Please use this identifier to cite or link to this item:
標題: HLJ1為新的caspase-3受質且其表現量可以促進非小細胞肺癌因UV所引起之細胞凋亡
HLJ1 is a novel caspase-3 substrate and its expression enhances UV-induced apoptosis in non-small cell lung carcinoma
作者: 林聖怡
Lin, Sheng-Yi
關鍵字: heat shock protein;熱休克蛋白;apoptosis;lung cancer;UV irradiation;細胞凋亡;肺癌;紫外線輻射
出版社: 生命科學系所
引用: Akashiba, H., N. Matsuki, et al. (2006). "Calpain activation is required for glutamate-induced p27 down-regulation in cultured cortical neurons." J Neurochem 99(3): 733-44. Akyol, S., C. Gercel-Taylor, et al. (2006). "HSP-10 in ovarian cancer: expression and suppression of T-cell signaling." Gynecol Oncol 101(3): 481-6. Albelda, S. M. (1993). "Role of integrins and other cell adhesion molecules in tumor progression and metastasis." Lab Invest 68(1): 4-17. Aloy, M. T., E. Hadchity, et al. (2008). "Protective role of Hsp27 protein against gamma radiation-induced apoptosis and radiosensitization effects of Hsp27 gene silencing in different human tumor cells." Int J Radiat Oncol Biol Phys 70(2): 543-53. Babizhayev, M. A., G. M. Nikolayev, et al. (2010). "A survey and analysis of the role of molecular chaperone proteins and imidazole-containing dipeptide-based compounds as molecular escorts into the skin during stress, injury, water structuring and other types of cutaneous pathophysiology." Int J Cosmet Sci. Bai, L., S. O. Yoon, et al. (2004). "ZBP-89-induced apoptosis is p53-independent and requires JNK." Cell Death Differ 11(6): 663-73. Banerjea, A., R. M. Feakins, et al. (2005). "Immunogenic hsp-70 is overexpressed in colorectal cancers with high-degree microsatellite instability." Dis Colon Rectum 48(12): 2322-8. Barnes, J. A., D. J. Dix, et al. (2001). "Expression of inducible Hsp70 enhances the proliferation of MCF-7 breast cancer cells and protects against the cytotoxic effects of hyperthermia." Cell Stress Chaperones 6(4): 316-25. Beere, H. M., B. B. Wolf, et al. (2000). "Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome." Nat Cell Biol 2(8): 469-75. Bergink, S., N. G. Jaspers, et al. (2007). "Regulation of UV-induced DNA damage response by ubiquitylation." DNA Repair (Amst) 6(9): 1231-42. Boljesikova, E. and M. Chorvath (2001). "Radiation-induced meningiomas." Neoplasma 48(6): 442-4. Borges, J. C., H. Fischer, et al. (2005). "Low resolution structural study of two human HSP40 chaperones in solution. DJA1 from subfamily A and DJB4 from subfamily B have different quaternary structures." J Biol Chem 280(14): 13671-81. Bork, P., C. Sander, et al. (1992). "A module of the DnaJ heat shock proteins found in malaria parasites." Trends Biochem Sci 17(4): 129. Cai, Z., P. Cloutier, et al. (2006). "Enhanced DNA damage induced by secondary electron emission from a tantalum surface exposed to soft x rays." Radiat Res 165(3): 365-71. Calderwood, S. K., M. A. Khaleque, et al. (2006). "Heat shock proteins in cancer: chaperones of tumorigenesis." Trends Biochem Sci 31(3): 164-72. Chang, E. J., Y. S. Im, et al. (2008). "The role of nerve growth factor in hyperosmolar stress induced apoptosis." J Cell Physiol 216(1): 69-77. Chen, J. J., K. Peck, et al. (2001). "Global analysis of gene expression in invasion by a lung cancer model." Cancer Res 61(13): 5223-30. Chien, C. M., S. Y. Chang, et al. (2010). "Taiwan cobra cardiotoxin III inhibits Src kinase leading to apoptosis and cell cycle arrest of oral squamous cell carcinoma Ca9-22 cells." Toxicon. Cho, J. W., J. C. Park, et al. (2001). "The levels of MDM2 protein are decreased by a proteasome-mediated proteolysis prior to caspase-3-dependent pRb and PARP cleavages." J Korean Med Sci 16(2): 135-9. Chu, Y. W., P. C. Yang, et al. (1997). "Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line." Am J Respir Cell Mol Biol 17(3): 353-60. Chung, J., A. K. Nguyen, et al. (2008). "HSP72 protects against obesity-induced insulin resistance." Proc Natl Acad Sci U S A 105(5): 1739-44. Dai, C. and L. Whitesell (2005). "HSP90: a rising star on the horizon of anticancer targets." Future Oncol 1(4): 529-40. Earnshaw, W. C., L. M. Martins, et al. (1999). "Mammalian caspases: structure, activation, substrates, and functions during apoptosis." Annu Rev Biochem 68: 383-424. Eckhart, L., C. Ballaun, et al. (2008). "Identification of novel mammalian caspases reveals an important role of gene loss in shaping the human caspase repertoire." Mol Biol Evol 25(5): 831-41. Flint, M. S., G. Kim, et al. (2009). "Stress hormones mediate drug resistance to paclitaxel in human breast cancer cells through a CDK-1-dependent pathway." Psychoneuroendocrinology 34(10): 1533-41. Fullgrabe, J., N. Hajji, et al. (2010). "Cracking the death code: apoptosis-related histone modifications." Cell Death Differ. Gabai, V. L., A. B. Meriin, et al. (1997). "Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance." J Biol Chem 272(29): 18033-7. Gabai, V. L., A. B. Meriin, et al. (2000). "Suppression of stress kinase JNK is involved in HSP72-mediated protection of myogenic cells from transient energy deprivation. HSP72 alleviates the stewss-induced inhibition of JNK dephosphorylation." J Biol Chem 275(48): 38088-94. Gabai, V. L. and M. Y. Sherman (2002). "Invited review: Interplay between molecular chaperones and signaling pathways in survival of heat shock." J Appl Physiol 92(4): 1743-8. Galea-Lauri, J., A. J. Richardson, et al. (1996). "Increased heat shock protein 90 (hsp90) expression leads to increased apoptosis in the monoblastoid cell line U937 following induction with TNF-alpha and cycloheximide: a possible role in immunopathology." J Immunol 157(9): 4109-18. Garrido, C., E. Schmitt, et al. (2003). "HSP27 and HSP70: potentially oncogenic apoptosis inhibitors." Cell Cycle 2(6): 579-84. Georgopoulos, C. and W. J. Welch (1993). "Role of the major heat shock proteins as molecular chaperones." Annu Rev Cell Biol 9: 601-34. Goedegebuure, P. S., K. Y. Lee, et al. (1994). "Classification of CD4+ T helper cell clones in human melanoma." Cell Immunol 156(1): 170-9. Guilford, P. (1999). "E-cadherin downregulation in cancer: fuel on the fire?" Mol Med Today 5(4): 172-7. Guo, W. and F. G. Giancotti (2004). "Integrin signalling during tumour progression." Nat Rev Mol Cell Biol 5(10): 816-26. Gurley, K. E., R. Moser, et al. (2009). "DNA-PK suppresses a p53-independent apoptotic response to DNA damage." EMBO Rep 10(1): 87-93. Hanahan, D. and R. A. Weinberg (2000). "The hallmarks of cancer." Cell 100(1): 57-70. Hatayama, T., N. Yamagishi, et al. (2001). "Role of hsp105 in protection against stress-induced apoptosis in neuronal PC12 cells." Biochem Biophys Res Commun 288(3): 528-34. Hattori, A., N. Soga, et al. (1992). "Stress platelets in normal individuals and patients with idiopathic thrombocytopenic purpura." Blood Cells 18(2): 281-94. Havasi, A., Z. Li, et al. (2008). "Hsp27 inhibits Bax activation and apoptosis via a phosphatidylinositol 3-kinase-dependent mechanism." J Biol Chem 283(18): 12305-13. Hoe, K. L., M. Won, et al. (1998). "Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from human liver." Biochim Biophys Acta 1383(1): 4-8. Hollander, J. M., K. M. Lin, et al. (2003). "Overexpression of PHGPx and HSP60/10 protects against ischemia/reoxygenation injury." Free Radic Biol Med 35(7): 742-51. Horne, B. E., T. Li, et al. (2010). "The Hsp40 J-domain stimulates Hsp70 when tethered by the client to the ATPase domain." J Biol Chem. Jaattela, M. (1993). "Overexpression of major heat shock protein hsp70 inhibits tumor necrosis factor-induced activation of phospholipase A2." J Immunol 151(8): 4286-94. Jaattela, M., D. Wissing, et al. (1998). "Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases." Embo J 17(21): 6124-34. Jang, Y. H., S. Namkoong, et al. (2008). "Cleavage of phospholipase D1 by caspase promotes apoptosis via modulation of the p53-dependent cell death pathway." Cell Death Differ 15(11): 1782-93. Jolly, C. and R. I. Morimoto (2000). "Role of the heat shock response and molecular chaperones in oncogenesis and cell death." J Natl Cancer Inst 92(19): 1564-72. Kajander, T., J. N. Sachs, et al. (2009). "Electrostatic interactions of Hsp-organizing protein tetratricopeptide domains with Hsp70 and Hsp90: computational analysis and protein engineering." J Biol Chem 284(37): 25364-74. Kalogeridi, M. A., P. Georgolopoulou, et al. (2010). "Long-term follow-up confirms the efficacy of linac radiosurgery for acoustic neuroma and meningioma patients. A single institution''s experience." J Buon 15(1): 68-73. Kamradt, M. C., F. Chen, et al. (2001). "The small heat shock protein alpha B-crystallin negatively regulates cytochrome c- and caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturation." J Biol Chem 276(19): 16059-63. Kaul, A. and W. A. Maltese (2009). "Killing of cancer cells by the photoactivatable protein kinase C inhibitor, calphostin C, involves induction of endoplasmic reticulum stress." Neoplasia 11(9): 823-34. Kelley, W. L. and C. Georgopoulos (1992). "Chaperones and protein folding." Curr Opin Cell Biol 4(6): 984-91. Kim, M. A., H. J. Kim, et al. (2009). "Akt2, but not Akt1, is required for cell survival by inhibiting activation of JNK and p38 after UV irradiation." Oncogene 28(9): 1241-7. King, P. and S. Goodbourn (1998). "STAT1 is inactivated by a caspase." J Biol Chem 273(15): 8699-704. Kodera, Y., K. Isobe, et al. (1994). "Expression of nm23 H-1 RNA levels in human gastric cancer tissues. A negative correlation with nodal metastasis." Cancer 73(2): 259-65. Kroemer, G., B. Dallaporta, et al. (1998). "The mitochondrial death/life regulator in apoptosis and necrosis." Annu Rev Physiol 60: 619-42. Kurokawa, M. and S. Kornbluth (2009). "Caspases and kinases in a death grip." Cell 138(5): 838-54. Kwon, K. B., E. K. Park, et al. (2002). "D4-GDI is cleaved by caspase-3 during daunorubicin-induced apoptosis in HL-60 cells." Exp Mol Med 34(1): 32-7. Landry, J. and J. Huot (1999). "Regulation of actin dynamics by stress-activated protein kinase 2 (SAPK2)-dependent phosphorylation of heat-shock protein of 27 kDa (Hsp27)." Biochem Soc Symp 64: 79-89. Laudanski, K. and D. Wyczechowska (2006). "The distinctive role of small heat shock proteins in oncogenesis." Arch Immunol Ther Exp (Warsz) 54(2): 103-11. Lee, A. Y., Y. Lee, et al. (2008). "HS 1-associated protein X-1 is cleaved by caspase-3 during apoptosis." Mol Cells 25(1): 86-90. Li, C. Y., J. S. Lee, et al. (2000). "Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation." J Biol Chem 275(33): 25665-71. Li, P., D. Nijhawan, et al. (1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade." Cell 91(4): 479-89. Lindquist, S. (1986). "The heat-shock response." Annu Rev Biochem 55: 1151-91. Matsuda, N., H. Teramae, et al. (2010). "Increased death receptor pathway of apoptotic signaling in septic mouse aorta: effect of systemic delivery of FADD siRNA." Am J Physiol Heart Circ Physiol 298(1): H92-101. Mehlen, P., A. Mehlen, et al. (1997). "hsp27 as a switch between differentiation and apoptosis in murine embryonic stem cells." J Biol Chem 272(50): 31657-65. Meldrum, K. K., A. L. Burnett, et al. (2003). "Liposomal delivery of heat shock protein 72 into renal tubular cells blocks nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and subsequent ischemia-induced apoptosis." Circ Res 92(3): 293-9. Meriin, A. B., J. A. Yaglom, et al. (1999). "Protein-damaging stresses activate c-Jun N-terminal kinase via inhibition of its dephosphorylation: a novel pathway controlled by HSP72." Mol Cell Biol 19(4): 2547-55. Meyer, T. and I. R. Hart (1998). "Mechanisms of tumour metastasis." Eur J Cancer 34(2): 214-21. Mikolajczyk, M. and M. A. Nelson (2004). "Regulation of stability of cyclin-dependent kinase CDK11p110 and a caspase-processed form, CDK11p46, by Hsp90." Biochem J 384(Pt 3): 461-7. Mosser, D. D., A. W. Caron, et al. (1997). "Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis." Mol Cell Biol 17(9): 5317-27. Munsterberg, H. (1896). "The X-Rays." Science 3(57): 161-3. Nam, C., K. Doi, et al. (2010). "Etoposide induces G2/M arrest and apoptosis in neural progenitor cells via DNA damage and an ATM/p53-related pathway." Histol Histopathol 25(4): 485-93. Nicholson-Dykstra, S., H. N. Higgs, et al. (2005). "Actin dynamics: growth from dendritic branches." Curr Biol 15(9): R346-57. Ohtsuka, K. and M. Hata (2000). "Molecular chaperone function of mammalian Hsp70 and Hsp40--a review." Int J Hyperthermia 16(3): 231-45. Okamoto, M., S. Koga, et al. (2010). "Differential regulation of caspase-9 by ionizing radiation- and UV-induced apoptotic pathways in thymic cells." Mutat Res 688(1-2): 78-87. Osada, M., S. Imaoka, et al. (2004). "Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein." FEBS Lett 575(1-3): 59-63. Pfeifer, G. P., Y. H. You, et al. (2005). "Mutations induced by ultraviolet light." Mutat Res 571(1-2): 19-31. Poccia, F., P. Piselli, et al. (1992). "Recognition and killing of tumour cells expressing heat shock protein 65 kD with immunotoxins containing saporin." Br J Cancer 66(3): 427-32. Poccia, F., P. Piselli, et al. (1996). "Heat-shock protein expression on the membrane of T cells undergoing apoptosis." Immunology 88(1): 6-12. Prasad, S., V. A. Soldatenkov, et al. (1998). "Identification of keratins 18, 19 and heat-shock protein 90 beta as candidate substrates of proteolysis during ionizing radiation-induced apoptosis of estrogen-receptor negative breast tumor cells." Int J Oncol 13(4): 757-64. Raffray, M. and G. M. Cohen (1997). "Apoptosis and necrosis in toxicology: a continuum or distinct modes of cell death?" Pharmacol Ther 75(3): 153-77. Rafiee, P., Y. Shi, et al. (2003). "Cellular redistribution of inducible Hsp70 protein in the human and rabbit heart in response to the stress of chronic hypoxia: role of protein kinases." J Biol Chem 278(44): 43636-44. Roduit, R. and D. F. Schorderet (2008). "MAP kinase pathways in UV-induced apoptosis of retinal pigment epithelium ARPE19 cells." Apoptosis 13(3): 343-53. Sahai, E. and C. J. Marshall (2002). "RHO-GTPases and cancer." Nat Rev Cancer 2(2): 133-42. Said, T., M. Dutot, et al. (2007). "Cytoprotective effect against UV-induced DNA damage and oxidative stress: role of new biological UV filter." Eur J Pharm Sci 30(3-4): 203-10. Samali, A., J. Cai, et al. (1999). "Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells." Embo J 18(8): 2040-8. Sampson, S. R., E. Bucris, et al. (2010). "Insulin increases H(2)O (2)-induced pancreatic beta cell death." Apoptosis. Sreedhar, A. S. and P. Csermely (2004). "Heat shock proteins in the regulation of apoptosis: new strategies in tumor therapy: a comprehensive review." Pharmacol Ther 101(3): 227-57. Sreenath, T., L. M. Matrisian, et al. (1992). "Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential." Cancer Res 52(18): 4942-7. Steeg, P. S. (2003). "Metastasis suppressors alter the signal transduction of cancer cells." Nat Rev Cancer 3(1): 55-63. Suk, W. A. (2010). "Environmental factors in cancer: radiation." Rev Environ Health 25(1): 57-62. Takai, Y., T. Sasaki, et al. (2001). "Small GTP-binding proteins." Physiol Rev 81(1): 153-208. Taleb, M., C. S. Brandon, et al. (2008). "Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock." J Assoc Res Otolaryngol 9(3): 277-89. Tewari, M., L. T. Quan, et al. (1995). "Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase." Cell 81(5): 801-9. Thornberry, N. A. and Y. Lazebnik (1998). "Caspases: enemies within." Science 281(5381): 1312-6. Thornberry, N. A., T. A. Rano, et al. (1997). "A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis." J Biol Chem 272(29): 17907-11. Timmer, J. C. and G. S. Salvesen (2007). "Caspase substrates." Cell Death Differ 14(1): 66-72. Tournier, C., P. Hess, et al. (2000). "Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway." Science 288(5467): 870-4. Tsai, M. F., C. C. Wang, et al. (2006). "A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma." J Natl Cancer Inst 98(12): 825-38. Tsan, M. F. and B. Gao (2004). "Heat shock protein and innate immunity." Cell Mol Immunol 1(4): 274-9. Udono, H., T. Yamano, et al. (2001). "Generation of cytotoxic T lymphocytes by MHC class I ligands fused to heat shock cognate protein 70." Int Immunol 13(10): 1233-42. Wang, L. and L. Lu (2007). "Pathway-specific effect of caffeine on protection against UV irradiation-induced apoptosis in corneal epithelial cells." Invest Ophthalmol Vis Sci 48(2): 652-60. Wang, L. E., C. Li, et al. (2007). "Repair capacity for UV light induced DNA damage associated with risk of nonmelanoma skin cancer and tumor progression." Clin Cancer Res 13(21): 6532-9. White, E. (1996). "Life, death, and the pursuit of apoptosis." Genes Dev 10(1): 1-15. Wyllie, A. H., J. F. Kerr, et al. (1980). "Cell death: the significance of apoptosis." Int Rev Cytol 68: 251-306. Yamagishi, N., Y. Saito, et al. (2002). "Enhancement of oxidative stress-induced apoptosis by Hsp105alpha in mouse embryonal F9 cells." Eur J Biochem 269(16): 4143-51. Yamane, M., H. Hattori, et al. (1995). "Cotranslocation and colocalization of hsp40 (DnaJ) with hsp70 (DnaK) in mammalian cells." Cell Struct Funct 20(2): 157-66. Yan, F., D. Xia, et al. (2010). "Heat shock cognate protein 70 gene is required for prevention of apoptosis induced by WSSV infection." Arch Virol 155(7): 1077-83. Zhang, T. H., J. F. Liu, et al. (2007). "Ceramide induces apoptosis in human lung adenocarcinoma A549 cells through mitogen-activated protein kinases." Acta Pharmacol Sin 28(3): 439-45.
全世界癌症病患者,肺癌為主要的死亡原因之一。通常癌症是因為細胞的基因變異所引起,包含基因突變、異常的基因調控及致癌基因的過度表現,而腫瘤發生決定於癌細胞的生長與死亡速率。HLJ1屬於熱休克蛋40 (Hsp40)基因家族的一員,是一新的腫瘤抑制基因,與非小細胞肺癌病人的存活率及疾病復發率有顯著相關。然而HLJ1在細胞凋亡的角色至今尚未清楚。近來的研究認為熱休克蛋白可以調控細胞凋亡的發生,在本研究中,首先以不同內源性HLJ1蛋白質表現量的非小細胞肺癌細胞株照射UV輻射,之後以流式細胞儀分析。在七株肺癌細胞株中發現,細胞凋亡的比例與HLJ1的表現呈現正相關性。為了進一步了解HLJ1在細胞凋亡的角色,我們建立HLJ1轉殖細胞株,進行UV輻射的處理,發現在低HLJ1表現的CL1-5細胞株中大量表現HLJ1,會透過增強JNK及caspase-3的活化,最後促進UV輻射所導致的細胞凋亡增加。此外,UV輻射會降低凋亡的細胞內HLJ1表現程度。以廣泛性的caspase抑制劑zVAD-fmk及caspase-3專一性的抑制劑DEVD-fmk事先處理細胞,可以避免細胞受到UV輻射的傷害,減少細胞內HLJ1的下降。進一步的實驗,我們也發現位於HLJ1胺基酸第125-128的位置,具有一非典型的caspase-3辨認切位MEID。被切割的HLJ1會導致更多的細胞凋亡及抑制癌細胞貼附非依賴性的生長。此外,與野生型的HLJ1相比,caspase切位突變的HLJ1會抑制細胞凋亡及促進細胞的生長。由我們的研究結果證明在細胞凋亡的過程中HLJ1為caspase-3的受質,且與細胞凋亡的發生有正相關。

Lung cancer is the most common cause of cancer deaths in the world. Cancer is often caused by gene alterations including genetic mutations, aberration of epigenetic regulation and gene expression. Tumorigenesis is determined by the balance of cell proliferation and death rates. HLJ1, a member of the DnaJ-like Hsp40 family, is a newly identified tumor suppressor protein whose expression is highly associated with relapse and survival in non-small cell lung cancer (NSCLC) patients. However, the role of HLJ1 in apoptosis is still unknown. Recently, it has been demonstrated that heat shock proteins (HSPs) can regulate apoptosis. In this study, NSCLC cell lines with the varying HLJ1 expression levels were subjected to UV irradiation, followed by flow cytometry analysis. Interestingly, cell apoptosis in these cell lines were positively correlated with HLJ1 expression. To understand the role of HLJ1 during cell apoptosis, a human lung adenocarcinoma cell line with enforced expression of HLJ1 was established and exposed to UV irradiation. The enforcing expression of HLJ1 in low HLJ1-expressing cells promoted UV-induced apoptosis through enhancing JNK and caspase-3 activation. Additionally, UV irradiation led to the decrease of HLJ1 predominantly in apoptotic cells. The pan-caspase inhibitor, zVAD-fmk, and caspase-3-specific inhibitor, DEVD-fmk, prevented UV-induced degradation of HLJ1 by the late stage of apoptosis. Furthermore, we found a non-typical caspase-3 cleavage site (MEID) at amino acid 125-128 of HLJ1. Cleavage of HLJ1 led to more apoptosis and inhibited cancer cell anchorage independent growth. Moreover, the caspase-resistant mutant HLJ1 inhibited apoptosis and promoted tumor growth as compared to wild-type HLJ1. Take together, our results suggest that HLJ1 is a novel substrate of caspase-3 and the expression of HLJ1 is positively correlated with apoptosis.
其他識別: U0005-3007201022041600
Appears in Collections:生命科學系所

Show full item record

Google ScholarTM


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.