口腔癌是世界上最普遍的癌症之一，而近年的統計數據也顯示口腔癌的發病率和死亡率仍在持續增加。在本研究的第一部分，我們探討discoidin domain receptor 1（DDR1）酪氨酸激酶於口腔鱗狀細胞癌（OSCC）腫瘤發生中所扮演的角色，我們的報告顯示DDR1在OSCC組織中表現量有顯著上升的情形，且其表現量與miR-486-3p表現量呈負相關，而實驗結果也顯示miR-486-3p會透過靶向DDR1 mRNA 3'-UTR 抑制DDR1表現。 此外降低DDR1表現會抑制癌細胞生長並誘發細胞凋亡，而大量表現miR-486-3p也會出現類似的功能，進一步我們發現miR-486-3p與其宿主基因ANK1會經由表觀遺傳抑制而受到轉錄的共同調控，而DNA甲基化抑制劑處理會促使ANK1和miR-486-3p重新表現。有趣的是，檳榔中主要的生物鹼為檳榔鹼，在我們的研究中發現它會促使DNMT3B與ANK1啟動子結合導致DNA甲基化，進而減弱OSCC中miR-486-3p的表達，這些結果暗示檳榔生物鹼可能促使DNMT3B去調節miR-486-3p / DDR1路徑並影響OSCC的腫瘤進展。在本研究的第二部分，許多文獻指出polycomb group（PcG）基因家族參與腫瘤的形成和進展。在這裡，我們研究顯示chromobox 8（CBX8）在OSCC病人檢體及細胞株皆有顯著上升趨勢，而降低CBX8表現後能夠減少OSCC細胞株和動物模型中的腫瘤生長和轉移，我們以抑制CBX8後的樣本進行cDNA array分析，設法去尋找CBX8所調控的目標基因，並藉由RT-qPCR及western blot分析，我們認為MIPOL1為一頗具潛力的CBX8目標基因。再者MIPOL1的大量表現可抑制癌細胞入侵及轉移能力，而MIPOL1表現靜默則會拮抗降低CBX8表現時入侵及轉移能力下降的影響。此外我們也發現降低CBX8表現能誘導p53絲氨酸15的位置磷酸化並增加p27，p21表現量，進而導致細胞週期G2M期停滯，而p53表現的靜默則會阻斷CBX8表現被抑制時細胞中p21及p27的積累。此外研究結果顯示miR-410-3p會透過靶向CBX8 mRNA 3'-UTR來抑制CBX8表現並減少癌細胞入侵及轉移能力，進一步若是同時大量表現CBX8則能抑制大量表現miR-410-3p所導致的入侵及轉移能力下降情形。在實驗的最後我們也發現，於臨床病人檢體中低的miR-410-3p表現與CBX8表現上升及MIPOL1表現下降具有相關性。綜合以上所述，本論文結果顯示miR-486-3p / DDR1，miR-410-3p / CBX8 / MIPOL1和p53路徑可影響OSCC腫瘤發生，並可當作OSCC潛在的標靶治療標的。

Oral cancer is amongst the most common cancers in the world. The recent statistical data showed that the incidence and mortality of oral cancer have continued to increase. In the first part of this study, we investigated the role of discoidin domain receptor 1 (DDR1) tyrosine kinase in oral squamous cell carcinoma (OSCC) tumorigenesis. Here, we reported that DDR1 was significantly upregulated in OSCC tissues and its levels were inversely correlated with miR-486-3p expression. The experimental results showed that miR-486-3p decreased DDR1 expression by targeting the 3’-UTR of DDR1 mRNA. Additionally, knockdown of DDR1 led to growth inhibition and apoptosis induction with a similar function in overexpression of miR-486-3p. Moreover, we found that miR-486-3p could be transcriptionally co-regulated with its host gene ANK1 through epigenetic repression. DNA methylation inhibitor treatment re-expressed ANK1 and miR-486-3p. Interestingly, arecoline, a major betel nut alkaloid, recruited DNMT3B binding to ANK1 promoter for DNA methylation and then attenuated the expression of miR-486-3p in OSCC. These results suggested that betel nut alkaloid may recruit DNMT3B to regulate miR-486-3p/DDR1 axis and affect tumor progression in OSCC. In the second part of this study, I studied the role of chromobox 8 (CBX8) in OSCC. There are many literatures supporting the polycomb group (PcG) gene family is involved in tumor development and progression. Here we showed that CBX8 was upregulated in OSCC patient samples and cell lines. CBX8 knockdown suppressed tumor growth and metastasis in OSCC cell lines and animal models. We identified CBX8-mediated target genes by using CBX8 knockdown cDNA array analysis. MIPOL1, a potential target gene of CBX8 was validated by RT-qPCR and western blot analysis. Ectopic expression of MIPOL1 in CBX8 depleted cells inhibit invasion and migration, whereas MIPOL1 silencing reversed these effects. Moreover, we found that CBX8 knockdown induced p53 phosphorylation at serine 15 and increased p27, p21 expression, resulting G2M cell cycle arrest, whereas p53 silencing could block p21 and p27 accumulation in CBX8 knockdown cells. Furthermore, we found that miR-410-3p could inhibit CBX8 expression and reduce invasion and migration by targeting the 3’-UTR of CBX8 mRNA, whereas ectopic expression of CBX8 rescued miR-410-3p-mediated invasion and migration suppression. Finally, the loss of miR-410-3p expression correlates with CBX8 upregulation and MIPOL1 downregulation in clinical patient samples. Taken together, these results suggested that miR-486-3p/DDR1, miR-410-3p/CBX8/MIPOL1 and p53 axes could affect OSCC tumorigenesis that might serve as potential therapeutic targets of OSCC.

摘要 I
Abstract III
Acknowledgement V
Table of Content VI
List of Figures IX
List of Tables XI
Chapter 1 : Introduction 1
1-1 Oral cancer 1
1-2 Discoidin domain receptor 1 1
1-3 miRNAs and DDR1 3
1-4 Polycomb group 4
1-5 Chromobox proteins 6
Chapter 2 : Materials and Methods 8
2-1 Clinical samples and patient characteristics 8
2-2 Microarray profiling 8
2-3 Immunohistochemistry (IHC) 9
2-4 Cell culture, vectors and reagents 9
2-5 Protein extraction and western blotting analysis 10
2-6 RNA extraction, reverse transcription and quantitative-PCR 11
2-7 Targeting miRNAs prediction 11
2-8 Plasmid construction and luciferase reporter assay 12
2-9 Cell proliferation assay 13
2-10 Cell apoptosis assay 13
2-11 Invasion and migration assay 14
2-12 Virus production and infection of target cells 15
2-13 Methylation specific PCR (MSP) 15
2-14 Chromatin immunoprecipitation (ChIP) assays 16
2-15 Xenograft animal studies 16
2-16 Zebrafish metastasis model 17
2-17 Cell cycle profile analysis 18
2-18 Statistical analysis 18
Chapter 3 : Results and Discussions 25
3-1 MicroRNA-486-3p functions as a tumor suppressor in oral cancer by targeting DDR1 25
3-1-1 DDR1 is upregulated in oral cancer patients and cell lines 25
3-1-2 Knockdown of DDR1 inhibits proliferation and induces apoptosis in OSCC cells 26
3-1-3 MiR-486-3p targets DDR1 in oral cancer 27
3-1-4 Overexpression of miR-486-3p also inhibits proliferation and activates apoptosis in OSCC cells 29
3-1-5 ANK1 methylation status affects miR-486-3p expression in OSCC cells 30
3-1-6 DNMT3B involved in arecoline induced ANK1 promoter methylation 31
3-1-7 Discussion 33
3-1-8 Conclusion 37
3-2 A novel mechanism of miRNA-mediated CBX8 associated with tumorigenesis in oral cancer 38
3-2-1 CBX8 expression is upregulated in OSCC 38
3-2-2 Altered CBX8 expression affects OSCC proliferation, invasion, migration, and EMT 39
3-2-3 To identify CBX8-mediated target genes 42
3-2-4 CBX8 affects OSCC invasion and migration via negative regulation of MIPOL1 42
3-2-5 CBX8 regulates p27 and p21 through mediating the p53 pathway 44
3-2-6 CBX8 is a direct target of miR-410-3p 46
3-2-7 miR-410-3p inhibits HNSCC invasion and migration via negative regulation of CBX8 47
3-2-8 Statistical correlation among the level of miR-410-3p, CBX8, and MIPOL1 48
3-2-9 Discussion 49
3-2-10 Conclusion 52
References 53
Appendix 109

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69-90.
2. Pfister DG, Spencer S, Brizel DM, Burtness B, Busse PM, Caudell JJ, et al. Head and Neck Cancers, Version 1.2015. Journal of the National Comprehensive Cancer Network : JNCCN 2015;13(7):847-56.
3. Haddad RI, Shin DM. Recent advances in head and neck cancer. The New England journal of medicine 2008;359(11):1143-54.
4. Cripps C, Winquist E, Devries MC, Stys-Norman D, Gilbert R. Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer. Current oncology (Toronto, Ont) 2010;17(3):37-48.
5. Ko YC, Huang YL, Lee CH, Chen MJ, Lin LM, Tsai CC. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 1995;24(10):450-3.
6. Takeshima M, Saitoh M, Kusano K, Nagayasu H, Kurashige Y, Malsantha M, et al. High frequency of hypermethylation of p14, p15 and p16 in oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 2008;37(8):475-9.
7. Mahnke AH, Miranda RC, Homanics GE. Epigenetic mediators and consequences of excessive alcohol consumption. Alcohol (Fayetteville, NY) 2017;60:1-6.
8. Marsit CJ, Houseman EA, Schned AR, Karagas MR, Kelsey KT. Promoter hypermethylation is associated with current smoking, age, gender and survival in bladder cancer. Carcinogenesis 2007;28(8):1745-51.
9. Chen D, Fang L, Li H, Tang MS, Jin C. Cigarette smoke component acrolein modulates chromatin assembly by inhibiting histone acetylation. The Journal of biological chemistry 2013;288(30):21678-87.
10. Shiu MN, Chen TH, Chang SH, Hahn LJ. Risk factors for leukoplakia and malignant transformation to oral carcinoma: a leukoplakia cohort in Taiwan. British journal of cancer 2000;82(11):1871-4.
11. Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer metastasis reviews 2012;31(1-2):295-321.
12. Carafoli F, Hohenester E. Collagen recognition and transmembrane signalling by discoidin domain receptors. Biochimica et biophysica acta 2013;1834(10):2187-94.
13. Leitinger B. Discoidin domain receptor functions in physiological and pathological conditions. International review of cell and molecular biology 2014;310:39-87.
14. Vogel WF, Abdulhussein R, Ford CE. Sensing extracellular matrix: an update on discoidin domain receptor function. Cellular signalling 2006;18(8):1108-16.
15. Xu H, Raynal N, Stathopoulos S, Myllyharju J, Farndale RW, Leitinger B. Collagen binding specificity of the discoidin domain receptors: binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1. Matrix biology : journal of the International Society for Matrix Biology 2011;30(1):16-26.
16. Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997;1(1):13-23.
17. Yang SH, Baek HA, Lee HJ, Park HS, Jang KY, Kang MJ, et al. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung carcinomas. Oncology reports 2010;24(2):311-9.
18. Valencia K, Ormazabal C, Zandueta C, Luis-Ravelo D, Anton I, Pajares MJ, et al. Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces cell survival, homing, and colonization in lung cancer bone metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research 2012;18(4):969-80.
19. Johnson JD, Edman JC, Rutter WJ. A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. Proceedings of the National Academy of Sciences of the United States of America 1993;90(12):5677-81.
20. Ram R, Lorente G, Nikolich K, Urfer R, Foehr E, Nagavarapu U. Discoidin domain receptor-1a (DDR1a) promotes glioma cell invasion and adhesion in association with matrix metalloproteinase-2. Journal of neuro-oncology 2006;76(3):239-48.
21. Yamanaka R, Arao T, Yajima N, Tsuchiya N, Homma J, Tanaka R, et al. Identification of expressed genes characterizing long-term survival in malignant glioma patients. Oncogene 2006;25(44):5994-6002.
22. Hidalgo-Carcedo C, Hooper S, Chaudhry SI, Williamson P, Harrington K, Leitinger B, et al. Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nature cell biology 2011;13(1):49-58.
23. Squire JA, Bayani J, Luk C, Unwin L, Tokunaga J, MacMillan C, et al. Molecular cytogenetic analysis of head and neck squamous cell carcinoma: By comparative genomic hybridization, spectral karyotyping, and expression array analysis. Head & neck 2002;24(9):874-87.
24. Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, et al. Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Molecular cancer 2010;9:227.
25. Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010;466(7308):835-40.
26. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nature reviews Genetics 2009;10(10):704-14.
27. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 2005;438(7068):685-9.
28. Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 2008;111(9):4797-808.
29. Chetoui N, El Azreq MA, Boisvert M, Bergeron ME, Aoudjit F. Discoidin domain receptor 1 expression in activated T cells is regulated by the ERK MAP kinase signaling pathway. Journal of cellular biochemistry 2011;112(12):3666-74.
30. Almeida MI, Reis RM, Calin GA. MicroRNA history: discovery, recent applications, and next frontiers. Mutation research 2011;717(1-2):1-8.
31. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature reviews Genetics 2008;9(2):102-14.
32. Yi B, Piazza GA, Su X, Xi Y. MicroRNA and cancer chemoprevention. Cancer Prev Res (Phila) 2013;6(5):401-9.
33. Plaisier CL, Pan M, Baliga NS. A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers. Genome research 2012;22(11):2302-14.
34. Lee SK, Calin GA. Non-coding RNAs and cancer: new paradigms in oncology. Discovery medicine 2011;11(58):245-54.
35. Favreau AJ, Cross EL, Sathyanarayana P. miR-199b-5p directly targets PODXL and DDR1 and decreased levels of miR-199b-5p correlate with elevated expressions of PODXL and DDR1 in acute myeloid leukemia. American journal of hematology 2012;87(4):442-6.
36. Hu Y, Liu J, Jiang B, Chen J, Fu Z, Bai F, et al. MiR-199a-5p loss up-regulated DDR1 aggravated colorectal cancer by activating epithelial-to-mesenchymal transition related signaling. Digestive diseases and sciences 2014;59(9):2163-72.
37. Kim BK, Kim I, Yoon SK. Identification of miR-199a-5p target genes in the skin keratinocyte and their expression in cutaneous squamous cell carcinoma. Journal of dermatological science 2015;79(2):137-47.
38. Shiah SG, Hsiao JR, Chang WM, Chen YW, Jin YT, Wong TY, et al. Downregulated miR329 and miR410 promote the proliferation and invasion of oral squamous cell carcinoma by targeting Wnt-7b. Cancer Res 2014;74(24):7560-72.
39. Poynter ST, Kadoch C. Polycomb and trithorax opposition in development and disease. Wiley interdisciplinary reviews Developmental biology 2016;5(6):659-88.
40. Bayat S, Shekari Khaniani M, Choupani J, Alivand MR, Mansoori Derakhshan S. HDACis (class I), cancer stem cell, and phytochemicals: Cancer therapy and prevention implications. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2018;97:1445-53.
41. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell 2004;118(4):409-18.
42. Min J, Zhang Y, Xu RM. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev 2003;17(15):1823-8.
43. Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev 2004;18(13):1592-605.
44. Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nature reviews Molecular cell biology 2009;10(10):697-708.
45. Cao L, Bombard J, Cintron K, Sheedy J, Weetall ML, Davis TW. BMI1 as a novel target for drug discovery in cancer. Journal of cellular biochemistry 2011;112(10):2729-41.
46. Pasini D, Di Croce L. Emerging roles for Polycomb proteins in cancer. Current opinion in genetics & development 2016;36:50-8.
47. Siddique HR, Saleem M. Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem cells (Dayton, Ohio) 2012;30(3):372-8.
48. Yan KS, Lin CY, Liao TW, Peng CM, Lee SC, Liu YJ, et al. EZH2 in Cancer Progression and Potential Application in Cancer Therapy: A Friend or Foe? Int J Mol Sci 2017;18(6).
49. Ma RG, Zhang Y, Sun TT, Cheng B. Epigenetic regulation by polycomb group complexes: focus on roles of CBX proteins. Journal of Zhejiang University Science B 2014;15(5):412-28.
50. Senthilkumar R, Mishra RK. Novel motifs distinguish multiple homologues of Polycomb in vertebrates: expansion and diversification of the epigenetic toolkit. BMC genomics 2009;10:549.
51. Klauke K, Radulovic V, Broekhuis M, Weersing E, Zwart E, Olthof S, et al. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nature cell biology 2013;15(4):353-62.
52. Levine SS, Weiss A, Erdjument-Bromage H, Shao Z, Tempst P, Kingston RE. The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Molecular and cellular biology 2002;22(17):6070-8.
53. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, et al. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. The EMBO journal 2007;26(6):1637-48.
54. Lee SH, Um SJ, Kim EJ. CBX8 suppresses Sirtinol-induced premature senescence in human breast cancer cells via cooperation with SIRT1. Cancer letters 2013;335(2):397-403.
55. Li G, Warden C, Zou Z, Neman J, Krueger JS, Jain A, et al. Altered expression of polycomb group genes in glioblastoma multiforme. PLoS One 2013;8(11):e80970.
56. Xiao W, Ou C, Qin J, Xing F, Sun Y, Li Z, et al. CBX8, a novel DNA repair protein, promotes tumorigenesis in human esophageal carcinoma. International journal of clinical and experimental pathology 2014;7(8):4817-26.
57. Zhang L, Zhou Y, Cheng C, Cui H, Cheng L, Kong P, et al. Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma. American journal of human genetics 2015;96(4):597-611.
58. Chung CY, Sun Z, Mullokandov G, Bosch A, Qadeer ZA, Cihan E, et al. Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis. Cell reports 2016;16(2):472-86.
59. Yuan GJ, Chen X, Lu J, Feng ZH, Chen SL, Chen RX, et al. Chromobox homolog 8 is a predictor of muscle invasive bladder cancer and promotes cell proliferation by repressing the p53 pathway. Cancer Sci 2017;108(11):2166-75.
60. Zhang CZ, Chen SL, Wang CH, He YF, Yang X, Xie D, et al. CBX8 exhibits oncogenic activity via AKT/beta-Catenin activation in hepatocellular carcinoma. Cancer Res 2017.
61. Tan J, Jones M, Koseki H, Nakayama M, Muntean AG, Maillard I, et al. CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer cell 2011;20(5):563-75.
62. Beguelin W, Teater M, Gearhart MD, Calvo Fernandez MT, Goldstein RL, Cardenas MG, et al. EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. Cancer cell 2016;30(2):197-213.
63. Yen YC, Shiah SG, Chu HC, Hsu YM, Hsiao JR, Chang JY, et al. Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells. Molecular cancer 2014;13:6.
64. Peng HY, Cheng YC, Hsu YM, Wu GH, Kuo CC, Liou JP, et al. MPT0B098, a Microtubule Inhibitor, Suppresses JAK2/STAT3 Signaling Pathway through Modulation of SOCS3 Stability in Oral Squamous Cell Carcinoma. PLoS One 2016;11(7):e0158440.
65. Peng HY, Jiang SS, Hsiao JR, Hsiao M, Hsu YM, Wu GH, et al. IL-8 induces miR-424-5p expression and modulates SOCS2/STAT5 signaling pathway in oral squamous cell carcinoma. Molecular oncology 2016;10(6):895-909.
66. Tang J, Wang G, Zhang M, Li FY, Sang Y, Wang B, et al. Paradoxical role of CBX8 in proliferation and metastasis of colorectal cancer. Oncotarget 2014;5(21):10778-90.
67. Jung DW, Oh ES, Park SH, Chang YT, Kim CH, Choi SY, et al. A novel zebrafish human tumor xenograft model validated for anti-cancer drug screening. Molecular bioSystems 2012;8(7):1930-9.
68. Teng Y, Xie X, Walker S, White DT, Mumm JS, Cowell JK. Evaluating human cancer cell metastasis in zebrafish. BMC cancer 2013;13:453.
69. Omura N, Mizuma M, MacGregor A, Hong SM, Ayars M, Almario JA, et al. Overexpression of ankyrin1 promotes pancreatic cancer cell growth. Oncotarget 2016;7(23):34977-87.
70. Huang SH, Chang PY, Liu CJ, Lin MW, Hsia KT. O6-methylguanine-DNA methyltransferase gene coding region polymorphisms and oral cancer risk. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 2010;39(8):645-50.
71. Jeng JH, Chang MC, Hahn LJ. Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. Oral oncology 2001;37(6):477-92.
72. Shimada K, Nakamura M, Ishida E, Higuchi T, Yamamoto H, Tsujikawa K, et al. Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. Cancer Sci 2008;99(1):39-45.
73. Cader FZ, Vockerodt M, Bose S, Nagy E, Brundler MA, Kearns P, et al. The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 2013;122(26):4237-45.
74. Kim HG, Hwang SY, Aaronson SA, Mandinova A, Lee SW. DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation. The Journal of biological chemistry 2011;286(20):17672-81.
75. Ongusaha PP, Kim JI, Fang L, Wong TW, Yancopoulos GD, Aaronson SA, et al. p53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop. The EMBO journal 2003;22(6):1289-301.
76. Mata R, Palladino C, Nicolosi ML, Lo Presti AR, Malaguarnera R, Ragusa M, et al. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget 2016;7(7):7683-700.
77. Deng Y, Zhao F, Hui L, Li X, Zhang D, Lin W, et al. Suppressing miR-199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression. Journal of ovarian research 2017;10(1):50.
78. Chen Z, Yu T, Cabay RJ, Jin Y, Mahjabeen I, Luan X, et al. miR-486-3p, miR-139-5p, and miR-21 as Biomarkers for the Detection of Oral Tongue Squamous Cell Carcinoma. Biomarkers in cancer 2017;9:1-8.
79. Swierniak M, Wojcicka A, Czetwertynska M, Stachlewska E, Maciag M, Wiechno W, et al. In-depth characterization of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma. The Journal of clinical endocrinology and metabolism 2013;98(8):E1401-9.
80. Venkatesan N, Deepa PR, Khetan V, Krishnakumar S. Computational and in vitro Investigation of miRNA-Gene Regulations in Retinoblastoma Pathogenesis: miRNA Mimics Strategy. Bioinformatics and biology insights 2015;9:89-101.
81. Ye H, Yu X, Xia J, Tang X, Tang L, Chen F. MiR-486-3p targeting ECM1 represses cell proliferation and metastasis in cervical cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2016;80:109-14.
82. Jiang X, Du L, Duan W, Wang R, Yan K, Wang L, et al. Serum microRNA expression signatures as novel noninvasive biomarkers for prediction and prognosis of muscle-invasive bladder cancer. Oncotarget 2016;7(24):36733-42.
83. Zeng MN, Ma WL, Zheng WL. [Bioinformatics analysis of microRNA comprehensive regulatory network in B- cell acute lymphoblastic leukemia]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 2016;37(7):585-90.
84. Fotinos A, Nagarajan N, Martins AS, Fritz DT, Garsetti D, Lee AT, et al. Bone morphogenetic protein-focused strategies to induce cytotoxicity in lung cancer cells. Anticancer research 2014;34(5):2095-104.
85. Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nature neuroscience 2014;17(9):1164-70.
86. Tessema M, Yingling CM, Picchi MA, Wu G, Ryba T, Lin Y, et al. ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status. Cancer letters 2017;410:191-200.
87. Miao L, Zhu S, Wang Y, Li Y, Ding J, Dai J, et al. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung cancer and promotes cell invasion via epithelial-to-mesenchymal transition. Medical oncology (Northwood, London, England) 2013;30(3):626.
88. Huo Y, Yang M, Liu W, Yang J, Fu X, Liu D, et al. High expression of DDR1 is associated with the poor prognosis in Chinese patients with pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR 2015;34:88.
89. Hur H, Ham IH, Lee D, Jin H, Aguilera KY, Oh HJ, et al. Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma. BMC cancer 2017;17(1):87.
90. Xie X, Rui W, He W, Shao Y, Sun F, Zhou W, et al. Discoidin domain receptor 1 activity drives an aggressive phenotype in bladder cancer. American journal of translational research 2017;9(5):2500-07.
91. Huang YH, Lin KH, Chen HC, Chang ML, Hsu CW, Lai MW, et al. Identification of postoperative prognostic microRNA predictors in hepatocellular carcinoma. PLoS One 2012;7(5):e37188.
92. Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E, et al. Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. European journal of pharmacology 2008;599(1-3):44-53.
93. Hummel R, Wang T, Watson DI, Michael MZ, Van der Hoek M, Haier J, et al. Chemotherapy-induced modification of microRNA expression in esophageal cancer. Oncology reports 2011;26(4):1011-7.
94. Cheung AK, Lung HL, Ko JM, Cheng Y, Stanbridge EJ, Zabarovsky ER, et al. Chromosome 14 transfer and functional studies identify a candidate tumor suppressor gene, mirror image polydactyly 1, in nasopharyngeal carcinoma. Proceedings of the National Academy of Sciences of the United States of America 2009;106(34):14478-83.
95. Loughery J, Cox M, Smith LM, Meek DW. Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters. Nucleic acids research 2014;42(12):7666-80.
96. Hsu SP, Lin PH, Chou CM, Lee WS. Progesterone up-regulates p27 through an increased binding of the progesterone receptor-A-p53 protein complex onto the non-canonical p53 binding motif in HUVEC. The Journal of steroid biochemistry and molecular biology 2018.
97. Liu J, Wang D, Long Z, Liu J, Li W. CircRNA8924 Promotes Cervical Cancer Cell Proliferation, Migration and Invasion by Competitively Binding to MiR-518d-5p /519-5p Family and Modulating the Expression of CBX8. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2018;48(1):173-84.
98. Maertens GN, El Messaoudi-Aubert S, Racek T, Stock JK, Nicholls J, Rodriguez-Niedenfuhr M, et al. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus. PLoS One 2009;4(7):e6380.
99. Lechner M, Chakravarthy AR, Walter V, Masterson L, Feber A, Jay A, et al. Frequent HPV-independent p16/INK4A overexpression in head and neck cancer. Oral oncology 2018;83:32-37.
100. Wang G, Tang J, Zhan W, Zhang R, Zhang M, Liao D, et al. CBX8 Suppresses Tumor Metastasis via Repressing Snail in Esophageal Squamous Cell Carcinoma. Theranostics 2017;7(14):3478-88.
101. Brown HK, Schiavone K, Tazzyman S, Heymann D, Chico TJ. Zebrafish xenograft models of cancer and metastasis for drug discovery. Expert opinion on drug discovery 2017;12(4):379-89.
102. Simhadri C, Daze KD, Douglas SF, Quon TT, Dev A, Gignac MC, et al. Chromodomain antagonists that target the polycomb-group methyllysine reader protein chromobox homolog 7 (CBX7). Journal of medicinal chemistry 2014;57(7):2874-83.