覆盆子萃取物抑制人類鼻咽癌細胞轉移和侵襲之機制探討

Study of the inhibitory effects of Rubus idaeus extracts on metastasis and invasion of nasopharyngeal carcinoma cells

何鈺婷

鼻咽癌 ； 基質金屬蛋白水解酶覆盆子萃取物 ； Nasopharyngeal carcinoma ； matrix metalloproteinases ； extracts of Rubus idaeus

中山醫學大學醫學研究所學位論文

2016年

碩士

楊順發

繁體中文

鼻咽癌是一種發生在頭頸部的癌症，好發於東亞地區，其中男性發生率比女性高三倍，而造成鼻咽癌病患死亡的主要原因是癌症轉移。在癌症轉移中，腫瘤會釋出基質金屬蛋白酶 (Matrix metalloproteinase, MMP)，分解細胞外基質 (extracellular matrix, ECM)，並藉由血液流動轉移到其他組織，文獻也指出在鼻咽癌的轉移中，MMP-2及MMP-9扮演了重要的角色。有些研究中發現覆盆子 (Rubus idaeus) 在肺癌中有抑制癌症侵襲的能力，然而目前覆盆子萃取物對鼻咽癌的影響尚未釐清。因此在本篇研究中將探討覆盆子萃取物在鼻咽癌中是否能抑制鼻咽癌細胞的轉移和侵襲能力。首先以細胞毒性實驗觀察到覆盆子萃取物在鼻咽癌細胞 (HONE-1, NPC-39 and NPC-BM cell lines) 中並無細胞毒性，接著以Wound healing Assay和Boyden Chamber Assay發現覆盆子萃取物確實能抑制鼻咽癌細胞的爬行和侵襲能力。再利用Gelatin zymography Assay觀察到覆盆子萃取物會抑制鼻咽癌細胞分泌到細胞外的MMP-2；另外，在蛋白表現和mRNA表現方面也觀察到有相同的抑制效果。進而探討其相關的傳遞路徑，觀察到磷酸化ERK蛋白表現量會隨著覆盆子萃取物的濃度上升而被抑制；進一步加入ERK上游蛋白MEK抑制劑 (U0126)，觀察到覆盆子萃取物對鼻咽癌細胞的爬行能力有加成的抑制效果，在細胞外的MMP-2表現也有相同抑制的效果。總結以上結果顯示：在不影響細胞存活率下，覆盆子萃取物透過ERK路徑抑制MMP-2 mRNA、蛋白表現與活性，進而抑制鼻咽癌細胞轉移能力。

Nasopharyngeal carcinoma (NPC) is prevalent in southern China and Southeast Asia. Metastasis involves multiple sequential cascades including degradation of basement membrane and extracellular matrix (ECM) by the matrix metalloproteinases (MMPs). Among these enzymes, MMP-2 and MMP-9 can degrade most components of the ECM and are profoundly involved in the development of NPC invasion and metastasis. Recently reports indicate that crude extracts of Rubus idaeus (RIE) have anticancer ability in the lung cancer cells. However, its effects and mechanism on invasion and metastasis of NPC cancer cells are unclear. The present study aimed to examine the antimetastatic properties of RIE in NPC cell lines. The results of wound healing assays and boyden chamber assays revealed that RIE significantly reduced the migration and invasion of three NPC cells (HONE-1, NPC-39 and NPC-BM cell lines). Gelatin zymography and western blotting analyses showed that RIE significantly inhibited the activity and expression of MMP-2. Western blot analysis also showed that RIE significantly decreased phosphorylated extracellular signal-regulated kinase (Erk) levels. Moreover, blocking of the Erk 1/2 pathway also enhanced the anti-metastatic ability of RIE in NPC cells. In conclusion, RIE inhibited MMP-2 expression and NPC cell metastasis by downregulating Erk1/2 signals pathways and, thus, exerts beneficial effects in chemoprevention.

1. Abdel Razek, A., and A. King. 2012. MRI and CT of nasopharyngeal carcinoma. AJR Am J Roentgenol. 198:11-18.
   連結：
2. Al-Sarraf, M., M. LeBlanc, P.G. Giri, K.K. Fu, J. Cooper, T. Vuong, A.A. Forastiere, G. Adams, W.A. Sakr, D.E. Schuller, and J.F. Ensley. 1998. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 16:1310-1317.
   連結：
3. Aroui, S., B. Aouey, Y. Chtourou, A.C. Meunier, H. Fetoui, and A. Kenani. 2016. Naringin suppresses cell metastasis and the expression of matrix metalloproteinases (MMP-2 and MMP-9) via the inhibition of ERK-P38-JNK signaling pathway in human glioblastoma. Chem Biol Interact. 244:195-203.
   連結：
4. Au, E., E.H. Tan, and P.T. Ang. 1998. Activity of paclitaxel by three-hour infusion in Asian patients with metastatic undifferentiated nasopharyngeal cancer. Ann Oncol. 9:327-329.
   連結：
5. Bohle, A.S., and H. Kalthoff. 1999. Molecular mechanisms of tumor metastasis and angiogenesis. Langenbecks Arch Surg. 384:133-140.
   連結：
6. Chan, A.T., E.P. Hui, and S.F. Leung. 2007. Nasopharyngeal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 18 Suppl 2:ii67-68.
   連結：
7. Chan, A.T., P.M. Teo, T.W. Leung, and P.J. Johnson. 1998. The role of chemotherapy in the management of nasopharyngeal carcinoma. Cancer. 82:1003-1012.
   連結：
8. Chang, R. 2002. Bioactive polysaccharides from traditional Chinese medicine herbs as anticancer adjuvants. J Altern Complement Med. 8:559-565.
   連結：
9. Chang, Y.C., P.N. Chen, S.C. Chu, C.Y. Lin, W.H. Kuo, and Y.S. Hsieh. 2012. Black tea polyphenols reverse epithelial-to-mesenchymal transition and suppress cancer invasion and proteases in human oral cancer cells. J Agric Food Chem. 60:8395-8403.
   連結：
10. Cheng, Y.C., Y.M. Ding, D.Y. Hueng, J.Y. Chen, and Y. Chen. 2016. Caffeine suppresses the progression of human glioblastoma via cathepsin B and MAPK signaling pathway. J Nutr Biochem. 33:63-72.
    連結：
11. Chien, G., P.W. Yuen, D. Kwong, and Y.L. Kwong. 2001. Comparative genomic hybridization analysis of nasopharygeal carcinoma: consistent patterns of genetic aberrations and clinicopathological correlations. Cancer Genet Cytogenet. 126:63-67.
    連結：
12. Chou, C.H., C.M. Teng, K.Y. Tzen, Y.C. Chang, J.H. Chen, and J.C. Cheng. 2012. MMP-9 from sublethally irradiated tumor promotes Lewis lung carcinoma cell invasiveness and pulmonary metastasis. Oncogene. 31:458-468.
    連結：
13. Chow, L.S., K.W. Lo, J. Kwong, K.F. To, K.S. Tsang, C.W. Lam, R. Dammann, and D.P. Huang. 2004. RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma. Int J Cancer. 109:839-847.
    連結：
14. Chu, S.C., Y.S. Hsieh, L.S. Hsu, K.S. Chen, C.C. Chiang, and P.N. Chen. 2014. Rubus idaeus L Inhibits Invasion Potential of Human A549 Lung Cancer Cells by Suppression Epithelial-to-Mesenchymal Transition and Akt Pathway In Vitro and Reduces Tumor Growth In Vivo. Integr Cancer Ther. 13:259-273.
    連結：
15. Condliffe, A.M., K.A. Cadwallader, T.R. Walker, R.C. Rintoul, A.S. Cowburn, and E.R. Chilvers. 2000. Phosphoinositide 3-kinase: a critical signalling event in pulmonary cells. Respir Res. 1:24-29.
    連結：
16. Davis, R.J. 2000. Signal transduction by the JNK group of MAP kinases. Cell. 103:239-252.
    連結：
17. de Ancos, B., E.M. Gonzalez, and M.P. Cano. 2000. Ellagic acid, vitamin C, and total phenolic contents and radical scavenging capacity affected by freezing and frozen storage in raspberry fruit. J Agric Food Chem. 48:4565-4570.
    連結：
18. Dhillon, A.S., S. Hagan, O. Rath, and W. Kolch. 2007. MAP kinase signalling pathways in cancer. Oncogene. 26:3279-3290.
    連結：
19. Fan, C.S., N. Wong, S.F. Leung, K.F. To, K.W. Lo, S.W. Lee, T.S. Mok, P.J. Johnson, and D.P. Huang. 2000. Frequent c-myc and Int-2 overrepresentations in nasopharyngeal carcinoma. Hum Pathol. 31:169-178.
    連結：
20. Fang, C.Y., C.C. Wu, H.Y. Hsu, H.Y. Chuang, S.Y. Huang, C.H. Tsai, Y. Chang, G.S. Tsao, C.L. Chen, and J.Y. Chen. 2015. EGCG inhibits proliferation, invasiveness and tumor growth by up-regulation of adhesion molecules, suppression of gelatinases activity, and induction of apoptosis in nasopharyngeal carcinoma cells. Int J Mol Sci. 16:2530-2558.
    連結：
21. Fidler, I.J. 2003. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer. 3:453-458.
    連結：
22. Guan, X. 2015. Cancer metastases: challenges and opportunities. Acta Pharm Sin B. 5:402-418.
    連結：
23. Hanahan, D., and R.A. Weinberg. 2011. Hallmarks of cancer: the next generation. Cell. 144:646-674.
    連結：
24. He, C.M., and L.Z. Wen. 2004. [Experimental study on antivirus activity of traditional Chinese medicine]. Zhongguo Zhong Yao Za Zhi. 29:452-455.
    連結：
25. Henderson, B.E., E. Louie, J. SooHoo Jing, P. Buell, and M.B. Gardner. 1976. Risk factors associated with nasopharyngeal carcinoma. N Engl J Med. 295:1101-1106.
    連結：
26. Hers, I., E.E. Vincent, and J.M. Tavare. 2011. Akt signalling in health and disease. Cell Signal. 23:1515-1527.
    連結：
27. Ho, F.C., I.W. Tham, A. Earnest, K.M. Lee, and J.J. Lu. 2012. Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: A meta-analysis of clinical evidence. BMC Cancer. 12:98.
    連結：
28. Ho, H.Y., Y.C. Ho, M.J. Hsieh, S.F. Yang, C.Y. Chuang, C.W. Lin, and C.H. Hsin. 2016. Hispolon suppresses migration and invasion of human nasopharyngeal carcinoma cells by inhibiting the urokinase-plasminogen activator through modulation of the Akt signaling pathway. Environ Toxicol.
    連結：
29. Ho, J.H. 1978. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 4:182-198.
    連結：
30. Hsieh, Y.S., S.C. Chu, L.S. Hsu, K.S. Chen, M.T. Lai, C.H. Yeh, and P.N. Chen. 2013. Rubus idaeus L. reverses epithelial-to-mesenchymal transition and suppresses cell invasion and protease activities by targeting ERK1/2 and FAK pathways in human lung cancer cells. Food Chem Toxicol. 62:908-918.
    連結：
31. Huang, Y.W., C.Y. Chuang, Y.S. Hsieh, P.N. Chen, S.F. Yang, L. Shih Hsuan, Y.Y. Chen, C.W. Lin, and Y.C. Chang. 2016. Rubus idaeus extract suppresses migration and invasion of human oral cancer by inhibiting MMP-2 through modulation of the Erk1/2 signaling pathway. Environ Toxicol.
    連結：
32. Hui, A.B., K.W. Lo, S.F. Leung, P. Teo, M.K. Fung, K.F. To, N. Wong, P.H. Choi, J.C. Lee, and D.P. Huang. 1999. Detection of recurrent chromosomal gains and losses in primary nasopharyngeal carcinoma by comparative genomic hybridisation. Int J Cancer. 82:498-503.
    連結：
33. Irani, S. 2011. Metastasis to head and neck area: a 16-year retrospective study. Am J Otolaryngol. 32:24-27.
    連結：
34. Jean-Gilles, D., L. Li, H. Ma, T. Yuan, C.O. Chichester, 3rd, and N.P. Seeram. 2012. Anti-inflammatory effects of polyphenolic-enriched red raspberry extract in an antigen-induced arthritis rat model. J Agric Food Chem. 60:5755-5762.
    連結：
35. Jeyakumar, A., T.M. Brickman, A. Jeyakumar, and T. Doerr. 2006. Review of nasopharyngeal carcinoma. Ear Nose Throat J. 85:168-170, 172-163, 184.
    連結：
36. Ji, W., and B.Q. Gong. 2008. Hypolipidemic activity and mechanism of purified herbal extract of Salvia miltiorrhiza in hyperlipidemic rats. J Ethnopharmacol. 119:291-298.
    連結：
37. Johnson, G.L., and R. Lapadat. 2002. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 298:1911-1912.
    連結：
38. Johnson, J.L., J.A. Bomser, J.C. Scheerens, and M.M. Giusti. 2011. Effect of black raspberry ( Rubus occidentalis L.) extract variation conditioned by cultivar, production site, and fruit maturity stage on colon cancer cell proliferation. J Agric Food Chem. 59:1638-1645.
    連結：
39. Juretic, N., J.F. Santibanez, C. Hurtado, and J. Martinez. 2001. ERK 1,2 and p38 pathways are involved in the proliferative stimuli mediated by urokinase in osteoblastic SaOS-2 cell line. J Cell Biochem. 83:92-98.
    連結：
40. Kao, E.S., M.Y. Yang, C.H. Hung, C.N. Huang, and C.J. Wang. 2016. Polyphenolic extract from Hibiscus sabdariffa reduces body fat by inhibiting hepatic lipogenesis and preadipocyte adipogenesis. Food Funct. 7:171-182.
    連結：
41. Kerkela, E., and U. Saarialho-Kere. 2003. Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer. Exp Dermatol. 12:109-125.
    連結：
42. Kim, D., S. Kim, H. Koh, S.O. Yoon, A.S. Chung, K.S. Cho, and J. Chung. 2001. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J. 15:1953-1962.
    連結：
43. Kim, D., and S. Rhee. 2016. Matrix metalloproteinase2 regulates MDAMB231 breast cancer cell invasion induced by active mammalian diaphanous-related formin 1. Mol Med Rep. 14:277-282.
    連結：
44. Kim, S., J.H. Choi, H.I. Lim, S.K. Lee, W.W. Kim, J.S. Kim, J.H. Kim, J.H. Choe, J.H. Yang, S.J. Nam, and J.E. Lee. 2009. Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf/MEK/ERK pathway in MCF-7 human breast cancer cells. Phytomedicine. 16:573-580.
    連結：
45. Krauze-Baranowska, M., M. Majdan, R. Halasa, D. Glod, M. Kula, I. Fecka, and A. Orzel. 2014. The antimicrobial activity of fruits from some cultivar varieties of Rubus idaeus and Rubus occidentalis. Food Funct. 5:2536-2541.
    連結：
46. Kyriakis, J.M., and J. Avruch. 2001. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 81:807-869.
    連結：
47. Lee, A.W., W.T. Ng, L.K. Chan, O.S. Chan, W.M. Hung, C.C. Chan, P.T. Cheng, H. Sze, T.S. Lam, and T.K. Yau. 2012. The strength/weakness of the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer and suggestions for future improvement. Oral Oncol.
    連結：
48. Lei, K., A. Nimnual, W.X. Zong, N.J. Kennedy, R.A. Flavell, C.B. Thompson, D. Bar-Sagi, and R.J. Davis. 2002. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol. 22:4929-4942.
    連結：
49. Li, J.X., T.X. Lu, Y. Huang, and F. Han. 2012. Clinical characteristics of recurrent nasopharyngeal carcinoma in high-incidence area. ScientificWorldJournal. 2012:719754.
    連結：
50. Li, X.Y., Y.C. Lin, W.L. Huang, C.Q. Hong, J.Y. Chen, Y.J. You, and W.B. Li. 2011. Zoledronic acid inhibits proliferation and impairs migration and invasion through downregulating VEGF and MMPs expression in human nasopharyngeal carcinoma cells. Med Oncol.
    連結：
51. Liu, B., J. Cui, J. Sun, J. Li, X. Han, J. Guo, M. Yi, N. Amizuka, X. Xu, and M. Li. 2016a. Immunolocalization of MMP9 and MMP2 in osteolytic metastasis originating from MDA-MB-231 human breast cancer cells. Mol Med Rep.
    連結：
52. Liu, J., X. Wen, B. Liu, Q. Zhang, J. Zhang, H. Miao, and R. Zhu. 2016b. Diosmetin inhibits the metastasis of hepatocellular carcinoma cells by downregulating the expression levels of MMP2 and MMP9. Mol Med Rep. 13:2401-2408.
    連結：
53. Liu, W.S., M.F. Wu, H.C. Tseng, J.T. Liu, J.H. Weng, Y.C. Li, and J.K. Lee. 2012. The role of pretreatment FDG-PET in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 82:561-566.
    連結：
54. Lo, K.W., and D.P. Huang. 2002. Genetic and epigenetic changes in nasopharyngeal carcinoma. Semin Cancer Biol. 12:451-462.
    連結：
55. Lo, K.W., K.F. To, and D.P. Huang. 2004. Focus on nasopharyngeal carcinoma. Cancer Cell. 5:423-428.
    連結：
56. Ma, L., S. Wen, Y. Zhan, Y. He, X. Liu, and J. Jiang. 2008. Anticancer effects of the Chinese medicine matrine on murine hepatocellular carcinoma cells. Planta Med. 74:245-251.
    連結：
57. Man, M.Q., Y. Shi, M. Man, S.H. Lee, M. Demerjian, S. Chang, K.R. Feingold, and P.M. Elias. 2008. Chinese herbal medicine (Tuhuai extract) exhibits topical anti-proliferative and anti-inflammatory activity in murine disease models. Exp Dermatol. 17:681-687.
    連結：
58. Mercer, K.E., and C.A. Pritchard. 2003. Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta. 1653:25-40.
    連結：
59. Nagase, H. 1997. Activation mechanisms of matrix metalloproteinases. Biol Chem. 378:151-160.
    連結：
60. Nagase, H., and J.F. Woessner, Jr. 1999. Matrix metalloproteinases. J Biol Chem. 274:21491-21494.
    連結：
61. Nam, J.M., J.K. McLaughlin, and W.J. Blot. 1992. Cigarette smoking, alcohol, and nasopharyngeal carcinoma: a case-control study among U.S. whites. J Natl Cancer Inst. 84:619-622.
    連結：
62. Nash, G.F., L.F. Turner, M.F. Scully, and A.K. Kakkar. 2002. Platelets and cancer. Lancet Oncol. 3:425-430.
    連結：
63. Ng, S.H., T.C. Chang, S.F. Ko, P.S. Yen, Y.L. Wan, L.M. Tang, and M.H. Tsai. 1997. Nasopharyngeal carcinoma: MRI and CT assessment. Neuroradiology. 39:741-746.
    連結：
64. Nishio, K., K. Motozawa, D. Omagari, T. Gojoubori, T. Ikeda, M. Asano, and N. Gionhaku. 2016. Comparison of MMP2 and MMP9 expression levels between primary and metastatic regions of oral squamous cell carcinoma. J Oral Sci. 58:59-65.
    連結：
65. Overall, C.M., and O. Kleifeld. 2006. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 6:227-239.
    連結：
66. Page-McCaw, A., A.J. Ewald, and Z. Werb. 2007. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 8:221-233.
    連結：
67. Palona, I., H. Namba, N. Mitsutake, D. Starenki, A. Podtcheko, I. Sedliarou, A. Ohtsuru, V. Saenko, Y. Nagayama, K. Umezawa, and S. Yamashita. 2006. BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor kappaB activation. Endocrinology. 147:5699-5707.
    連結：
68. Petersson, F. 2015. Nasopharyngeal carcinoma: a review. Semin Diagn Pathol. 32:54-73.
    連結：
69. Raffetto, J.D., and R.A. Khalil. 2008. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol. 75:346-359.
    連結：
70. Raman, M., W. Chen, and M.H. Cobb. 2007. Differential regulation and properties of MAPKs. Oncogene. 26:3100-3112.
    連結：
71. Rao, J.S. 2003. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer. 3:489-501.
    連結：
72. Sangiovanni, E., U. Vrhovsek, G. Rossoni, E. Colombo, C. Brunelli, L. Brembati, S. Trivulzio, M. Gasperotti, F. Mattivi, E. Bosisio, and M. Dell'Agli. 2013. Ellagitannins from Rubus berries for the control of gastric inflammation: in vitro and in vivo studies. PLoS One. 8:e71762.
    連結：
73. Seeram, N.P., L.S. Adams, Y. Zhang, R. Lee, D. Sand, H.S. Scheuller, and D. Heber. 2006. Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro. J Agric Food Chem. 54:9329-9339.
    連結：
74. Shanmugaratnam, K., and L.H. Sobin. 1993. The World Health Organization histological classification of tumours of the upper respiratory tract and ear. A commentary on the second edition. Cancer. 71:2689-2697.
    連結：
75. Sternlicht, M.D., A. Lochter, C.J. Sympson, B. Huey, J.P. Rougier, J.W. Gray, D. Pinkel, M.J. Bissell, and Z. Werb. 1999. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell. 98:137-146.
    連結：
76. Su, Y., D. Wan, and W. Song. 2016. Dryofragin inhibits the migration and invasion of human osteosarcoma U2OS cells by suppressing MMP-2/9 and elevating TIMP-1/2 through PI3K/AKT and p38 MAPK signaling pathways. Anticancer Drugs. 27:660-668.
    連結：
77. Teo, P., P. Yu, W.Y. Lee, S.F. Leung, W.H. Kwan, K.H. Yu, P. Choi, and P.J. Johnson. 1996. Significant prognosticators after primary radiotherapy in 903 nondisseminated nasopharyngeal carcinoma evaluated by computer tomography. Int J Radiat Oncol Biol Phys. 36:291-304.
    連結：
78. Tsang, Y.S., K.W. Lo, S.F. Leung, P.H. Choi, Y. Fong, J.C. Lee, and D.P. Huang. 1999. Two distinct regions of deletion on chromosome 13q in primary nasopharyngeal carcinoma. Int J Cancer. 83:305-308.
    連結：
79. Ventura, J.J., N.J. Kennedy, J.A. Lamb, R.A. Flavell, and R.J. Davis. 2003. c-Jun NH(2)-terminal kinase is essential for the regulation of AP-1 by tumor necrosis factor. Mol Cell Biol. 23:2871-2882.
    連結：
80. Wang, J., Q. Wang, Z.Z. Wang, Z. Feng, S.Y. Liu, Q.Q. Zhang, Q.W. Cai, and J.J. Pan. 2010. [Comparative study on hypoglycemic effects of different traditional Chinese medicine treatments in rats with diabetes mellitus induced by alloxan]. Zhong Xi Yi Jie He Xue Bao. 8:781-784.
    連結：
81. Wang, S.Y., and H.S. Lin. 2000. Antioxidant activity in fruits and leaves of blackberry, raspberry, and strawberry varies with cultivar and developmental stage. J Agric Food Chem. 48:140-146.
    連結：
82. Weston, C.R., and R.J. Davis. 2002. The JNK signal transduction pathway. Curr Opin Genet Dev. 12:14-21.
    連結：
83. Yang, S.F., M.K. Chen, Y.S. Hsieh, J.S. Yang, A.I. Zavras, Y.H. Hsieh, S.C. Su, T.Y. Kao, P.N. Chen, and S.C. Chu. 2010. Antimetastatic effects of Terminalia catappa L. on oral cancer via a down-regulation of metastasis-associated proteases. Food Chem Toxicol. 48:1052-1058.
    連結：
84. Yau, T.K., A.W. Lee, D.H. Wong, R.M. Yeung, E.W. Chan, W.T. Ng, M. Tong, and I.S. Soong. 2006. Induction chemotherapy with cisplatin and gemcitabine followed by accelerated radiotherapy and concurrent cisplatin in patients with stage IV(A-B) nasopharyngeal carcinoma. Head Neck. 28:880-887.
    連結：
85. Yosimichi, G., T. Nakanishi, T. Nishida, T. Hattori, T. Takano-Yamamoto, and M. Takigawa. 2001. CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK). Eur J Biochem. 268:6058-6065.
    連結：
86. Young, L.S., and P.G. Murray. 2003. Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene. 22:5108-5121.
    連結：
87. Yu, X., Q. Wu, L. Wang, Y. Zhao, Q. Zhang, Q. Meng, Pawan, and S. Wang. 2016. Silencing of ST6GalNAc I suppresses the proliferation, migration and invasion of hepatocarcinoma cells through PI3K/AKT/NF-kappaB pathway. Tumour Biol.
    連結：
88. Zhang, Z., T.J. Knobloch, L.G. Seamon, G.D. Stoner, D.E. Cohn, E.D. Paskett, J.M. Fowler, and C.M. Weghorst. 2011. A black raspberry extract inhibits proliferation and regulates apoptosis in cervical cancer cells. Gynecol Oncol. 123:401-406.
    連結：
89. Chen, Z., T.B. Gibson, F. Robinson, L. Silvestro, G. Pearson, B. Xu, A. Wright, C. Vanderbilt, and M.H. Cobb. 2001. MAP kinases. Chem Rev. 101:2449-2476.
90. Lee, J.Y., K. Park, E. Lee, T. Ahn, H.H. Jung, S.H. Lim, M. Hong, I.G. Do, E.Y. Cho, D.H. Kim, J.Y. Kim, J.S. Ahn, Y.H. Im, and Y.H. Park. 2016. Gene Expression Profiling of Breast Cancer Brain Metastasis. Sci Rep. 6:28623.
91. Li, Z., L. Wang, X. Zhang, L. Zhang, B. Zhang, Y. Yu, Z. Zeng, M. Zhou, W. Huang, Z. Chen, S. Chen, and G. Li. 2001. [Chromosomal aberration analyzed by comparative genomic hybridization in nasopharyngeal carcinoma]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 18:338-342.
92. Lo, K.W., P.M. Teo, A.B. Hui, K.F. To, Y.S. Tsang, S.Y. Chan, K.F. Mak, J.C. Lee, and D.P. Huang. 2000. High resolution allelotype of microdissected primary nasopharyngeal carcinoma. Cancer Res. 60:3348-3353.
93. Parvanescu, V., M. Georgescu, I. Georgescu, V. Surlin, S. Patrascu, A.M. Picleanu, and E. Georgescu. 2015. The Role of Matrix Metalloproteinase-9 (MMP-9) as a Prognostic Factor in Epithelial and Lymphatic Neoplasia. Chirurgia (Bucur). 110:506-510.