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系統識別號 U0026-2408201601083100
論文名稱(中文) 口腔癌相關miRNAs與其標的基因之研究
論文名稱(英文) The study of oral-cancer associated miRNAs and their target genes
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 104
學期 2
出版年 105
研究生(中文) 郭怡孜
研究生(英文) Yi-Zih Kuo
學號 s58961183
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-吳梨華
召集委員-陳玉玲
口試委員-張文粲
口試委員-洪文俊
口試委員-戴明泓
中文關鍵字 口腔癌  微小核醣核-99a  肌管素相關蛋白3  微小核醣核酸-22  玻尿酸  玻尿酸合成酶3  腫瘤壞死因子 
英文關鍵字 Oral cancer  miR-99a  MTMR3  miR-22  hyaluronan  HAS3  TNF-a 
學科別分類
中文摘要 口腔癌是一種致命的疾病,且在所有癌症死亡率排名第八。微型核糖核酸(microRNAs; miRNAs)是一種小片段非編碼核糖核酸其主要是透過基因表達的後轉錄作用,進而造成分解或抑制標的基因的訊息核糖核酸(mRNA);雖然目前已經有相當多的證據指出miRNAs在惡性腫瘤中可能扮演著致癌基因或抑癌基因的角色,然而卻很少有研究在探討miRNA(s)在口腔癌癌化中所扮演的角色。為了找出口腔癌相關的miRNAs,我們利用微型核糖核酸生物晶片雜交分析比對發現在三株口腔癌細胞相較於正常口腔角質細胞有54個miRNAs的表現下降,其中以miR-99a下降的倍數最高(~32倍),再次確認miR-99a在口腔癌細胞株以及臨床檢體的表現均下降,因此進一步地研究miR-99a在口腔癌中所扮演的角色,大量表現miR-99a會抑制口腔癌細胞的移動及侵犯能力;相反地,使用miR-99a抑制劑-ant-miR-99a則有相反的結果。我們找出Myotubularin- related protein 3 (MTMR3)其在3’非轉譯區域(3’UTR)有miR-99a高度保留的結合位置,故MTMR3為miR-99a新的標靶基因;抑制MTMR3的表現可明顯地降低細胞生長、細胞移動和侵犯能力;進一步地分析miR-99a和MTMR3蛋白表現在口腔癌細胞株和臨床檢體中皆呈反向關係;綜合上述結果可知miR-99a藉由部分地減少MTMR3的表現達到抑制口腔癌細胞移動及侵犯能力。除了miR-99a之外,我們同樣地也發現miR-22在口腔癌細胞株和病人檢體的表現下降,接著找出Hyaluronan synthases 3 (HAS3)為miR-22新的假定標的基因,過度表現miR-22均可降低內生性或外生性的HAS3表現,參與大量合成低分子量玻尿酸的HAS3其mRNA在口腔癌細胞的表現同為高度表達;為了進一步地瞭解HAS3在口腔癌的作用,過度表現HAS3會明顯地促進口腔癌細胞移動、細胞侵犯以及異種移植的腫瘤生成能力,且同時伴隨著增加異種移植腫瘤的發炎因子TNF-α和MCP-1;相反地,減少HAS3的表達則會明顯地廢除HAS3所引起的刺激反應,HAS3引起的致癌作用可能是部分地透過活化EGFR-Src訊息傳導路徑所達成,進一步地發現含有HAS3所產生的低分子量玻尿酸培養液會促進穿透內皮層屏障的單核球移動以及增加MCP-1的表現,此作用則會受到HAS3抗體和其抑制劑-4MU所拮抗。符合細胞激素和生長因子對HAS3表達的刺激作用,我們同樣地也發現口腔癌細胞中HAS3其表現會隨著TNF-α劑量增加而增加,且部分地透過NF-κB活化而表現。口腔癌臨床病人檢體的分析結果顯示在晚期病患有高度表現HAS3的整體存活率較差,然而同時高度表現TNF-α將會進一步地否定這些病患的臨床療效;當大量表現HAS3 (miR-22的標靶基因)其促進腫瘤形成所需的關鍵生物活性以及提供發展口腔癌病程有利的環境。綜合以上結果,MTMR3和HAS3,而不是miR-99a或miR-22,或許可作為口腔癌的治療診斷指標,但未來可能還需要更多的研究來證明它們的可能性。
英文摘要 Oral cancer is a deadly disease, ranking the eighth among all cancers in mortality. MicroRNAs (miRNAs) are small non-coding RNAs that mediate gene expression at the post-transcriptional level by degrading or repressing the translation of target mRNAs. Although accumulating evidence suggests that miRNAs function as oncogenes or tumor suppressors in human malignancy, there are still few studies focused on the role of miRNA(s) in oral carcinogenesis. To clarify the miRNAs involved in oral cancer, human miRNA microarray was used to identify the down-regulation of 54 miRNAs in three oral cancer cell lines when compared to normal oral keratinocytes (NOK). miR-99a as the most down-regulated in oral cancer cells (~32 folds). MiR-99a down-regulation was also confirmed both in tested oral cancer cell lines and clinical specimens. To study the role of miR-99a in oral cancer, etopic miR-99a expression inhibited oral cancer cell migration and invasion. Anti-miR-99a, silencing miR-99a functions, had the opposite effect. Myotubularin- related protein 3 (MTMR3) with one evolutionarily conserved seed region in the 3’-untranslated region was a novel miR-99a target. Depleting MTMR3 expression significantly reduced cell proliferation, migration, or invasion. There was an inverse expression of miR-99a and MTMR3 protein in oral cancer lines and clinical specimens. Together, miR-99a repressed oral cancer cell migration and invasion partly through decreasing MTMR3 expression. In addition to miR-99a, we also identified the downregulation of miR-22 in oral cancer cell lines and clinical specimens. Hyaluronan synthases 3 (HAS3) was predicted as a novel target of miR-22 and ectopic miR-22 repressed the levels of both endogenous and ectopic HAS3. The expression of HAS3 mRNA, involved in pro-inflammatory low molecular mass HA (LMM-HA) accumulation, was also highly expressed in oral cancer. To assess the functionality, ectopic HAS3 expression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increase of pro-inflammatory TNF-α and MCP-1 expression. Conversely, HAS3 depletion significantly abrogated HAS3-mediated stimulation. The oncogenic action of HAS3 was partly through the activation of EGFR-Src signaling axis. The release of HAS3-derived LMM-HA into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which could be attenuated by the addition of HAS3 antibody or an inhibitor, 4-Methylumbelliferone (4-MU). Consistent with the stimulatory effects of cytokines and growth factors on HAS3 expression, we also found TNF-α dose-dependently increased HAS3 mRNA expression partly through the activation of NF-κB in oral cancer cells. The increase of HAS3 mRNA expression significantly reduced the overall survival of late-stage oral cancer patients and high TNF-α expression further negated the clinical outcome among these patients. Overexpressed HAS3, a target of miR-22, enhanced crucial biological activities necessary for tumorigenesis and thus offered an advantageous environment for oral cancer progression. Taken together, MTMR3 and HAS3, rather than miR-99a or miR-22, might serve as theranostic targets for oral cancer treatment although more studies are needed to validate this possibility.
論文目次 Contents
Abstract I
中文摘要 III
誌謝 V
Contents VII
Contents of tables XI
Contents of figures XII
Abbreviations XIV
Chapter 1 - Introduction 1
1-1 Oral cancer 1
1-1.1 Genetic alterations in oral cancer 1
1-2 MicroRNAs (miRNAs) 2
1-2.1 Biogenesis of miRNAs 2
1-2.2 miRNAs involvement in human cancers 3
1-2.3 miRNAs deregulation in oral cancer 3
1-2.4 miR-99a 4
1-2.5 miR-22 5
1-3 Myotubularin-related protein 3 (MTMR3) 5
1-4 Hyaluronan (HA) 6
1-4.1 HA metabolism 6
1-4.2 The role of HA in the inflammation 7
1-4.3 The role of HA in the tumor 8
1-4.4 HAS3 regulation 9
1-5 Specific aims 10
Chapter 2 - Materials and Methods 11
2-1 Reagents and inhibitors 11
2-2 Antibodies 13
2-3 Patient specimens and RNA isolation 14
2-4 Cell culture 14
2-5 Quantitation of microRNA expression by qRT-PCR 14
2-6 Transient expression of ectopic miRNA or anti-miRNA in the cells 15
2-7 Generation of oral cancer cell lines stably expressing miR-99a 15
2-8 Construction of 3’UTR luciferase reporters 15
2-9 3’UTR luciferase reporter assay 16
2-10 Transient expression of MTMR3-expressing clone 16
2-11 HAS3-expressing stable clone establishments 16
2-12 MTMR3 or HAS3 knockdowns in oral cancer cells 17
2-13 Gene expression detected by quantitative RT-PCR (qRT-PCR) 17
2-14 Western blot analysis 18
2-15 Cell proliferation assay 18
2-16 Wound healing assay 18
2-17 Trans-well migration or invasion assay 19
2-18 Xenograft transplantation and immunohistochemistry 19
2-19 In vivo murine metastasis 19
2-20 Conditioned medium (CM) preparation 20
2-21 HA concentration measured by ELISA 20
2-22 Transendothelial migration of monocytes 20
2-23 Treatment with growth factors and inhibitors 21
2-24 HAS3 inhibition or neutralization 21
2-25 Promoter-driven luciferase reporter assays 21
2-26 Chromatin immunoprecipitation (ChIP) –qPCR 21
2-27 Statistical analysis 22
Chapter 3 - Results 23
3-1 MiR-99a exerts anti-metastasis through inhibiting myotubularin-related protein 3 expression in oral cancer 23
3-1.1 Down-regulation of miR-99 in oral cancer cells and clinical specimens 23
3-1.2 Deregulated miR-99a impacts cell proliferation, migration, invasion, and transendothelial migration. 23
3-1.3 MTMR3 is a novel miR-99a target 24
3-1.4 MiR-99a inhibits cell migration and invasion partly through MTMR3 25
3-1.5 MTMR3 knockdown but not ectopic miR-99a expression decreased in vivo metastasis 26
3-1.6 Inverse expression of MTMR3 and miR-99a in clinical specimens 27
3-2 Hyaluronan synthase 3-mediated oncogenic action forms an autoregulatory loop with tumor necrosis factor alpha in oral cancer 28
3.2-1 miR-22 is down-regulated in oral cancer cells and clinical specimens. 28
3-2.2 HAS3, a target of miR-22, was overexpressed in most oral cancer cell lines. 28
3-2.3 Increased HAS3 mainly promoted oral cancer migration and invasion 29
3-2.4 Ectopic HAS3 promoted in vivo xenograft tumorigenesis 30
3-2.5 The oncogenic action of HAS3 mediated by Src-EGFR activating phosphorylation in oral cancer cells 31
3-2.6 HAS3-derived CM promoted monocyte recruitment and the expression of monocyte chemoattractant protein-1 (MCP-1) 31
3-2.7 HA accumulation was required for the oncogenic action mediated by HAS3 overexpression 32
3-2.8 TNF-α-mediated transcriptional stimulation of HAS3 expression through NF-κB activation in oral cancer cells 33
3-2.9 The increase of both TNF-α and HAS3 expression reduced oral cancer patient overall survival 34
Chapter 4 - Discussion 36
4-1 MiR-99a exerts anti-metastasis through inhibiting myotubularin-related protein 3 expression in oral cancer 36
4-1.1 miR-99a functioned as a tumor suppressor in oral cancer 36
4-1.2 MTMR3 was a novel oncogene for oral cancer 36
4-2 Hyaluronan synthase 3-mediated oncogenic action forms an autoregulatory loop with tumor necrosis factor alpha in oral cancer 38
4-2.1 HAS3 was a target of miR-22 38
4-2.2 HAS3 promoted tumorigenesis through HA accumulation in oral cancer 38
4-2.3 HA and their receptor signaling involved in HAS3 activation 39
4-2.4 Interregulation of HAS3 and cytokine expression in vitro and in vivo 39
4-2.5 TNF-a stimulated HAS3 overexpression by NF-κB activation in oral cancer 40
4-2.6 TNF-α further regulated the poor clinical outcome of high HAS3-expressing oral cancer patients 41
Chapter 5 - Conclusion 42
References 43
Appendix 113
參考文獻 References
1. India Project Team of the International Cancer Genome C. Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups. Nat Commun 2013;4:2873.
2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65(2):87-108.
3. Estilo CL, P Oc, Talbot S, Socci ND, Carlson DL, Ghossein R, et al. Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis. BMC Cancer 2009;9:11.
4. Sasahira T, Kirita T, Kuniyasu H. Update of molecular pathobiology in oral cancer: a review. Int J Clin Oncol 2014;19(3):431-6.
5. Tsantoulis PK, Kastrinakis NG, Tourvas AD, Laskaris G, Gorgoulis VG. Advances in the biology of oral cancer. Oral Oncol 2007;43(6):523-34.
6. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9-29.
7. Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W, et al. Stromal features are predictive of disease mortality in oral cancer patients. J Pathol 2011;223(4):470-81.
8. van der Riet P, Nawroz H, Hruban RH, Corio R, Tokino K, Koch W, et al. Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res 1994;54(5):1156-8.
9. Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996;56(11):2488-92.
10. Reed AL, Califano J, Cairns P, Westra WH, Jones RM, Koch W, et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res 1996;56(16):3630-3.
11. Dong SM, Sun DI, Benoit NE, Kuzmin I, Lerman MI, Sidransky D. Epigenetic inactivation of RASSF1A in head and neck cancer. Clin Cancer Res 2003;9(10 Pt 1):3635-40.
12. Kisielewski AE, Xiao GH, Liu SC, Klein-Szanto AJ, Novara M, Sina J, et al. Analysis of the FHIT gene and its product in squamous cell carcinomas of the head and neck. Oncogene 1998;17(1):83-91.
13. Rousseau A, Lim MS, Lin Z, Jordan RC. Frequent cyclin D1 gene amplification and protein overexpression in oral epithelial dysplasias. Oral Oncol 2001;37(3):268-75.
14. Ambros V. The functions of animal microRNAs. Nature 2004;431(7006):350-5.
15. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136(2):215-33.
16. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res 2008;36(Database issue):D154-8.
17. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75(5):843-54.
18. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000;403(6772):901-6.
19. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 1993;75(5):855-62.
20. Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 2011;39(Database issue):D152-7.
21. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004;23(20):4051-60.
22. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003;425(6956):415-9.
23. Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 2003;17(24):3011-6.
24. Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 2004;10(2):185-91.
25. Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD. 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.
26. Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009;136(4):642-55.
27. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010;11(9):597-610.
28. Yang JS, Lai EC. Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Mol Cell 2011;43(6):892-903.
29. Ladewig E, Okamura K, Flynt AS, Westholm JO, Lai EC. Discovery of hundreds of mirtrons in mouse and human small RNA data. Genome Res 2012;22(9):1634-45.
30. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116(2):281-97.
31. Gorenchtein M, Poh CF, Saini R, Garnis C. MicroRNAs in an oral cancer context - from basic biology to clinical utility. J Dent Res 2012;91(5):440-6.
32. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99(24):15524-9.
33. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005;65(14):6029-33.
34. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 2006;103(7):2257-61.
35. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene 2007;26(19):2799-803.
36. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006;6(11):857-66.
37. Li J, Huang H, Sun L, Yang M, Pan C, Chen W, et al. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin Cancer Res 2009;15(12):3998-4008.
38. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 2007;282(19):14328-36.
39. Zhang T, Wang Q, Zhao D, Cui Y, Cao B, Guo L, et al. The oncogenetic role of microRNA-31 as a potential biomarker in oesophageal squamous cell carcinoma. Clin Sci (Lond) 2011;121(10):437-47.
40. Mutallip M, Nohata N, Hanazawa T, Kikkawa N, Horiguchi S, Fujimura L, et al. Glutathione S-transferase P1 (GSTP1) suppresses cell apoptosis and its regulation by miR-133alpha in head and neck squamous cell carcinoma (HNSCC). Int J Mol Med 2011;27(3):345-52.
41. Wong TS, Liu XB, Chung-Wai Ho A, Po-Wing Yuen A, Wai-Man Ng R, Ignace Wei W. Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling. Int J Cancer 2008;123(2):251-7.
42. Shi LJ, Zhang CY, Zhou ZT, Ma JY, Liu Y, Bao ZX, et al. MicroRNA-155 in oral squamous cell carcinoma: Overexpression, localization, and prognostic potential. Head Neck 2015;37(7):970-6.
43. Huang WC, Chan SH, Jang TH, Chang JW, Ko YC, Yen TC, et al. miRNA-491-5p and GIT1 serve as modulators and biomarkers for oral squamous cell carcinoma invasion and metastasis. Cancer Res 2014;74(3):751-64.
44. Chang CC, Yang YJ, Li YJ, Chen ST, Lin BR, Wu TS, et al. MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma. Oral Oncol 2013;49(9):923-31.
45. Shiiba M, Shinozuka K, Saito K, Fushimi K, Kasamatsu A, Ogawara K, et al. MicroRNA-125b regulates proliferation and radioresistance of oral squamous cell carcinoma. Br J Cancer 2013;108(9):1817-21.
46. Liu CJ, Lin SC, Yang CC, Cheng HW, Chang KW. Exploiting salivary miR-31 as a clinical biomarker of oral squamous cell carcinoma. Head Neck 2012;34(2):219-24.
47. Yang CC, Hung PS, Wang PW, Liu CJ, Chu TH, Cheng HW, et al. miR-181 as a putative biomarker for lymph-node metastasis of oral squamous cell carcinoma. J Oral Pathol Med 2011;40(5):397-404.
48. Harris T, Jimenez L, Kawachi N, Fan JB, Chen J, Belbin T, et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol 2012;180(3):917-28.
49. Childs G, Fazzari M, Kung G, Kawachi N, Brandwein-Gensler M, McLemore M, et al. Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am J Pathol 2009;174(3):736-45.
50. Avissar M, McClean MD, Kelsey KT, Marsit CJ. MicroRNA expression in head and neck cancer associates with alcohol consumption and survival. Carcinogenesis 2009;30(12):2059-63.
51. Ohgaki K, Iida A, Kasumi F, Sakamoto G, Akimoto M, Nakamura Y, et al. Mapping of a new target region of allelic loss to a 6-cM interval at 21q21 in primary breast cancers. Genes Chromosomes Cancer 1998;23(3):244-7.
52. Sakata K, Tamura G, Nishizuka S, Maesawa C, Suzuki Y, Iwaya T, et al. Commonly deleted regions on the long arm of chromosome 21 in differentiated adenocarcinoma of the stomach. Genes Chromosomes Cancer 1997;18(4):318-21.
53. Yamada H, Yanagisawa K, Tokumaru S, Taguchi A, Nimura Y, Osada H, et al. Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosomes Cancer 2008;47(9):810-8.
54. Yamamoto N, Uzawa K, Miya T, Watanabe T, Yokoe H, Shibahara T, et al. Frequent allelic loss/imbalance on the long arm of chromosome 21 in oral cancer: evidence for three discrete tumor suppressor gene loci. Oncol Rep 1999;6(6):1223-7.
55. Catto JW, Miah S, Owen HC, Bryant H, Myers K, Dudziec E, et al. Distinct microRNA alterations characterize high- and low-grade bladder cancer. Cancer Res 2009;69(21):8472-81.
56. Chen Z, Jin Y, Yu D, Wang A, Mahjabeen I, Wang C, et al. Down-regulation of the microRNA-99 family members in head and neck squamous cell carcinoma. Oral Oncol 2012;48(8):686-91.
57. Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W, et al. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res 2010;70(11):4666-75.
58. Gao W, Shen H, Liu L, Xu J, Xu J, Shu Y. MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis. J Cancer Res Clin Oncol 2011;137(4):557-66.
59. Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008;14(9):2690-5.
60. Sun D, Lee YS, Malhotra A, Kim HK, Matecic M, Evans C, et al. miR-99 family of MicroRNAs suppresses the expression of prostate-specific antigen and prostate cancer cell proliferation. Cancer Res 2011;71(4):1313-24.
61. Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI. Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue. Clin Cancer Res 2008;14(9):2588-92.
62. Sun J, Chen Z, Tan X, Zhou F, Tan F, Gao Y, et al. MicroRNA-99a/100 promotes apoptosis by targeting mTOR in human esophageal squamous cell carcinoma. Med Oncol 2013;30(1):411.
63. Cui L, Zhou H, Zhao H, Zhou Y, Xu R, Xu X, et al. MicroRNA-99a induces G1-phase cell cycle arrest and suppresses tumorigenicity in renal cell carcinoma. BMC Cancer 2012;12:546.
64. Li D, Liu X, Lin L, Hou J, Li N, Wang C, et al. MicroRNA-99a inhibits hepatocellular carcinoma growth and correlates with prognosis of patients with hepatocellular carcinoma. J Biol Chem 2011;286(42):36677-85.
65. Zhou J, Song T, Gong S, Zhong M, Su G. microRNA regulation of the expression of the estrogen receptor in endometrial cancer. Mol Med Rep 2010;3(3):387-92.
66. Izzotti A, Calin GA, Arrigo P, Steele VE, Croce CM, De Flora S. Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke. FASEB J 2009;23(3):806-12.
67. Lerman G, Avivi C, Mardoukh C, Barzilai A, Tessone A, Gradus B, et al. MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R. PLoS One 2011;6(6):e20916.
68. Xiong J, Yu D, Wei N, Fu H, Cai T, Huang Y, et al. An estrogen receptor alpha suppressor, microRNA-22, is downregulated in estrogen receptor alpha-positive human breast cancer cell lines and clinical samples. FEBS J 2010;277(7):1684-94.
69. Wan WN, Zhang YQ, Wang XM, Liu YJ, Zhang YX, Que YH, et al. Down-regulated miR-22 as predictive biomarkers for prognosis of epithelial ovarian cancer. Diagn Pathol 2014;9:178.
70. Kawahigashi Y, Mishima T, Mizuguchi Y, Arima Y, Yokomuro S, Kanda T, et al. MicroRNA profiling of human intrahepatic cholangiocarcinoma cell lines reveals biliary epithelial cell-specific microRNAs. J Nippon Med Sch 2009;76(4):188-97.
71. Wang W, Li F, Zhang Y, Tu Y, Yang Q, Gao X. Reduced expression of miR-22 in gastric cancer is related to clinicopathologic characteristics or patient prognosis. Diagn Pathol 2013;8:102.
72. Zhang G, Xia S, Tian H, Liu Z, Zhou T. Clinical significance of miR-22 expression in patients with colorectal cancer. Med Oncol 2012;29(5):3108-12.
73. Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S, et al. microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 2010;103(8):1215-20.
74. Yang C, Ning S, Li Z, Qin X, Xu W. miR-22 is down-regulated in esophageal squamous cell carcinoma and inhibits cell migration and invasion. Cancer Cell Int 2014;14(1):138.
75. Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, et al. MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 2013;154(2):311-24.
76. Bar N, Dikstein R. miR-22 forms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics. PLoS One 2010;5(5):e10859.
77. Clague MJ, Lorenzo O. The myotubularin family of lipid phosphatases. Traffic 2005;6(12):1063-9.
78. Mei J, Li Z, Gui JF. Cooperation of Mtmr8 with PI3K regulates actin filament modeling and muscle development in zebrafish. PLoS One 2009;4(3):e4979.
79. Taguchi-Atarashi N, Hamasaki M, Matsunaga K, Omori H, Ktistakis NT, Yoshimori T, et al. Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy. Traffic 2010;11(4):468-78.
80. Zou J, Chang SC, Marjanovic J, Majerus PW. MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis. J Biol Chem 2009;284(4):2064-71.
81. Naughtin MJ, Sheffield DA, Rahman P, Hughes WE, Gurung R, Stow JL, et al. The myotubularin phosphatase MTMR4 regulates sorting from early endosomes. J Cell Sci 2010;123(Pt 18):3071-83.
82. Yoo YD, Cho SM, Kim JS, Chang YS, Ahn CM, Kim HJ. The human myotubularin-related protein suppresses the growth of lung carcinoma cells. Oncol Rep 2004;12(3):667-71.
83. Adamia S, Maxwell CA, Pilarski LM. Hyaluronan and hyaluronan synthases: potential therapeutic targets in cancer. Curr Drug Targets Cardiovasc Haematol Disord 2005;5(1):3-14.
84. Toole BP, Zoltan-Jones A, Misra S, Ghatak S. Hyaluronan: a critical component of epithelial-mesenchymal and epithelial-carcinoma transitions. Cells Tissues Organs 2005;179(1-2):66-72.
85. Hamerman D, Schuster H. Hyaluronate in normal human synovial fluid. J Clin Invest 1958;37(1):57-64.
86. Torii S, Bashey R. High content of hyaluronic acid in normal human heart valves. Nature 1966;209(5022):506-7.
87. Armstrong SE, Bell DR. Relationship between lymph and tissue hyaluronan in skin and skeletal muscle. Am J Physiol Heart Circ Physiol 2002;283(6):H2485-94.
88. Franzmann EJ, Schroeder GL, Goodwin WJ, Weed DT, Fisher P, Lokeshwar VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors. Int J Cancer 2003;106(3):438-45.
89. Shigeishi H, Higashikawa K, Takechi M. Role of receptor for hyaluronan-mediated motility (RHAMM) in human head and neck cancers. J Cancer Res Clin Oncol 2014;140(10):1629-40.
90. Stern R, Jedrzejas MJ. Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev 2006;106(3):818-39.
91. Karihtala P, Soini Y, Auvinen P, Tammi R, Tammi M, Kosma VM. Hyaluronan in breast cancer: correlations with nitric oxide synthases and tyrosine nitrosylation. J Histochem Cytochem 2007;55(12):1191-8.
92. Jiang D, Liang J, Noble PW. Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 2007;23:435-61.
93. Kothapalli D, Zhao L, Hawthorne EA, Cheng Y, Lee E, Pure E, et al. Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells. J Cell Biol 2007;176(4):535-44.
94. Pure E, Assoian RK. Rheostatic signaling by CD44 and hyaluronan. Cell Signal 2009;21(5):651-5.
95. Itano N, Kimata K. Mammalian hyaluronan synthases. IUBMB Life 2002;54(4):195-9.
96. Tammi RH, Kultti A, Kosma VM, Pirinen R, Auvinen P, Tammi MI. Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. Semin Cancer Biol 2008;18(4):288-95.
97. Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol 2001;20(8):499-508.
98. Itano N. Simple primary structure, complex turnover regulation and multiple roles of hyaluronan. J Biochem 2008;144(2):131-7.
99. Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL. HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Cancer Res 2005;65(17):7782-9.
100. Lokeshwar VB, Young MJ, Goudarzi G, Iida N, Yudin AI, Cherr GN, et al. Identification of bladder tumor-derived hyaluronidase: its similarity to HYAL1. Cancer Res 1999;59(17):4464-70.
101. Tan JX, Wang XY, Su XL, Li HY, Shi Y, Wang L, et al. Upregulation of HYAL1 expression in breast cancer promoted tumor cell proliferation, migration, invasion and angiogenesis. PLoS One 2011;6(7):e22836.
102. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008;27(45):5904-12.
103. Petrey AC, de la Motte CA. Hyaluronan, a crucial regulator of inflammation. Front Immunol 2014;5:101.
104. Prevo R, Banerji S, Ferguson DJ, Clasper S, Jackson DG. Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J Biol Chem 2001;276(22):19420-30.
105. Noble PW, McKee CM, Cowman M, Shin HS. Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop in murine macrophages. J Exp Med 1996;183(5):2373-8.
106. Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, et al. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 2002;195(1):99-111.
107. Termeer CC, Hennies J, Voith U, Ahrens T, Weiss JM, Prehm P, et al. Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 2000;165(4):1863-70.
108. Horton MR, Shapiro S, Bao C, Lowenstein CJ, Noble PW. Induction and regulation of macrophage metalloelastase by hyaluronan fragments in mouse macrophages. J Immunol 1999;162(7):4171-6.
109. Horton MR, Olman MA, Bao C, White KE, Choi AM, Chin BY, et al. Regulation of plasminogen activator inhibitor-1 and urokinase by hyaluronan fragments in mouse macrophages. Am J Physiol Lung Cell Mol Physiol 2000;279(4):L707-15.
110. McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest 1996;98(10):2403-13.
111. Hodge-Dufour J, Noble PW, Horton MR, Bao C, Wysoka M, Burdick MD, et al. Induction of IL-12 and chemokines by hyaluronan requires adhesion-dependent priming of resident but not elicited macrophages. J Immunol 1997;159(5):2492-500.
112. Ijuin C, Ohno S, Tanimoto K, Honda K, Tanne K. Regulation of hyaluronan synthase gene expression in human periodontal ligament cells by tumour necrosis factor-alpha, interleukin-1beta and interferon-gamma. Arch Oral Biol 2001;46(8):767-72.
113. Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic Acid in Inflammation and Tissue Regeneration. Wounds 2016;28(3):78-88.
114. Nakamura K, Yokohama S, Yoneda M, Okamoto S, Tamaki Y, Ito T, et al. High, but not low, molecular weight hyaluronan prevents T-cell-mediated liver injury by reducing proinflammatory cytokines in mice. J Gastroenterol 2004;39(4):346-54.
115. Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 2005;11(11):1173-9.
116. Kultti A, Li X, Jiang P, Thompson CB, Frost GI, Shepard HM. Therapeutic targeting of hyaluronan in the tumor stroma. Cancers (Basel) 2012;4(3):873-903.
117. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013;62(1):112-20.
118. Auvinen P, Tammi R, Parkkinen J, Tammi M, Agren U, Johansson R, et al. Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol 2000;156(2):529-36.
119. Ropponen K, Tammi M, Parkkinen J, Eskelinen M, Tammi R, Lipponen P, et al. Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res 1998;58(2):342-7.
120. Knudson W. Tumor-associated hyaluronan. Providing an extracellular matrix that facilitates invasion. Am J Pathol 1996;148(6):1721-6.
121. Kultti A, Zhao C, Singha NC, Zimmerman S, Osgood RJ, Symons R, et al. Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment. Biomed Res Int 2014;2014:817613.
122. Liu N, Gao F, Han Z, Xu X, Underhill CB, Zhang L. Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells. Cancer Res 2001;61(13):5207-14.
123. Teng BP, Heffler MD, Lai EC, Zhao YL, LeVea CM, Golubovskaya VM, et al. Inhibition of hyaluronan synthase-3 decreases subcutaneous colon cancer growth by increasing apoptosis. Anticancer Agents Med Chem 2011;11(7):620-8.
124. Twarock S, Freudenberger T, Poscher E, Dai G, Jannasch K, Dullin C, et al. Inhibition of oesophageal squamous cell carcinoma progression by in vivo targeting of hyaluronan synthesis. Mol Cancer 2011;10:30.
125. Chang IW, Liang PI, Li CC, Wu WJ, Huang CN, Lin VC, et al. HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder. Tumour Biol 2015;36(7):5441-50.
126. Kohi S, Sato N, Cheng XB, Koga A, Higure A, Hirata K. A novel epigenetic mechanism regulating hyaluronan production in pancreatic cancer cells. Clin Exp Metastasis 2016;33(3):225-30.
127. Yamada Y, Itano N, Narimatsu H, Kudo T, Morozumi K, Hirohashi S, et al. Elevated transcript level of hyaluronan synthase1 gene correlates with poor prognosis of human colon cancer. Clin Exp Metastasis 2004;21(1):57-63.
128. Adamia S, Reiman T, Crainie M, Mant MJ, Belch AR, Pilarski LM. Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma. Blood 2005;105(12):4836-44.
129. Koistinen V, Karna R, Koistinen A, Arjonen A, Tammi M, Rilla K. Cell protrusions induced by hyaluronan synthase 3 (HAS3) resemble mesothelial microvilli and share cytoskeletal features of filopodia. Exp Cell Res 2015;337(2):179-91.
130. Kessler SP, Obery DR, de la Motte C. Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model. Int J Cell Biol 2015;2015:745237.
131. Bullard KM, Kim HR, Wheeler MA, Wilson CM, Neudauer CL, Simpson MA, et al. Hyaluronan synthase-3 is upregulated in metastatic colon carcinoma cells and manipulation of expression alters matrix retention and cellular growth. Int J Cancer 2003;107(5):739-46.
132. Nykopp TK, Rilla K, Tammi MI, Tammi RH, Sironen R, Hamalainen K, et al. Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma. BMC Cancer 2010;10:512.
133. Auvinen P, Rilla K, Tumelius R, Tammi M, Sironen R, Soini Y, et al. Hyaluronan synthases (HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival. Breast Cancer Res Treat 2014;143(2):277-86.
134. Chow G, Tauler J, Mulshine JL. Cytokines and growth factors stimulate hyaluronan production: role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer. J Biomed Biotechnol 2010;2010:485468.
135. Yamada Y, Itano N, Hata K, Ueda M, Kimata K. Differential regulation by IL-1beta and EGF of expression of three different hyaluronan synthases in oral mucosal epithelial cells and fibroblasts and dermal fibroblasts: quantitative analysis using real-time RT-PCR. J Invest Dermatol 2004;122(3):631-9.
136. Campo GM, Avenoso A, Campo S, Angela D, Ferlazzo AM, Calatroni A. TNF-alpha, IFN-gamma, and IL-1beta modulate hyaluronan synthase expression in human skin fibroblasts: synergistic effect by concomital treatment with FeSO4 plus ascorbate. Mol Cell Biochem 2006;292(1-2):169-78.
137. Fang WY, Chen YW, Hsiao JR, Liu CS, Kuo YZ, Wang YC, et al. Elevated S100A9 expression in tumor stroma functions as an early recurrence marker for early-stage oral cancer patients through increased tumor cell invasion, angiogenesis, macrophage recruitment and interleukin-6 production. Oncotarget 2015;6(29):28401-24.
138. Ades EW, Candal FJ, Swerlick RA, George VG, Summers S, Bosse DC, et al. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol 1992;99(6):683-90.
139. Bourguignon LY, Zhu H, Shao L, Chen YW. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J Biol Chem 2001;276(10):7327-36.
140. Wang SJ BL. Hyaluronan and the Interaction Between CD44 and Epidermal Growth Factor Receptor in Oncogenic Signaling and Chemotherapy Resistance in Head and Neck Cancer. Arch Otolaryngol Head Neck Surg 2006 132(7):771-8.
141. Sato K. Cellular functions regulated by phosphorylation of EGFR on Tyr845. Int J Mol Sci 2013;14(6):10761-90.
142. Kobayashi N, Miyoshi S, Mikami T, Koyama H, Kitazawa M, Takeoka M, et al. Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization. Cancer Res 2010;70(18):7073-83.
143. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 2009;29(6):313-26.
144. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel) 2014;6(3):1670-90.
145. Liu G, Xia XP, Gong SL, Zhao Y. The macrophage heterogeneity: difference between mouse peritoneal exudate and splenic F4/80+ macrophages. J Cell Physiol 2006;209(2):341-52.
146. Schutze S, Wiegmann K, Machleidt T, Kronke M. TNF-induced activation of NF-kappa B. Immunobiology 1995;193(2-4):193-203.
147. Wang S, Zhen L, Liu Z, Ai Q, Ji Y, Du G, et al. Identification and analysis of the promoter region of the human HAS3 gene. Biochem Biophys Res Commun 2015;460(4):1008-14.
148. Lee SH, Hong HS, Liu ZX, Kim RH, Kang MK, Park NH, et al. TNFalpha enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. Biochem Biophys Res Commun 2012;424(1):58-64.
149. Hu Z, Wu C, Shi Y, Guo H, Zhao X, Yin Z, et al. A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat Genet 2011;43(8):792-6.
150. Song SY, Kang MR, Yoo NJ, Lee SH. Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability. APMIS 2010;118(5):389-93.
151. Oppelt A, Lobert VH, Haglund K, Mackey AM, Rameh LE, Liestol K, et al. Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration. EMBO Rep 2013;14(1):57-64.
152. Oneyama C, Ikeda J, Okuzaki D, Suzuki K, Kanou T, Shintani Y, et al. MicroRNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways. Oncogene 2011;30(32):3489-501.
153. Turcatel G, Rubin N, El-Hashash A, Warburton D. MIR-99a and MIR-99b modulate TGF-beta induced epithelial to mesenchymal plasticity in normal murine mammary gland cells. PLoS One 2012;7(1):e31032.
154. Liang J, Jiang D, Noble PW. Hyaluronan as a therapeutic target in human diseases. Adv Drug Deliv Rev 2015.
155. Sironen RK, Tammi M, Tammi R, Auvinen PK, Anttila M, Kosma VM. Hyaluronan in human malignancies. Exp Cell Res 2011;317(4):383-91.
156. Stern R. Hyaluronan metabolism: a major paradox in cancer biology. Pathol Biol (Paris) 2005;53(7):372-82.
157. Triggs-Raine B, Natowicz MR. Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism. World J Biol Chem 2015;6(3):110-20.
158. Chanmee T, Ontong P, Kimata K, Itano N. Key Roles of Hyaluronan and Its CD44 Receptor in the Stemness and Survival of Cancer Stem Cells. Frontiers in Oncology 2015;5.
159. Beck-Schimmer B, Oertli B, Pasch T, Wuthrich RP. Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells. J Am Soc Nephrol 1998;9(12):2283-90.
160. Rayahin JE, Buhrman JS, Zhang Y, Koh TJ, Gemeinhart RA. High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomater Sci Eng 2015;1(7):481-93.
161. Campo GM, Avenoso A, Campo S, D'Ascola A, Nastasi G, Calatroni A. Small hyaluronan oligosaccharides induce inflammation by engaging both toll-like-4 and CD44 receptors in human chondrocytes. Biochem Pharmacol 2010;80(4):480-90.
162. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008;8(8):618-31.
163. Wu Y, Zhou BP. TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer 2010;102(4):639-44.
164. Calcinotto A, Grioni M, Jachetti E, Curnis F, Mondino A, Parmiani G, et al. Targeting TNF- to Neoangiogenic Vessels Enhances Lymphocyte Infiltration in Tumors and Increases the Therapeutic Potential of Immunotherapy. The Journal of Immunology 2012;188(6):2687-94.
165. Solis MA, Chen YH, Wong TY, Bittencourt VZ, Lin YC, Huang LL. Hyaluronan regulates cell behavior: a potential niche matrix for stem cells. Biochem Res Int 2012;2012:346972.
166. Kultti A, Pasonen-Seppanen S, Jauhiainen M, Rilla KJ, Karna R, Pyoria E, et al. 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res 2009;315(11):1914-23.
167. Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer 2009;9(5):361-71.
168. Hsu TC, Nair R, Tulsian P, Camalier CE, Hegamyer GA, Young MR, et al. Transformation nonresponsive cells owe their resistance to lack of p65/nuclear factor-kappaB activation. Cancer Res 2001;61(10):4160-8.
169. Nakano Y KW, Sugai S, Kimura H, Yagihashi S. Expression of Tumor Necrosis Factor-α and Interleukin-6 in Oral Squamous Cell. Jpn J Cancer Res 1999;90(8):858-66.

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