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研究生:趙大中
研究生(外文):Ta-Chung Chao
論文名稱:評估抑制胸腺素貝他-4表現對大腸直腸癌之治療潛力以及對正常腸道上皮細胞之影響
論文名稱(外文):Assessment of the therapeutic potential in colorectal cancer as well as the influences on normal intestinal epithelial cells of thymosin beta-4 knockdown
指導教授:蘇瑀蘇瑀引用關係
指導教授(外文):Yeu Su
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:103
語文別:英文
論文頁數:89
中文關鍵詞:大腸直腸癌胸腺素貝他-4腸道上皮細胞
外文關鍵詞:Colorectal CancerThymosin beta-4Intestinal epithelial cell
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胸腺素貝他-4(Tβ4)已知與腫瘤形成有關,而且這個含43個胺基酸的胜肽,被發現在包括大腸直腸癌(colorectal carcinoma, CRC)在內的多種不同類型的人類癌症中有過度表現的情況。由於Tβ4對大腸直腸癌惡化過程中的不同步驟皆有促進的作用,因此它被認為可以做為治療大腸直腸癌的新標靶,尤其對於已轉移的腫瘤。雖然先前他人的研究結果顯示,藉由小髮夾式RNA(small hairpin RNA, shRNA)抑制數種癌細胞內Tβ4基因的表現,可干擾這些細胞之生體外(in vitro)的生長,甚至誘發其凋亡(apoptosis)﹔但對於此方法能否抑制生體內(in vivo)的腫瘤則還不清楚。因此,在本研究中,我們利用可表現Tβ4 shRNA之重組腺病毒(adenovirus, 以下簡稱為AdTβ4sh),感染生體外培養的CT-26小鼠大腸直腸癌細胞,發現該細胞的生長受到明顯的抑制,同時也出現明顯的凋亡現象。進一步將這些已為AdTβ4sh感染的CT-26細胞植入裸鼠(nude mice),該細胞在生體內的生長也明顯受到干擾。更重要的是,我們將未受感染的CT-26細胞先植入裸鼠,等到腫瘤形成(約50 mm3)後,再多次將AdTβ4sh直接注射至腫瘤中,發現腫瘤的生長也明顯受到抑制。換言之,我們是第一個報導利用重組腺病毒直接感染生體內的大腸直腸癌,藉其表現之Tβ4 shRNA抑制癌細胞中該基因的表現而干擾腫瘤的生長之團隊。此結果進一步顯示,利用病毒感染後所表現出來的Tβ4 shRNA,經由抑制大腸直腸癌內生性Tβ4基因的表現,而阻斷該腫瘤生長的「基因治療」是可行的。然而,若不能將目前常用的腺病毒其外套膜上用以附著細胞的纖維蛋白,修飾成具有專一性與癌細胞結合功能的話,要想經由全身或局部注射,而達到腫瘤專一性感染的目的是非常困難的。因此,我們同時也需要評估當腫瘤附近的正常腸道細胞也受到AdTβ4sh感染時,其導致的副作用(或損傷)為何﹔所以,在本研究的第二部分,我們以IEC-6大鼠小腸上皮細胞株當作正常腸道上皮細胞模式,檢視該細胞因其內生性Tβ4基因的表現,為AdTβ4sh感染而受到抑制後所發生的變化。我們發現,當IEC-6細胞內的Tβ4表現受到抑制時,不僅其生長會被干擾,甚至出現凋亡。同時也發現G0/G1族群在這些Tβ4表現量降低的IEC-6細胞內明顯減少,但具多倍性(polyploid)染色體的細胞明顯增多。由於在後續中實驗發現,不但DNA新合成(de novo synthesis)增加,且Cdc6(一DNA複製的認證因子, licensing factor), cyclin A,及磷酸化之checkpoint kinase 1 (CHK1)也都明顯上升,因此推測此種多倍性染色體增加的現象,很可能是由於DNA的再複製(re-replication)所造成的。我們進一步發現,在這些Tβ4表現量降低的IEC-6細胞中,Emil(早期有絲分裂抑制蛋白1,early mitotic inhibitor 1)之RNA及蛋白質的表現量皆有明顯的下降﹔其原因則在於一種活化Emil基因表現的轉譯因子E2F1的表現,由於其負調控蛋白—肝醣合成酶3β (glycogen synthase-3β, GSK-3β)的增加而下降﹔當Emil不足時,無法阻止Cdc6等蛋白去形成“前複製複合物(pre-replication complex)”,導致染色體的再複製。根據上述的結果,我們認為抑制正常腸道上皮細胞內Tβ4的表現,會引發染色體的再複製,這似乎意味著此球型肌動蛋白(G-actin)阻絕者(sequester),或許在細胞中也扮演維持基因體穩定(genome stability)的角色。更重要的是,我們的結果提醒臨床腫瘤醫生,在設計以Tβ4為標靶的大腸直腸癌治療方法時,必要留意抑制該基因對正常腸道細胞的不良影響。
Thymosin beta-4 (Tβ4) is known to be involved in tumorigenesis and overexpression of this 43-residue peptide has been observed in a wide variety of human cancers, including colorectal carcinoma (CRC). Accordingly, because of its multiple promoting effects on the malignant progression of CRC, Tβ4 has been proposed to be a novel therapeutic target for this tumor, especially its metastatic form. Although in vitro tumor-suppressive effects of Tβ4 gene silencing mediated by small hairpin RNA (shRNA) have already been demonstrated, the in vivo efficacy of such an approach has not yet been reported. Herein, we first demonstrated that infection CT-26 mouse CRC cells in culture with recombinant adenoviruses expressing an shRNA targeting Tβ4 not only markedly suppressed the growth but also robustly induced the apoptosis of these cells. As expected, tumors grown in nude mice from the CT-26 cells whose Tβ4 expression already been downregulated by virus infection were also drastically reduced. Most importantly, significant growth arrest of tumors derived from the parental CT-26 cells was observed after multiple intratumoral injections of these viruses. Together, our results show for the first time that in vivo silencing of Tβ4 expression by its shRNA generated after adenoviral infection can suppress CRC growth. These results further demonstrate the feasibility of treating CRC by a Tβ4 knockdown gene therapeutic approach.
Without modifying the cellular attachment protein fibers of the currently-used adenoviruses, tumor-specific Tβ4 knockdown will be very difficult to achieve regardless of the way (systemic or local) they were administered. Hence, it is necessary to assess the possible damages (or injuries) caused by the non-specific Tβ4 silencing in the surrounding normal cells. Therefore, in the second part of this study, we examined the consequences of shRNA-mediated knockdown of Tβ4 in IEC-6 normal rat small intestinal cells. Indeed, suppression of Tβ4 expression in these cells not only diminished their growth but also induced their apoptosis. Marked decrease of G0/G1 population together with drastic increase of polyploid ones were also observed in these cells. The increase of polyploidy likely resulted from DNA re-replication because not only the de novo DNA synthesis was greatly increased but also the expression levels of Cdc6 (a replication-licensing factor), cyclin A, and phosphorylated-checkpoint kinase 1 were all dramatically elevated. Moreover, marked reductions in both RNA and protein levels of Emi1 (early mitotic inhibitor 1) were also detected in Tβ4-downregulated IEC-6 cells which might be accounted by the downregulation of E2F1, a transcription factor capable of inducing Emi1 expression, mediated by glycogen synthase-3β (GSK-3β). In conclusion, inhibiting Tβ4 expression triggers DNA re-replication in normal intestinal epithelial cells, suggesting that this G-actin sequester may play a crucial role in maintaining genome stability in these cells. More importantly, clinical oncologists should take this novel activity into consideration when design CRC therapy based on targeting Tβ4.

1. Contents ------------------- i
2. English Abstract ---------- iii
3. Chinese Abstract ----- v
4. List of Abbreviations ---- vii
5. Introduction --------------- 1
Section 1: Colorectal carcinoma and its current therapies ---- 1
Section 2: Thymosin beta-4 in tumorigenesis ------------ 3
Section 3: Gene therapy in colorectal carcinoma and exploration of the
possibility of using thymosin beta-4 as a target ------- 6
Section 4: Regulation of DNA replication -------------- 10
Section 5: Specific aims ------------- 11
6. Materials and Methods ---- 13
7. Results ------------------- 22
Part I
Efficacy of T4 downregulation in CT-26 mouse colon cancer cells using adenovirus-delivered shRNA ---------------- 22
T4 knockdown suppresses CT-26 cell growth and induces apoptosis in vitro ----------------------- 22
Inhibition of in vivo CT-26 xenograft tumor growth upon T4 suppression ----------------------------- 23
Intratumoral injection of T4 shRNA-expressing recombinant adenovirus suppresses the in vivo tumorigenicity of CT-26 cells ---------------------- 24
F-actin disruption may be responsible for the growth suppression of CT-26 cells triggered by T4 knockdown - 24

Part II
T4 knockdown induces growth suppression of IEC6 cells --25
Tβ4 knockdown induces cell cycle arrest, polyploidy, and DNA damage ---------------------------- 26
Tβ4 knockdown induces DNA re-replication in IEC-6 cells -27
Tβ4 knockdown induces DNA re-replication through Emi1 suppression in IEC-6 cells -------------- 27
Discussion ---------------------- 29

Conclusion --------------------- 35

Perspectives --------------- 36

References --------------- 39

Figures and Tables -------- 55

Publications -------------- 73
1. Administration HP. Cancer Registry Report 2011, Health Promotion Administration, Ministry of Health and Welfare. Available at http://tcr.cph.ntu.edu.tw/uploadimages/CA15_LF100_20140415.pdf.
2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
3. van Vugt JL, Reisinger KW, Derikx JP, Boerma D, Stoot JH. Improving the outcomes in oncological colorectal surgery. World J Gastroenterol 2014;20:12445-57.
4. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014;383:1490-502.
5. Dietvorst MH, Eskens FA. Current and Novel Treatment Options for Metastatic Colorectal Cancer: Emphasis on Aflibercept. Biol Ther 2013;3:25-33.
6. Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109-16.
7. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013-9.
8. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44.
9. Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013;14:29-37.
10. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408-17.
11. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011;29:2011-9.
12. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:1023-34.
13. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697-705.
14. Jeong WJ, Cha PH, Choi KY. Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer. World J Gastroenterol 2014;20:9862-71.
15. Clark ME, Smith RR. Liver-directed therapies in metastatic colorectal cancer. J Gastrointest Oncol 2014;5:374-87.
16. Low TL, Hu SK, Goldstein AL. Complete amino acid sequence of bovine thymosin beta 4: a thymic hormone that induces terminal deoxynucleotidyl transferase activity in thymocyte populations. Proc Natl Acad Sci U S A 1981;78:1162-6.
17. Low TL, Goldstein AL. Chemical characterization of thymosin beta 4. J Biol Chem 1982;257:1000-6.
18. Hannappel E, Leibold, W. Biosynthesis rates and content of thymosin beta 4 in cell lines. Arch Biochem Biophys 1985;240:236-41.
19. Xiao Y, Chen Y, Wen J, Yan W, Zhou K, Cai W. Thymosin beta4: a potential molecular target for tumor therapy. Crit Rev Eukaryot Gene Expr 2012;22:109-16.
20. Sosne G, Chan CC, Thai K, Kennedy M, Szliter EA, Hazlett LD, et al. Thymosin beta 4 promotes corneal wound healing and modulates inflammatory mediators in vivo. Exp Eye Res 2001;72:605-8.
21. Sanders MC, Goldstein AL, Wang YL. Thymosin beta 4 (Fx peptide) is a potent regulator of actin polymerization in living cells. Proc Natl Acad Sci U S A 1992;89:4678-82.
22. Philp D, Badamchian M, Scheremeta B, Nguyen M, Goldstein AL, Kleinman HK. Thymosin beta 4 and a synthetic peptide containing its actin-binding domain promote dermal wound repair in db/db diabetic mice and in aged mice. Wound Repair Regen 2003;11:19-24.
23. Malinda KM, Sidhu GS, Mani H, Banaudha K, Maheshwari RK, Goldstein AL, et al. Thymosin beta4 accelerates wound healing. J Invest Dermatol 1999;113:364-8.
24. Safer D, Elzinga M, Nachmias VT. Thymosin beta 4 and Fx, an actin-sequestering peptide, are indistinguishable. J Biol Chem 1991;266:4029-32.
25. Cassimeris L, Safer D, Nachmias VT, Zigmond SH. Thymosin beta 4 sequesters the majority of G-actin in resting human polymorphonuclear leukocytes. J Cell Biol 1992;119:1261-70.
26. Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 2004;432:466-72.
27. Sanger JM, Golla R, Safer D, Choi JK, Yu KR, Sanger JW, et al. Increasing intracellular concentrations of thymosin beta 4 in PtK2 cells: effects on stress fibers, cytokinesis, and cell spreading. Cell Motil Cytoskeleton 1995;31:307-22.
28. Cha HJ, Jeong MJ, Kleinman HK. Role of thymosin beta4 in tumor metastasis and angiogenesis. J Natl Cancer Inst 2003;95:1674-80.
29. Philp D, Huff T, Gho YS, Hannappel E, Kleinman HK. The actin binding site on thymosin beta4 promotes angiogenesis. FASEB J 2003;17:2103-5.
30. Oh JM, Moon EY. Actin-sequestering protein, thymosin beta-4, induces paclitaxel resistance through ROS/HIF-1alpha stabilization in HeLa human cervical tumor cells. Life Sci 2010;87:286-93.
31. Wang WS, Chen PM, Hsiao HL, Ju SY, Su Y. Overexpression of the thymosin beta-4 gene is associated with malignant progression of SW480 colon cancer cells. Oncogene 2003;22:3297-306.
32. Clark EA, Golub TR, Lander ES, Hynes RO. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 2000;406:532-5.
33. Xie D, Jauch A, Miller CW, Bartram CR, Koeffler HP. Discovery of over-expressed genes and genetic alterations in breast cancer cells using a combination of suppression subtractive hybridization, multiplex FISH and comparative genomic hybridization. Int J Oncol 2002;21:499-507.
34. Vigneswaran N, Wu J, Sacks P, Gilcrease M, Zacharias W. Microarray gene expression profiling of cell lines from primary and metastatic tongue squamous cell carcinoma: possible insights from emerging technology. J Oral Pathol Med 2005;34:77-86.
35. Zhang Y, Feurino LW, Zhai Q, Wang H, Fisher WE, Chen C, et al. Thymosin Beta 4 is overexpressed in human pancreatic cancer cells and stimulates proinflammatory cytokine secretion and JNK activation. Cancer Biol Ther 2008;7:419-23.
36. Alldinger I, Dittert D, Peiper M, Fusco A, Chiappetta G, Staub E, et al. Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer. Pancreatology 2005;5:370-9.
37. Hall AK. Differential expression of thymosin genes in human tumors and in the developing human kidney. Int J Cancer 1991;48:672-7.
38. Wang WS, Chen PM, Hsiao HL, Wang HS, Liang WY, Su Y. Overexpression of the thymosin beta-4 gene is associated with increased invasion of SW480 colon carcinoma cells and the distant metastasis of human colorectal carcinoma. Oncogene 2004;23:6666-71.
39. Smart N, Rossdeutsch A, Riley P. Thymosin beta 4 and angiogenesis: modes of action and therapeutic potential. Angiogenesis 2007;10:229-41.
40. Oh SY, Song JH, Gil JE, Kim JH, Yeom YI, Moon EY. ERK activation by thymosin-beta-4 (TB4) overexpression induces paclitaxel-resistance. Exp Cell Res 2006;312:1651-7.
41. Caers J, Otjacques E, Hose D, Klein B, Vanderkerken K. Thymosin beta4 in multiple myeloma: friend or foe. Ann N Y Acad Sci 2010;1194:125-9.
42. Ryu YK, Lee YS, Lee GH, Song KS, Kim YS, Moon EY. Regulation of glycogen synthase kinase-3 by thymosin beta-4 is associated with gastric cancer cell migration. Int J Cancer 2012;131:2067-77.
43. Wang ZY, Zeng FQ, Zhu ZH, Jiang GS, Lv L, Wan F, et al. Evaluation of thymosin beta4 in the regulation of epithelial-mesenchymal transformation in urothelial carcinoma. Urol Oncol 2012;30:167-76.
44. Nummela P, Yin M, Kielosto M, Leaner V, Birrer MJ, Holtta E. Thymosin beta4 is a determinant of the transformed phenotype and invasiveness of S-adenosylmethionine decarboxylase-transfected fibroblasts. Cancer Res 2006;66:701-12.
45. Jo JO, Kim SR, Bae MK, Kang YJ, Ock MS, Kleinman HK, et al. Thymosin beta4 induces the expression of vascular endothelial growth factor (VEGF) in a hypoxia-inducible factor (HIF)-1alpha-dependent manner. Biochim Biophys Acta 2010;1803:1244-51.
46. Hardesty WM, Kelley MC, Mi D, Low RL, Caprioli RM. Protein signatures for survival and recurrence in metastatic melanoma. J Proteomics 2011;74:1002-14.
47. Moon EY, Song JH, Yang KH. Actin-sequestering protein, thymosin-beta-4 (TB4), inhibits caspase-3 activation in paclitaxel-induced tumor cell death. Oncol Res 2007;16:507-16.
48. Oh JM, Ryoo IJ, Yang Y, Kim HS, Yang KH, Moon EY. Hypoxia-inducible transcription factor (HIF)-1 alpha stabilization by actin-sequestering protein, thymosin beta-4 (TB4) in Hela cervical tumor cells. Cancer Lett 2008;264:29-35.
49. Huang HC, Hu CH, Tang MC, Wang WS, Chen PM, Su Y. Thymosin beta4 triggers an epithelial-mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase. Oncogene 2007;26:2781-90.
50. Hsiao HL, Wang WS, Chen PM, Su Y. Overexpression of thymosin beta-4 renders SW480 colon carcinoma cells more resistant to apoptosis triggered by FasL and two topoisomerase II inhibitors via downregulating Fas and upregulating Survivin expression, respectively. Carcinogenesis 2006;27:936-44.
51. Friedmann T. A brief history of gene therapy. Nat Genet 1992;2:93-8.
52. Wirth T, Parker N, Yla-Herttuala S. History of gene therapy. Gene. 2013;525:162-9.
53. Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009;374:1597-605.
54. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 2010;467:318-22.
55. Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, et al. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2010;363:355-64.
56. Das SK, Menezes ME, Bhatia S, Wang XY, Emdad L, Sarkar D, et al. Gene therapies for cancer: strategies, challenges and successes. J Cell Physiol 2014.
57. Krens LL, Baas JM, Gelderblom H, Guchelaar HJ. Therapeutic modulation of k-ras signaling in colorectal cancer. Drug Discov Today 2010;15:502-16.
58. Liu CC, Liu JH, Wu SC, Yen CC, Chen WS, Tsai YC. A novel E1B-55kD-deleted oncolytic adenovirus carrying mutant KRAS-regulated hdm2 transgene exerts specific antitumor efficacy on colorectal cancer cells. Mol Cancer Ther 2010;9:450-60.
59. Maitra R, Seetharam R, Tesfa L, Augustine TA, Klampfer L, Coffey MC, et al. Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan. Oncotarget 2014;5:2807-19.
60. Yamaki M, Shinozaki K, Sakaguchi T, Meseck M, Ebert O, Ohdan H, et al. The potential of recombinant vesicular stomatitis virus-mediated virotherapy against metastatic colon cancer. Int J Mol Med 2013;31:299-306.
61. Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002;3:932-43.
62. Jing Y, Zaias J, Duncan R, Russell SJ, Merchan JR. In vivo safety, biodistribution and antitumor effects of uPAR retargeted oncolytic measles virus in syngeneic cancer models. Gene Ther 2014;21:289-97.
63. Wu Y, Guo Z, Zhang D, Zhang W, Yan Q, Shi X, et al. A novel colon cancer gene therapy using rAAVmediated expression of human shRNA-FHL2. Int J Oncol 2013;43:1618-26.
64. Rao B, Gao Y, Zhou Q, Xiao P, Xia S, Ma J, et al. A recombinant adenovirus vector encoding the light chain of human coagulation factor VII and IgG1 Fc fragment to targeting tissue factor for colorectal cancer immunotherapy in the mouse model. J Cancer Res Clin Oncol 2013;139:1015-23.
65. Tu Z, Ma Y, Akers W, Achilefu S, Gu Y. Therapeutic effect of the treatment for colorectal cancer with adenoviral vectors mediated estrogen receptor beta gene therapy combined with thermotherapy. J Cancer Res Clin Oncol 2014;140:623-32.
66. Zhao DX, Li ZJ, Zhang Y, Zhang XN, Zhao KC, Li YG, et al. Enhanced antitumor immunity is elicited by adenovirus-mediated gene transfer of CCL21 and IL-15 in murine colon carcinomas. Cell Immunol 2014;289:155-61.
67. Ricci-Vitiani L, Mollinari C, di Martino S, Biffoni M, Pilozzi E, Pagliuca A, et al. Thymosin beta4 targeting impairs tumorigenic activity of colon cancer stem cells. FASEB J 2010;24:4291-301.
68. Yoon SY, Lee HR, Park Y, Kim JH, Kim SY, Yoon SR, et al. Thymosin beta4 expression correlates with lymph node metastasis through hypoxia inducible factor-alpha induction in breast cancer. Oncol Rep 2011;25:23-31.
69. Wirsching HG, Krishnan S, Florea AM, Frei K, Krayenbuhl N, Hasenbach K, et al. Thymosin beta 4 gene silencing decreases stemness and invasiveness in glioblastoma. Brain 2014;137:433-48.
70. Yekezare M, Gomez-Gonzalez B, Diffley JF. Controlling DNA replication origins in response to DNA damage - inhibit globally, activate locally. J Cell Sci 2013;126:1297-306.
71. Albertson DG. Gene amplification in cancer. Trends Genet 2006;22:447-55.
72. Hook SS, Lin JJ, Dutta A. Mechanisms to control rereplication and implications for cancer. Curr Opin Cell Biol 2007;19:663-71.
73. Schimke RT, Sherwood SW, Hill AB, Johnston RN. Overreplication and recombination of DNA in higher eukaryotes: potential consequences and biological implications. Proc Natl Acad Sci U S A 1986;83:2157-61.
74. Tada S. Cdt1 and geminin: role during cell cycle progression and DNA damage in higher eukaryotes. Front Biosci 2007;12:1629-41.
75. Heller RC, Kang S, Lam WM, Chen S, Chan CS, Bell SP. Eukaryotic origin-dependent DNA replication in vitro reveals sequential action of DDK and S-CDK kinases. Cell 2011;146:80-91.
76. Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem 2002;71:333-74.
77. Arias EE, Walter JC. Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. Genes Dev 2007;21:497-518.
78. Drury LS, Diffley JF. Factors affecting the diversity of DNA replication licensing control in eukaryotes. Curr Biol 2009;19:530-5.
79. Blow JJ, Dutta A. Preventing re-replication of chromosomal DNA. Nat Rev Mol Cell Biol 2005;6:476-86.
80. Fujita M. Cdt1 revisited: complex and tight regulation during the cell cycle and consequences of deregulation in mammalian cells. Cell Div 2006;1:22.
81. Moshe Y, Bar-On O, Ganoth D, Hershko A. Regulation of the action of early mitotic inhibitor 1 on the anaphase-promoting complex/cyclosome by cyclin-dependent kinases. J Biol Chem 2011;286:16647-57.
82. De Mey JR, Freund JN. Understanding epithelial homeostasis in the intestine: An old battlefield of ideas, recent breakthroughs and remaining controversies. Tissue Barriers 2013;1:e24965.
83. Tang MC, Su Y. Thymosin beta4 knockdown disrupts mitochondrial functions of SW480 human colon cancer cells. Cancer Sci 2011;102:1665-72.
84. Lien CY LO, Su Y. Cbfb enhances the osteogenic differentiation of both human and mouse mesenchymal stem cells induced by Cbfa-1 via reducing its ubiquitination-mediated degradation. Stem Cells 2007;25:1462-8.
85. Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods 1995;184:39-51.
86. Kim AD, Kang KA, Kim HS, Kim DH, Choi YH, Lee SJ, et al. A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells. Cell Death Dis 2013;4:e750.
87. Kaiser E, Kroll C, Ernst K, Schwan C, Popoff M, Fischer G, et al. Membrane translocation of binary actin-ADP-ribosylating toxins from Clostridium difficile and Clostridium perfringens is facilitated by cyclophilin A and Hsp90. Infect Immun 2011;79:3913-21.
88. Aktories K, Ankenbauer T, Schering B, Jakobs KH. ADP-ribosylation of platelet actin by botulinum C2 toxin. Eur J Biochem 1986;161:155-62.
89. Chow J, Poon RY. DNA damage and polyploidization. Adv Exp Med Biol 2010;676:57-71.
90. Sharma A, Singh K, Almasan A. Histone H2AX Phosphorylation: A Marker for DNA Damage. Methods Mol Biol 2012;920:613-26.
91. Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 2010;16:376-83.
92. Melixetian M, Ballabeni A, Masiero L, Gasparini P, Zamponi R, Bartek J, et al. Loss of Geminin induces rereplication in the presence of functional p53. J Cell Biol 2004;165:473-82.
93. Zhu W, Chen Y, Dutta A. Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint. Mol Cell Biol 2004;24:7140-50.
94. Green BM, Li JJ. Loss of rereplication control in Saccharomyces cerevisiae results in extensive DNA damage. Mol Biol Cell 2005;16:421-32.
95. Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, et al. A p53-dependent checkpoint pathway prevents rereplication. Mol Cell 2003;11:997-1008.
96. Fung TK, Poon RY. A roller coaster ride with the mitotic cyclins. Semin Cell Dev Biol 2005;16(3):335-42.
97. Machida YJ, Dutta A. The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev 2007;21:184-94.
98. Hsu JY, Reimann JDR, Sørensen CS, Lukas J, Jackson PK. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1. Nat Cell Biol 2002;4:358-66.
99. Zhou F ZL, Wang A, Song B, Gong K, Zhang L, Hu M, Zhang X, Zhao N, Gong Y. The association of GSK3 beta with E2F1 facilitates nerve growth factor-induced neural cell differentiation. J Biol Chem 2008;283:14506-15.
100. García-Alvarez G, Ventura V, Ros O, Aligué R, Gil J, Tauler A. Glycogen synthase kinase-3beta binds to E2F1 and regulates its transcriptional activity. Biochim Biophys Acta 2007;1773:375-82.
101. Iguchi K, Usami Y, Hirano K, Hamatake M, Shibata M, Ishida R. Decreased thymosin beta4 in apoptosis induced by a variety of antitumor drugs. Biochem Pharmacol 1999;57:1105-11.
102. Muller CS, Huff T, Hannappel E. Reduction of thymosin beta4 and actin in HL60 cells during apoptosis is preceded by a decrease of their mRNAs. Mol Cell Biochem 2003;250:179-88.
103. Otto AM, Muller CS, Huff T, Hannappel E. Chemotherapeutic drugs change actin skeleton organization and the expression of beta-thymosins in human breast cancer cells. J Cancer Res Clin Oncol 2002;128:247-56.
104. Chao TC, Chen KJ, Tang MC, Chan LC, Chen PM, Tzeng CH, et al. Thymosin Beta-4 Knockdown in IEC-6 Normal Intestinal Epithelial Cells Induces DNA Re-replication Via Downregulating Emi1. J Cell Physiol 2014.
105. Shin IJ, Ahn YT, Kim Y, Kim JM, An WG. Actin disruption agents induce phosphorylation of histone H2AX in human breast adenocarcinoma MCF-7 cells. Oncol Rep 2011;25:1313-9.
106. Shin IJ, Park BK, Ahn YT, Kim Y, An WG. Actin disruption inhibits hypoxia inducible factor-1alpha expression via inactivity of Mdm2-mediated p70S6K. Mol Med Rep 2010;3:815-9.
107. Ahn YT, Shin IJ, Kim JM, Kim YS, Lee C, Ju SA, et al. Counteracting the activation of pAkt by inhibition of MEK/Erk inhibition reduces actin disruption-mediated apoptosis in PTEN-null PC3M prostate cancer cell lines. Oncol Lett 2013;6:1383-9.
108. Yamada H, Abe T, Li SA, Tago S, Huang P, Watanabe M, et al. N'-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide is a dynamin GTPase inhibitor that suppresses cancer cell migration and invasion by inhibiting actin polymerization. Biochem Biophys Res Commun 2014;443:511-7.
109. Lash LL, Wallar BJ, Turner JD, Vroegop SM, Kilkuskie RE, Kitchen-Goosen SM, et al. Small-molecule intramimics of formin autoinhibition: a new strategy to target the cytoskeletal remodeling machinery in cancer cells. Cancer Res 2013;73:6793-803.
110. Mannherz HG, Hannappel E. The beta-thymosins: intracellular and extracellular activities of a versatile actin binding protein family. Cell Motil Cytoskeleton 2009;66:839-51.
111. Brieger A, Plotz G, Zeuzem S, Trojan J. Thymosin beta 4 expression and nuclear transport are regulated by hMLH1. Biochem Biophys Res Commun 2007;364:731-6
112. Bednarek R, Boncela J, Smolarczyk K, Cierniewska-Cieslak A, Wyroba E, Cierniewski CS. Ku80 as a novel receptor for thymosin β4 that mediates its intracellular activity different from G-actin sequestering. J Biol Chem 2008;283:1534-44.
113. Bennett MR. Reactive oxygen species and death: oxidative DNA damage in atherosclerosis. Circ Res 2001;88:648-50.
114. Hall JR, Kow E, Nevis KR, Lu CK, Luce KS, Zhong Q, et al. Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Mol Biol Cell 2007;18:3340-50.
115. Fernández-Morales B, Pavón L, Calés C. CDC6 expression is regulated by lineage-specific transcription factor GATA1. Cell Cycle 2012;11:3055-66.
116. Zhang K, Sha J, Harter ML. Activation of Cdc6 by MyoD is associated with the expansion of quiescent myogenic satellite cells. J Cell Biol 2010;188:39-48.
117. Tategu M, Nakagawa H, Sasaki K, Yamauchi R, Sekimachi S, Suita Y, et al. Transcriptional regulation of human polo-like kinases and early mitotic inhibitor. J Genet Genomics 2008;35:215-24.
118. Havens CG, Ho A, Yoshioka N, Dowdy SF. Regulation of late G1/S phase transition and APCCdh1 by reactive oxygen species. Mol Cell Biol 2006;26:4701-11.
119. Huff T, Muller CS, Otto AM, Netzker R, Hannappel E. beta-Thymosins, small acidic peptides with multiple functions. Int J Biochem Cell Biol 2001;33:205-20.
120. Choi SY, Noh MR, Kim DK, Sun W, Kim H. Neuroprotective function of thymosin-[beta] and its derivative peptides on the programmed cell death of chick and rat neurons. Biochem Biophys Res Commun 2007;362:587-93.
121. Coyne CB, Bergelson JM. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 2006;124:119-31.
122. Philipson L, Pettersson RF. The coxsackie-adenovirus receptor--a new receptor in the immunoglobulin family involved in cell adhesion. Curr Top Microbiol Immunol 2004;273:87-111.
123. Krasnykh VN, Mikheeva GV, Douglas JT, Curiel DT. Generation of recombinant adenovirus vectors with modified fibers for altering viral tropism. J Virol 1996;70:6839-46.
124. Azab B, Dash R, Das SK, Bhutia SK, Shen XN, Quinn BA, et al. Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the Apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells. J Cell Physiol 2012;227:2145-53.
125. Haisma HJ, Pinedo HM, Rijswijk A, der Meulen-Muileman I, Sosnowski BA, Ying W, et al. Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM. Gene Ther. 1999;6:1469-74.
126. Shashkova EV, Kuppuswamy MN, Wold WS, Doronin K. Anticancer activity of oncolytic adenovirus vector armed with IFN-alpha and ADP is enhanced by pharmacologically controlled expression of TRAIL. Cancer Gene Ther 2008;15:61-72.
127. Zhang Z, Krimmel J, Zhang Z, Hu Z, Seth P. Systemic delivery of a novel liver-detargeted oncolytic adenovirus causes reduced liver toxicity but maintains the antitumor response in a breast cancer bone metastasis model. Hum Gene Ther 2011;22:1137-42.
128. Bhatia S, Menezes ME, Das SK, Emdad L, Dasgupta S, Wang XY, et al. Innovative approaches for enhancing cancer gene therapy. Discov Med 2013;15:309-17.
129. Das SK, Sarkar S, Dash R, Dent P, Wang XY, Sarkar D, et al. Chapter One---Cancer terminator viruses and approaches for enhancing therapeutic outcomes. Adv Cancer Res 2012;115:1-38.
130. Dash R, Azab B, Shen XN, Sokhi UK, Sarkar S, Su ZZ, et al. Developing an effective gene therapy for prostate cancer: New technologies with potential to translate from the laboratory into the clinic. Discov Med 2011;11:46-56.
131. Dash R, Azab B, Quinn BA, Shen X, Wang XY, Das SK, et al. Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc Natl Acad Sci U S A 2011;108:8785-90.
132. Greco A, Di Benedetto A, Howard CM, Kelly S, Nande R, Dementieva Y, et al. Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach. Mol Ther 2010;18:295-306.

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