第一型血基質氧化酶 (Heme oxygenase-1, HO-1) 為細胞內具有重要保護功能的酵素。當細胞受到如自由基、細胞激素等外界刺激時，HO-1會被誘發表現進而催化血基質的分解釋放出亞鐵離子、一氧化碳和膽綠素。一氧化碳和膽綠素具有許多細胞保護功能，如抗氧化、抗發炎以及抑制細胞凋亡等作用，因此HO-1被視為細胞內重要的氧化壓力感應及調節酵素。正常生理情況下，HO-1是藉由碳鏈末端上的一段穿膜結構鑲嵌於內質網膜上的蛋白質，而位於氮鏈末端的酵素活性區域則暴露在細胞質中。過去的研究顯示HO-1在許多癌化組織中大量表現。另外在臨床攝護腺癌組織切片中有觀察到HO-1在細胞核內表現的現象，且此進核現象與癌症惡性程度具高度相關性，這項結果指出HO-1的進核表現有參與癌化過程的可能性。藉由抗生素篩選建立大量表現全長HO-1 (f-HO-1，存在於內質網膜上)以及碳端穿膜區域剔除之HO-1 (t-HO-1，同時存在於細胞核與細胞質中)的穩定癌細胞株，以觀察HO-1對於癌細胞的形態、生長速度以及癌化進程中所需具備的能力如細胞爬行、侵襲之能力有何影響。實驗結果顯示f-HO-1大量表現之HeLa子宮頸癌穩定細胞株的細胞型態明顯地由原本排列整齊的上皮細胞形狀趨變成不規則紡錘狀的間質細胞型態，且細胞生長速度、細胞爬行以及侵襲的能力有明顯增進，此結果支持HO-1有促進腫瘤細胞增生以及增進癌細胞侵襲能力的現象；而此現象亦能在t-HO-1的穩定細胞株中明顯地觀察到。利用clonogenic survival assay將各穩定細胞株以非常低的細胞密度培養並照射不同強度之伽瑪射線後，發現f-HO-1細胞能抵抗高強度的放射線傷害並有較強的生存能力；然而t-HO-1卻對細胞無明顯地保護作用。為釐清HO-1是否透過其酵素活性而達成促進癌細胞生長等作用，利用HO-1抑制劑tin protoporphyrin以及建立失去酵素活性之突變型HO-1 (H25A點突變)穩定細胞株進行相同實驗，結果顯示受到活性抑制劑處理或完全缺乏酵素活性的f-HO-1促進癌細胞爬行或侵襲的能力皆明顯降低；然而t-HO-1卻不受顯著影響，仍能大幅增進癌細胞爬行與侵襲的能力。綜合以上實驗結果，可推論f-HO-1主要藉由其酵素活性促進癌細胞生長、癌化；而t-HO-1則是透過與酵素活性無關的途徑達成相同的促進癌細胞生長及癌化能力的作用。此外，為更進一步釐清此作用是來自於細胞質或細胞核內，將t-HO-1序列前端接上一段出核序列(nuclear export signal, NES)，使t-HO-1只存在於細胞質當中。藉由細胞質體轉染後，進行細胞爬行及侵襲能力之比較，結果顯示存在於細胞質內的NES-t-HO-1無法增進細胞爬行及侵襲的能力，因此推論t-HO-1增進細胞癌化的能力主要是透過細胞核內之作用。

Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme catalyzing the oxidative degradation of heme to liberate iron, carbon monoxide, and biliverdin. Carbon monoxide, biliverdin and its subsequent metabolite bilirubin possess cytoprotective functions including anti-oxidant, anti-inflammation and anti-apoptosis actions. Therefore, HO-1 is recognized as a critical oxidative stress sensor and regulatory system. HO-1 anchors in the endoplasmic reticulum (ER) through a single transmembrane segment located at the carboxyl-terminus. Previous studies revealed that HO-1 is induced in several cancers. Moreover, HO-1 is detected in nuclei of prostate cancer cells in clinical specimens and its nuclear localization is correlated with disease progression. These findings suggest that nuclear HO-1 may have a functional role in tumorigenesis or tumor progression. In this study, stable cell clones overexpressing full-length HO-1 (f-HO-1) with ER-anchorage and carboxyl-terminal truncated HO-1 (t-HO-1) with nuclear distribution were established and used to study the effects of different HO-1 localization on cancer cell morphology, proliferation, migration and invasion. We showed that HeLa cells overexpressing f-HO-1 exhibited epithelial to mesenchymal-like morphological change and enhanced proliferation rate, migration and invasion abilities. These phenomena were also observed in t-HO-1 overexpressing cells. Clonogenic survival assay demonstrated that overexpression of f-HO-1 but not t-HO-1 exerted significant cytoprotective effect against radiation hazard. Further experiments demonstrated that tin protoporphyrin, a HO-1 inhibitor, inhibited the migration and invasion abilities of cells overexpressing f-HO-1 but not the cells overexpressing t-HO-1. To further confirm this phenomenon, stable cell lines overexpressing activity-defective HO-1 mutants carrying alanine mutation at histidine 25 residue (H25A) were established. Results showed that H25A mutation abolished the enhanced migration and invasion abilities in cells overexpressing f-HO-1, whereas it had no effect on t-HO-1-mediated increase in cell migration and invasion. These results indicate that ER-anchored HO-1 causes more aggressive phenotype mainly through its catalytic activity; while t-HO-1 promotes cancer cell progression through an activity-independent mechanism. Moreover, to further clarify the phenomena were attributed to the effects of t-HO-1 in cytoplasm or inside nucleus, t-HO-1 with a nuclear export signal (NES) placed at its N-terminus was constructed and transfected to cells. Results showed that cytoplasmic localized NES-t-HO-1 failed to enhance the cell migration and invasion. These results indicate that t-HO-1 may promote cell migration/invasion mainly through its effects inside the nucleus.

Chinese Abstract ------------------------------------------ i
English Abstract ------------------------------------------ iii
Introduction ------------------------------------------ 5
1. Types of heme oxygenase (HO)
2. Functions of HO
3. Nuclear translocation of HO-1
4. Role of HO-1 in cancer

Specific aim ------------------------------------------ 11
Materials and Methods ------------------------------------------ 12
1. Chemicals and reagents
2. Antibodies
3. Plasmids construction
4. Cell lines
5. Western blot
6. Proliferation assay
7. Clonogenic survival assay
8. Migration assay
9. Invasion assay
10. Immunofluorescent staining
11. Statistics

Results ------------------------------------------- 22
Figures ------------------------------------------ 26
Discussion ------------------------------------------ 37
Conclusion ------------------------------------------ 43
References ------------------------------------------ 44

1. Tenhunen, R., H.S. Marver, and R. Schmid, The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968; 61: 748-55.
2. Jozkowicz, A., H. Was, and J. Dulak, Heme oxygenase-1 in tumors: is it a false friend? Antioxid Redox Signal. 2007; 9: 2099-117.
3. Maines, M.D., Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 1988; 2: 2557-68.
4. Otterbein, L.E., M.P. Soares, K. Yamashita, and F.H. Bach, Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003; 24: 449-55.
5. Soares, M.P. and F.H. Bach, Heme oxygenase-1: from biology to therapeutic potential. Trends Mol Med. 2009; 15: 50-8.
6. Hwang, H.W., J.R. Lee, K.Y. Chou, C.S. Suen, M.J. Hwang, C. Chen, R.C. Shieh, and L.Y. Chau, Oligomerization is crucial for the stability and function of heme oxygenase-1 in the endoplasmic reticulum. J Biol Chem. 2009; 284: 22672-9.
7. Han, Z., S. Varadharaj, R.J. Giedt, J.L. Zweier, H.H. Szeto, and B.R. Alevriadou, Mitochondria-derived reactive oxygen species mediate heme oxygenase-1 expression in sheared endothelial cells. J Pharmacol Exp Ther. 2009; 329: 94-101.
8. Lavrovsky, Y., M.L. Schwartzman, R.D. Levere, A. Kappas, and N.G. Abraham, Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci U S A. 1994; 91: 5987-91.
9. Chen, Y.C., S.C. Shen, W.R. Lee, H.Y. Lin, C.H. Ko, and T.J. Lee, Nitric oxide and prostaglandin E2 participate in lipopolysaccharide/interferon-gamma-induced heme oxygenase 1 and prevent RAW264.7 macrophages from UV-irradiation-induced cell death. J Cell Biochem. 2002; 86: 331-9.
10. Lee, P.J., B.H. Jiang, B.Y. Chin, N.V. Iyer, J. Alam, G.L. Semenza, and A.M. Choi, Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem. 1997; 272: 5375-81.
11. Maines, M.D., The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997; 37: 517-54.
12. Terry, C.M., J.A. Clikeman, J.R. Hoidal, and K.S. Callahan, Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells. Am J Physiol. 1998; 274: H883-91.
13. Elbirt, K.K., A.J. Whitmarsh, R.J. Davis, and H.L. Bonkovsky, Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases. J Biol Chem. 1998; 273: 8922-31.
14. Kuwano, A., H. Ikeda, K. Takeda, H. Nakai, I. Kondo, and S. Shibahara, Mapping of the human gene for inducible heme oxygenase to chromosome 22q12. Tohoku J Exp Med. 1994; 172: 389-92.
15. Choi, A.M. and J. Alam, Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996; 15: 9-19.
16. Keyse, S.M., L.A. Applegate, Y. Tromvoukis, and R.M. Tyrrell, Oxidant stress leads to transcriptional activation of the human heme oxygenase gene in cultured skin fibroblasts. Mol Cell Biol. 1990; 10: 4967-9.
17. Takeda, K., H. Fujita, and S. Shibahara, Differential control of the metal-mediated activation of the human heme oxygenase-1 and metallothionein IIA genes. Biochem Biophys Res Commun. 1995; 207: 160-7.
18. Lavrovsky, Y., G.S. Drummond, and N.G. Abraham, Downregulation of the human heme oxygenase gene by glucocorticoids and identification of 56b regulatory elements. Biochem Biophys Res Commun. 1996; 218: 759-65.
19. Kurata, S. and H. Nakajima, Transcriptional activation of the heme oxygenase gene by TPA in mouse M1 cells during their differentiation to macrophage. Exp Cell Res. 1990; 191: 89-94.
20. Alam, J., Multiple elements within the 5' distal enhancer of the mouse heme oxygenase-1 gene mediate induction by heavy metals. J Biol Chem. 1994; 269: 25049-56.
21. Immenschuh, S. and G. Ramadori, Gene regulation of heme oxygenase-1 as a therapeutic target. Biochem Pharmacol. 2000; 60: 1121-8.
22. Elbirt, K.K. and H.L. Bonkovsky, Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians. 1999; 111: 438-47.
23. Otterbein, L.E. and A.M. Choi, Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol. 2000; 279: L1029-37.
24. Brouard, S., L.E. Otterbein, J. Anrather, E. Tobiasch, F.H. Bach, A.M. Choi, and M.P. Soares, Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med. 2000; 192: 1015-26.
25. Zhang, X., P. Shan, J. Alam, R.J. Davis, R.A. Flavell, and P.J. Lee, Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J Biol Chem. 2003; 278: 22061-70.
26. Stocker, R., Y. Yamamoto, A.F. McDonagh, A.N. Glazer, and B.N. Ames, Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: 1043-6.
27. Pae, H.O. and H.T. Chung, Heme oxygenase-1: its therapeutic roles in inflammatory diseases. Immune Netw. 2009; 9: 12-9.
28. Kinderlerer, A.R., I. Pombo Gregoire, S.S. Hamdulay, F. Ali, R. Steinberg, G. Silva, N. Ali, B. Wang, D.O. Haskard, M.P. Soares, and J.C. Mason, Heme oxygenase-1 expression enhances vascular endothelial resistance to complement-mediated injury through induction of decay-accelerating factor: a role for increased bilirubin and ferritin. Blood 2009; 113: 1598-607.
29. Kapitulnik, J., Bilirubin: an endogenous product of heme degradation with both cytotoxic and cytoprotective properties. Mol Pharmacol. 2004; 66: 773-9.
30. Berberat, P.O., M. Katori, E. Kaczmarek, D. Anselmo, C. Lassman, B. Ke, X. Shen, R.W. Busuttil, K. Yamashita, E. Csizmadia, S. Tyagi, L.E. Otterbein, S. Brouard, E. Tobiasch, F.H. Bach, J.W. Kupiec-Weglinski, and M.P. Soares, Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB J. 2003; 17: 1724-6.
31. Koorts, A.M. and M. Viljoen, Ferritin and ferritin isoforms II: protection against uncontrolled cellular proliferation, oxidative damage and inflammatory processes. Arch Physiol Biochem. 2007; 113: 55-64.
32. Abraham, N.G., A. Asija, G. Drummond, and S. Peterson, Heme oxygenase -1 gene therapy: recent advances and therapeutic applications. Curr Gene Ther. 2007; 7: 89-108.
33. Schuller, D.J., A. Wilks, P. Ortiz de Montellano, and T.L. Poulos, Crystallization of recombinant human heme oxygenase-1. Protein Sci. 1998; 7: 1836-8.
34. Schuller, D.J., A. Wilks, P.R. Ortiz de Montellano, and T.L. Poulos, Crystal structure of human heme oxygenase-1. Nat Struct Biol. 1999; 6: 860-7.
35. Xia, Z.W., W.P. Zhou, W.J. Cui, X.H. Zhang, Q.X. Shen, Y.Z. Li, and S.C. Yu, Structure prediction and activity analysis of human heme oxygenase-1 and its mutant. World J Gastroenterol. 2004; 10: 2352-6.
36. Lin, Q., S. Weis, G. Yang, Y.H. Weng, R. Helston, K. Rish, A. Smith, J. Bordner, T. Polte, F. Gaunitz, and P.A. Dennery, Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress. J Biol Chem. 2007; 282: 20621-33.
37. McAllister, S.C., S.G. Hansen, R.A. Ruhl, C.M. Raggo, V.R. DeFilippis, D. Greenspan, K. Fruh, and A.V. Moses, Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells. Blood 2004; 103: 3465-73.
38. Liu, Z.M., G.G. Chen, E.K. Ng, W.K. Leung, J.J. Sung, and S.C. Chung, Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells. Oncogene 2004; 23: 503-13.
39. Maines, M.D. and P.A. Abrahamsson, Expression of heme oxygenase-1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution. Urology 1996; 47: 727-33.
40. Doi, K., T. Akaike, S. Fujii, S. Tanaka, N. Ikebe, T. Beppu, S. Shibahara, M. Ogawa, and H. Maeda, Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br J Cancer. 1999; 80: 1945-54.
41. Deininger, M.H., R. Meyermann, K. Trautmann, F. Duffner, E.H. Grote, J. Wickboldt, and H.J. Schluesener, Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression. Brain Res. 2000; 882: 1-8.
42. Hara, E., K. Takahashi, T. Tominaga, T. Kumabe, T. Kayama, H. Suzuki, H. Fujita, T. Yoshimoto, K. Shirato, and S. Shibahara, Expression of heme oxygenase and inducible nitric oxide synthase mRNA in human brain tumors. Biochem Biophys Res Commun. 1996; 224: 153-8.
43. Berberat, P.O., Z. Dambrauskas, A. Gulbinas, T. Giese, N. Giese, B. Kunzli, F. Autschbach, S. Meuer, M.W. Buchler, and H. Friess, Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment. Clin Cancer Res. 2005; 11: 3790-8.
44. Was, H., T. Cichon, R. Smolarczyk, D. Rudnicka, M. Stopa, C. Chevalier, J.J. Leger, B. Lackowska, A. Grochot, K. Bojkowska, A. Ratajska, C. Kieda, S. Szala, J. Dulak, and A. Jozkowicz, Overexpression of heme oxygenase-1 in murine melanoma: increased proliferation and viability of tumor cells, decreased survival of mice. Am J Pathol. 2006; 169: 2181-98.
45. Marinissen, M.J., T. Tanos, M. Bolos, M.R. de Sagarra, O.A. Coso, and A. Cuadrado, Inhibition of heme oxygenase-1 interferes with the transforming activity of the Kaposi sarcoma herpesvirus-encoded G protein-coupled receptor. J Biol Chem. 2006; 281: 11332-46.
46. Fang, J., T. Sawa, T. Akaike, T. Akuta, S.K. Sahoo, G. Khaled, A. Hamada, and H. Maeda, In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor. Cancer Res. 2003; 63: 3567-74.
47. Jozkowicz, A., I. Huk, A. Nigisch, G. Weigel, W. Dietrich, R. Motterlini, and J. Dulak, Heme oxygenase and angiogenic activity of endothelial cells: stimulation by carbon monoxide and inhibition by tin protoporphyrin-IX. Antioxid Redox Signal. 2003; 5: 155-62.
48. Tanaka, S., T. Akaike, J. Fang, T. Beppu, M. Ogawa, F. Tamura, Y. Miyamoto, and H. Maeda, Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour. Br J Cancer. 2003; 88: 902-9.
49. Hirai, K., T. Sasahira, H. Ohmori, K. Fujii, and H. Kuniyasu, Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice. Int J Cancer. 2007; 120: 500-5.
50. Rushworth, S.A. and D.J. MacEwan, HO-1 underlies resistance of AML cells to TNF-induced apoptosis. Blood 2008; 111: 3793-801.
51. Sunamura, M., D.G. Duda, M.H. Ghattas, L. Lozonschi, F. Motoi, J. Yamauchi, S. Matsuno, S. Shibahara, and N.G. Abraham, Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer. Angiogenesis 2003; 6: 15-24.
52. Duckers, H.J., M. Boehm, A.L. True, S.F. Yet, H. San, J.L. Park, R. Clinton Webb, M.E. Lee, G.J. Nabel, and E.G. Nabel, Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med. 2001; 7: 693-8.
53. Jazwa, A., A. Loboda, S. Golda, J. Cisowski, M. Szelag, A. Zagorska, P. Sroczynska, J. Drukala, A. Jozkowicz, and J. Dulak, Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes. Free Radic Biol Med. 2006; 40: 1250-63.
54. Torisu-Itakura, H., M. Furue, M. Kuwano, and M. Ono, Co-expression of thymidine phosphorylase and heme oxygenase-1 in macrophages in human malignant vertical growth melanomas. Jpn J Cancer Res. 2000; 91: 906-10.
55. Hayen, W., M. Goebeler, S. Kumar, R. Riessen, and V. Nehls, Hyaluronan stimulates tumor cell migration by modulating the fibrin fiber architecture. J Cell Sci. 1999; 112 ( Pt 13): 2241-51.
56. Alaoui-Jamali, M.A., T.A. Bismar, A. Gupta, W.A. Szarek, J. Su, W. Song, Y. Xu, B. Xu, G. Liu, J.Z. Vlahakis, G. Roman, J. Jiao, and H.M. Schipper, A novel experimental heme oxygenase-1-targeted therapy for hormone-refractory prostate cancer. Cancer Res. 2009; 69: 8017-24.
57. Sacca, P., R. Meiss, G. Casas, O. Mazza, J.C. Calvo, N. Navone, and E. Vazquez, Nuclear translocation of haeme oxygenase-1 is associated to prostate cancer. Br J Cancer. 2007; 97: 1683-9.
58. Land, E.J., A.F. McDonagh, D.J. McGarvey, and T.G. Truscott, Photophysical studies of tin(IV)-protoporphyrin: potential phototoxicity of a chemotherapeutic agent proposed for the prevention of neonatal jaundice. Proc Natl Acad Sci U S A. 1988; 85: 5249-53.
59. Goodman, A.I., M. Choudhury, J.L. da Silva, M.L. Schwartzman, and N.G. Abraham, Overexpression of the heme oxygenase gene in renal cell carcinoma. Proc Soc Exp Biol Med. 1997; 214: 54-61.
60. Kikuchi, A., M. Yamaya, S. Suzuki, H. Yasuda, H. Kubo, K. Nakayama, M. Handa, T. Sasaki, S. Shibahara, K. Sekizawa, and H. Sasaki, Association of susceptibility to the development of lung adenocarcinoma with the heme oxygenase-1 gene promoter polymorphism. Hum Genet. 2005; 116: 354-60.
61. Lo, S.S., S.C. Lin, C.W. Wu, J.H. Chen, W.I. Yeh, M.Y. Chung, and W.Y. Lui, Heme oxygenase-1 gene promoter polymorphism is associated with risk of gastric adenocarcinoma and lymphovascular tumor invasion. Ann Surg Oncol. 2007; 14: 2250-6.
62. Yanagawa, T., K. Omura, H. Harada, K. Nakaso, S. Iwasa, Y. Koyama, K. Onizawa, H. Yusa, and H. Yoshida, Heme oxygenase-1 expression predicts cervical lymph node metastasis of tongue squamous cell carcinomas. Oral Oncol. 2004; 40: 21-7.
63. Ishikawa, T., N. Yoshida, H. Higashihara, M. Inoue, K. Uchiyama, T. Takagi, O. Handa, S. Kokura, Y. Naito, T. Okanoue, and T. Yoshikawa, Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice. Clin Exp Metastasis. 2003; 20: 445-50.
64. Hoppe-Seyler, F. and K. Butz, Repression of endogenous p53 transactivation function in HeLa cervical carcinoma cells by human papillomavirus type 16 E6, human mdm-2, and mutant p53. J Virol. 1993; 67: 3111-7.
65. Gatti, L., R. Supino, P. Perego, R. Pavesi, C. Caserini, N. Carenini, S.C. Righetti, V. Zuco, and F. Zunino, Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response. Cell Death Differ. 2002; 9: 1352-9.
66. Yilmaz, M. and G. Christofori, EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009; 28: 15-33.
67. Friedl, P. and K. Wolf, Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003; 3: 362-74.
68. Frame, M.C., V.J. Fincham, N.O. Carragher, and J.A. Wyke, v-Src's hold over actin and cell adhesions. Nat Rev Mol Cell Biol. 2002; 3: 233-45.
69. Liu, P.L., J.R. Tsai, A.L. Charles, J.J. Hwang, S.H. Chou, Y.H. Ping, F.Y. Lin, Y.L. Chen, C.Y. Hung, W.C. Chen, Y.H. Chen, and I.W. Chong, Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases. Mol Nutr Food Res. 2010; 54 Suppl 2: S196-204.
70. Kim, D.H., J.H. Kim, E.H. Kim, H.K. Na, Y.N. Cha, J.H. Chung, and Y.J. Surh, 15-Deoxy-Delta12,14-prostaglandin J2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: possible roles of iron and ROS. Carcinogenesis 2009; 30: 645-54.
71. Ning, W., R. Song, C. Li, E. Park, A. Mohsenin, A.M. Choi, and M.E. Choi, TGF-beta1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2002; 283: L1094-102.
72. Lee, J.M., S. Dedhar, R. Kalluri, and E.W. Thompson, The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006; 172: 973-81.
73. Ramis-Conde, I., M.A. Chaplain, A.R. Anderson, and D. Drasdo, Multi-scale modelling of cancer cell intravasation: the role of cadherins in metastasis. Phys Biol. 2009; 6: 016008.
74. Jeanes, A., C.J. Gottardi, and A.S. Yap, Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 2008; 27: 6920-9.
75. Carragher, N.O., M.A. Westhoff, D. Riley, D.A. Potter, P. Dutt, J.S. Elce, P.A. Greer, and M.C. Frame, v-Src-induced modulation of the calpain-calpastatin proteolytic system regulates transformation. Mol Cell Biol. 2002; 22: 257-69.
76. Huttenlocher, A., S.P. Palecek, Q. Lu, W. Zhang, R.L. Mellgren, D.A. Lauffenburger, M.H. Ginsberg, and A.F. Horwitz, Regulation of cell migration by the calcium-dependent protease calpain. J Biol Chem. 1997; 272: 32719-22.