordanNV, JohnsonGL, AbellAN. Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle. 2011;10(17):2865–73.
208. ShawTJ, MartinP. Wound repair: a showcase for cell plasticity and migration. Curr Opin Cell Biol. 2016;42:29–37.
209. G.S, ChandraV, PhadnisS, BhondeR. Glomerular parietal epithelial cells of adult murine kidney undergo EMT to generate cells with traits of renal progenitors. J Cell Mol Med. 2011;15(2):396–413.
210. ConigliaroA, AmiconeL, CostaV, DeSantis PuzzoniaM, ManconeC, SacchettiB, et al. Evidence for a common progenitor of epithelial and mesenchymal components of the liver. Cell Death Differ. 2013;20(8):1116–23.
211. YeX, TamWL, ShibueT, KaygusuzY, ReinhardtF, Ng EatonE, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015;525(7568):256–60.
212. BiddleA, LiangX, GammonL, FazilB, HarperLJ, EmichH, et al. Cancer Stem Cells in Squamous Cell Carcinoma Switch between Two Distinct Phenotypes That Are Preferentially Migratory or Proliferative. Cancer Res. 2011;71(15):5317–26.
213. LiuS, CongY, WangD, SunY, DengL, LiuY, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports. 2014;2(1):78–91.
214. Celia-TerrassaT, Meca-CortesO, MateoF, Martinez de PazA, RubioN, Arnal-EstapeA, et al. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest. 2012;122(5):1849–68.
215. BarriereG, FiciP, GalleraniG, FabbriF, RigaudM. Epithelial Mesenchymal Transition: a double-edged sword. Clin Transl Med. 2015;4:14.
216. Bednarz-KnollN, Alix-PanabieresC, PantelK. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev. 2012;31(3):673–87.
217. DavidL, PoloJM. Phases of reprogramming. Stem Cell Res. 2014;12(3):754–61.
218. ChenT, YuanD, WeiB, JiangJ, KangJ, LingK, et al. E-cadherin-mediated cell-cell contact is critical for induced pluripotent stem cell generation. Stem Cells. 2010;28(8):1315–25.
219. FaiolaF, YinN, FidalgoM, HuangX, SaundersA, DingJ, et al. NAC1 Regulates Somatic Cell Reprogramming by Controlling Zeb1 and E-cadherin Expression. Stem cell reports. 2017;9(3):913–26.