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系統識別號 U0026-2512201001304400
論文名稱(中文) Sprouty2蛋白在大腸癌的臨床意義及表皮生長因子阻斷治療的相關性
論文名稱(英文) The Role of Sprouty2 Protein in Colon Cancer-Clinical implication and Association with Epidermal Growth Factor Receptor Blockage Therapy
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 99
學期 1
出版年 99
研究生(中文) 馮盈勳
研究生(英文) Yin-Hsun Feng
學號 s9892102
學位類別 博士
語文別 英文
論文頁數 87頁
口試委員 指導教授-蕭璦莉
指導教授-李政昌
口試委員-曹朝榮
口試委員-張建國
口試委員-呂佩融
口試委員-呂增宏
中文關鍵字 Sprouty2  微型核糖核酸  大腸癌 
英文關鍵字 Sprouty2  microRNA-21  colon cancer 
學科別分類
中文摘要 Sprouty蛋白是許多生長因子受器途徑調控的重要抑制因子,其中Sprouty2已知是在許多人類癌症會有減少表現的情況,在癌症病人腫瘤組織中的微型核糖核酸-21的過度表現,目前發現有較短的存活期以及較差的輔助化學治療效果,但是Sprouty2蛋白在大腸癌的意義目前尚未明瞭。我們首先收集大腸癌病人的腫瘤及正常上皮配對的檢體,利用定量PCR分析Sprouty2 mRNA和微型核糖核酸-21的表現,發現Sprouty2 mRNA在晚期大腸癌的表現量有明顯降低的現象,而Sprouty2 mRNA和微型核糖核酸-21表現量上呈現負相關的關係。我們再利用大腸癌的細胞株研究發現,當Sprouty2蛋白表現時會抑制癌細胞的生長和移行,在訊號傳導上,會增加PTEN的表現但另一方面會減弱Akt和MAPK的磷酸化。進一步在小鼠的實驗中,Sprouty2會減慢腫瘤生長的速度及降低腫瘤發生的機率,由上述的結論證實Sprouty2在大腸癌具有抑制癌症的功能。
再者,我們探討Sprouty2是否可能影響大腸癌臨床治療的考量。Sprouty2研究發現會經由結合c-CBL來抑制蛋白質的分解,進而增加表皮生長因子受器的表現,gefitinib是一種表皮生長因子受器的酪氨酸磷酸脢抑制劑,Sprouty2是否會影響到大腸癌的gefitinib治療目前尚未明朗。首先我們先利用大腸癌的細胞株檢測發現Sprouty2表現量和gefitinib藥物敏感度相關,當在大腸癌HCT116細胞過度表現Sprouty2蛋白,會使得gefitinib的藥物敏感度增加,而在HT29細胞降低Sprouty2表現時,則會減低對gefitinib的藥物敏感性,當Sproyu2增加表現時,磷酸化和全部的表皮生長因子受器都增加了,同時PTEN蛋白也上升了。當使用表皮生長因子受器的單株抗體cetuximab,來抑制表皮生長因子受器的活化,會消除Sporuty2對gefitinib藥物敏感度的影響。至於抑制PTEN或K-ras的表現則無法改變Sprouty2對gefitinib的影響。其次使用裸鼠的動物實驗發現,HCT116細胞具有K-ras突變型的細胞株,當轉殖增加Sprouty2表現時,會增加gefitinib對裸鼠腫瘤的治療效果。由這部份的結果證實在大腸癌使用拮抗表皮生長因子治療策略,Sprouty2是具有相當潛力來預測治療效果的生物標記,如果能進一步分析臨床相關資料,將有助Sprouty2在未來癌症治療的重要性。
英文摘要 Sprouty protein is a novel feedback regulator involved in downstream inactivation of several growth factor receptor pathways. Sprouty2 (Spry2) protein was shown to be downregulated in human cancers. High levels of microRNA-21 (miRNA-21) expression have been associated with poor survival and poor response to adjuvant chemotherapy in cancer patients. But the effect of Spry2 in human colon cancer remained unknown. Paired tumor and normal mucosa samples from patients were examined for their expression of Spry2 mRNA and miRNA-21 by real-time quantitative RT-PCR analysis. Our results show that Spry2 was downregulated in human colon cancer, and its expression levels were lower in advanced-stage tumors than in early-stage tumors. There was a negative correlation between the expression levels of Spry2 and miRNA-21. Furthermore, overexpression of Spry2 suppressed the growth and migration of colon cancer cells with a concomitant increase in PTEN expression and reduction of Akt and MAPK phosphorylation. Spry2 inhibited the growth and tumorigenesis of colon cancer cells in vivo. Thus, Spry2 functions as a tumor suppressor in colon cancer.
Next, we explored the implication of Spry2 in therapeutic strategy of colon cancer. Sprt2 is known to increase the expression of epidermal growth factor receptors by conjugating with c-CBL to decrease protein degradation. The effect of Spry2 on the treatment of gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR), with regards to colon cancer is still unclear. The expressions of Spry2 protein were correlated with the sensitivity of gefitinib in six colon cancer cell lines. The sensitivity of gefitinib increased after over-expression of Spry2 in HCT116 cells and decreased after the knock-down of Spry2 in HT29 cells. Both phosphorylated and total epidermal growth factor receptors increased after enhanced expression of Spry2 in concordance with the increase of PTEN. Inhibition of EGFR by cetuximab, a monoclonal antibody blocking EGFR, abrogated the hypersensitivity of gefitinib induced by Spry2 expression. Knowndown of PTEN and K-ras failed to diminish the effect of Spry2 on gefitinib sensitivity. HCT116 cells which harbor codon 13 mutation of K-ras increase the response to gefitinib after ectopic expression of Spry2 in vitro and in xenografts of nude mice. These results suggest that Spry2 is a potential biomarker in predicting the response in anti-epidermal growth factor receptor treatment in colon cancer, and is mandatory to conduct clinical researches to incorporate Spry2 into the network of cancer treatment.
論文目次 考試合格證書 2
Contents 3
中文摘要 4
英文摘要 6
Acknowledgement 8
Figure contents 9
Introduction 12
Material and Methods 17
Results 29
Discussion 39
Summary 48
Reference 49
Figures 64
簡歷 84
博士研習發表期刊論文 85
參考文獻 Asangani, I.A., Rasheed, S.A., Nikolova, D.A., Leupold, J.H., Colburn, N.H., Post, S., Allgayer, H., MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27, 2128-2136. 2008.

Ciardiello, F., Caputo, R., Bianco, R., Damiano, V., Pomatico, G., De Placido, S., Bianco, A.R., Tortora, G., Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6, 2053-2063. 2000.

Cummins, J.M., He, Y., Leary, R.J., Pagliarini, R., Diaz, L.A., Jr., Sjoblom, T., Barad, O., Bentwich, Z., Szafranska, A.E., Labourier, E., Raymond, C.K., Roberts, B.S., Juhl, H., Kinzler, K.W., Vogelstein, B., Velculescu, V.E., The colorectal microRNAome. Proc Natl Acad Sci U S A 103, 3687-3692. 2006.

Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., Verslype, C., Chau, I., Van Cutsem, E., Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351, 337-345. 2004.

Ding, W., Warburton, D., Down-regulation of Sprouty2 via p38 MAPK plays a key role in the induction of cellular apoptosis by tumor necrosis factor-alpha. Biochem Biophys Res Commun 375, 460-464. 2008.

Douillard, J.Y., Shepherd, F.A., Hirsh, V., Mok, T., Socinski, M.A., Gervais, R., Liao, M.L., Bischoff, H., Reck, M., Sellers, M.V., Watkins, C.L., Speake, G., Armour, A.A., Kim, E.S., Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 28, 744-752.

Edwin, F., Singh, R., Endersby, R., Baker, S.J., Patel, T.B., The tumor suppressor PTEN is necessary for human Sprouty 2-mediated inhibition of cell proliferation. J Biol Chem 281, 4816-4822. 2006.

Egan, J.E., Hall, A.B., Yatsula, B.A., Bar-Sagi, D., The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci U S A 99, 6041-6046. 2002.

Fong, C.W., Chua, M.S., McKie, A.B., Ling, S.H., Mason, V., Li, R., Yusoff, P., Lo, T.L., Leung, H.Y., So, S.K., Guy, G.R., Sprouty 2, an inhibitor of mitogen-activated protein kinase signaling, is down-regulated in hepatocellular carcinoma. Cancer Res 66, 2048-2058. 2006.

Frank, M.J., Dawson, D.W., Bensinger, S.J., Hong, J.S., Knosp, W.M., Xu, L., Balatoni, C.E., Allen, E.L., Shen, R.R., Bar-Sagi, D., Martin, G.R., Teitell, M.A., Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas. Blood 113, 2478-2487. 2009.

Fritzsche, S., Kenzelmann, M., Hoffmann, M.J., Muller, M., Engers, R., Grone, H.J., Schulz, W.A., Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma. Endocr Relat Cancer 13, 839-849. 2006.

Gabriely, G., Wurdinger, T., Kesari, S., Esau, C.C., Burchard, J., Linsley, P.S., Krichevsky, A.M., MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28, 5369-5380. 2008.

Gross, I., Bassit, B., Benezra, M., Licht, J.D., Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J Biol Chem 276, 46460-46468. 2001.

Iqbal, S., Lenz, H.J., Integration of novel agents in the treatment of colorectal cancer. Cancer Chemother Pharmacol 54 Suppl 1, S32-39. 2004.

Ishida, M., Ichihara, M., Mii, S., Jijiwa, M., Asai, N., Enomoto, A., Kato, T., Majima, A., Ping, J., Murakumo, Y., Takahashi, M., Sprouty2 regulates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase. Cancer Sci 98, 815-821. 2007.

Jackman, D.M., Miller, V.A., Cioffredi, L.A., Yeap, B.Y., Janne, P.A., Riely, G.J., Ruiz, M.G., Giaccone, G., Sequist, L.V., Johnson, B.E., Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res 15, 5267-5273. 2009.

Kim, H.J., Bar-Sagi, D., Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 5, 441-450. 2004.

Kokubo, Y., Gemma, A., Noro, R., Seike, M., Kataoka, K., Matsuda, K., Okano, T., Minegishi, Y., Yoshimura, A., Shibuya, M., Kudoh, S., Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA). Br J Cancer 92, 1711-1719. 2005.

Krichevsky, A.M., Gabriely, G., miR-21: a small multi-faceted RNA. J Cell Mol Med 13, 39-53. 2009.

Laronga, C., Yang, H.Y., Neal, C., Lee, M.H., Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression. J Biol Chem 275, 23106-23112. 2000.

Laurent-Puig, P., Cayre, A., Manceau, G., Buc, E., Bachet, J.B., Lecomte, T., Rougier, P., Lievre, A., Landi, B., Boige, V., Ducreux, M., Ychou, M., Bibeau, F., Bouche, O., Reid, J., Stone, S., Penault-Llorca, F., Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27, 5924-5930. 2009.

Lee, C.C., Putnam, A.J., Miranti, C.K., Gustafson, M., Wang, L.M., Vande Woude, G.F., Gao, C.F., Overexpression of sprouty 2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis. Oncogene 23, 5193-5202. 2004.

Lee, M.H., Reynisdottir, I., Massague, J., Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 9, 639-649. 1995.

Lito, P., Mets, B.D., Appledorn, D.M., Maher, V.M., McCormick, J.J., Sprouty 2 regulates DNA damage-induced apoptosis in Ras-transformed human fibroblasts. J Biol Chem 284, 848-854. 2009.

Lito, P., Mets, B.D., Kleff, S., O'Reilly, S., Maher, V.M., McCormick, J.J., Evidence that sprouty 2 is necessary for sarcoma formation by HRAS oncogene transformed human fibroblasts. J Biol Chem 283, 2002-9. 2008.

Lo, T.L., Yusoff, P., Fong, C.W., Guo, K., McCaw, B.J., Phillips, W.A., Yang, H., Wong, E.S., Leong, H.F., Zeng, Q., Putti, T.C., Guy, G.R., The ras/mitogen-activated protein kinase pathway inhibitor and likely tumor suppressor proteins, sprouty 1 and sprouty 2 are deregulated in breast cancer. Cancer Res 64, 6127-6136. 2004.

Loupakis, F., Pollina, L., Stasi, I., Ruzzo, A., Scartozzi, M., Santini, D., Masi, G., Graziano, F., Cremolini, C., Rulli, E., Canestrari, E., Funel, N., Schiavon, G., Petrini, I., Magnani, M., Tonini, G., Campani, D., Floriani, I., Cascinu, S., Falcone, A., PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 27, 2622-2629. 2009.

Lynch, T.J., Bell, D.W., Sordella, R., Gurubhagavatula, S., Okimoto, R.A., Brannigan, B.W., Harris, P.L., Haserlat, S.M., Supko, J.G., Haluska, F.G., Louis, D.N., Christiani, D.C., Settleman, J., Haber, D.A., Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350, 2129-2139. 2004.

Mackenzie, M.J., Hirte, H.W., Glenwood, G., Jean, M., Goel, R., Major, P.P., Miller, W.H., Jr., Panasci, L., Lorimer, I.A., Batist, G., Matthews, S., Douglas, L., Seymour, L., A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer. Invest New Drugs 23, 165-170. 2005.

McKie, A.B., Douglas, D.A., Olijslagers, S., Graham, J., Omar, M.M., Heer, R., Gnanapragasam, V.J., Robson, C.N., Leung, H.Y., Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer. Oncogene 24, 2166-2174. 2005.

Mendelsohn, J., Baselga, J., Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21, 2787-2799. 2003.

Meng, F., Henson, R., Wehbe-Janek, H., Ghoshal, K., Jacob, S.T., Patel, T., MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133, 647-658. 2007.

Miyoshi, K., Wakioka, T., Nishinakamura, H., Kamio, M., Yang, L., Inoue, M., Hasegawa, M., Yonemitsu, Y., Komiya, S., Yoshimura, A., The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization. Oncogene 23, 5567-5576. 2004.

Mok, T.S., Wu, Y.L., Thongprasert, S., Yang, C.H., Chu, D.T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., Nishiwaki, Y., Ohe, Y., Yang, J.J., Chewaskulyong, B., Jiang, H., Duffield, E.L., Watkins, C.L., Armour, A.A., Fukuoka, M., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361, 947-957. 2009.

Nagahara, H., Mimori, K., Ohta, M., Utsunomiya, T., Inoue, H., Barnard, G.F., Ohira, M., Hirakawa, K., Mori, M., Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin Cancer Res 11, 1368-1371. 2005.

Noro, R., Gemma, A., Miyanaga, A., Kosaihira, S., Minegishi, Y., Nara, M., Kokubo, Y., Seike, M., Kataoka, K., Matsuda, K., Okano, T., Yoshimura, A., Kudoh, S., PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Int J Oncol 31, 1157-1163. 2007.

Paez, J.G., Janne, P.A., Lee, J.C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F.J., Lindeman, N., Boggon, T.J., Naoki, K., Sasaki, H., Fujii, Y., Eck, M.J., Sellers, W.R., Johnson, B.E., Meyerson, M., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497-1500. 2004.

Poppleton, H.M., Edwin, F., Jaggar, L., Ray, R., Johnson, L.R., Patel, T.B., Sprouty regulates cell migration by inhibiting the activation of Rac1 GTPase. Biochem Biophys Res Commun 323, 98-103. 2004.

Salmon P, T.D., 2007. Production and titration of lentiviral vectors.
Salomon, D.S., Brandt, R., Ciardiello, F., Normanno, N., Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19, 183-232. 1995.

Sayed, D., Rane, S., Lypowy, J., He, M., Chen, I.Y., Vashistha, H., Yan, L., Malhotra, A., Vatner, D., Abdellatif, M., MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol Biol Cell 19, 3272-3282. 2008.

Schetter, A.J., Leung, S.Y., Sohn, J.J., Zanetti, K.A., Bowman, E.D., Yanaihara, N., Yuen, S.T., Chan, T.L., Kwong, D.L., Au, G.K., Liu, C.G., Calin, G.A., Croce, C.M., Harris, C.C., MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. Jama 299, 425-436. 2008.

Shaw, A.T., Meissner, A., Dowdle, J.A., Crowley, D., Magendantz, M., Ouyang, C., Parisi, T., Rajagopal, J., Blank, L.J., Bronson, R.T., Stone, J.R., Tuveson, D.A., Jaenisch, R., Jacks, T., Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis. Genes Dev 21, 694-707. 2007.

Shim, K., Minowada, G., Coling, D.E., Martin, G.R., Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. Dev Cell 8, 553-564. 2005.

Slaby, O., Svoboda, M., Fabian, P., Smerdova, T., Knoflickova, D., Bednarikova, M., Nenutil, R., Vyzula, R., Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 72, 397-402. 2007.

Slaby, O., Svoboda, M., Michalek, J., Vyzula, R., MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer 8, 102. 2009.

Sutterluty, H., Mayer, C.E., Setinek, U., Attems, J., Ovtcharov, S., Mikula, M., Mikulits, W., Micksche, M., Berger, W., Down-regulation of Sprouty2 in non-small cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms. Mol Cancer Res 5, 509-520. 2007.

Taketomi, T., Yoshiga, D., Taniguchi, K., Kobayashi, T., Nonami, A., Kato, R., Sasaki, M., Sasaki, A., Ishibashi, H., Moriyama, M., Nakamura, K., Nishimura, J., Yoshimura, A., Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia. Nat Neurosci 8, 855-857. 2005.

Taniguchi, K., Sasaki, K., Watari, K., Yasukawa, H., Imaizumi, T., Ayada, T., Okamoto, F., Ishizaki, T., Kato, R., Kohno, R., Kimura, H., Sato, Y., Ono, M., Yonemitsu, Y., Yoshimura, A., Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis. PLoS One 4, e5467. 2009.

Tarnawski, A.S., Pai, R., Tanigawa, T., Matysiak-Budnik, T., Ahluwalia, A., PTEN silencing reverses aging-related impairment of angiogenesis in microvascular endothelial cells. Biochem Biophys Res Commun 394, 291-296. 2010.

Tefft, J.D., Lee, M., Smith, S., Leinwand, M., Zhao, J., Bringas, P., Jr., Crowe, D.L., Warburton, D., Conserved function of mSpry-2, a murine homolog of Drosophila sprouty, which negatively modulates respiratory organogenesis. Curr Biol 9, 219-222. 1999.

Tonra, J.R., Deevi, D.S., Corcoran, E., Li, H., Wang, S., Carrick, F.E., Hicklin, D.J., Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin Cancer Res 12, 2197-2207. 2006.

Wang, P., Zou, F., Zhang, X., Li, H., Dulak, A., Tomko, R.J., Jr., Lazo, J.S., Wang, Z., Zhang, L., Yu, J., microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res 69, 8157-8165. 2009.
Wells, A., EGF receptor. Int J Biochem Cell Biol 31, 637-643. 1999.

Yeh, K.T., Yang, M.Y., Liu, T.C., Chen, J.C., Chan, W.L., Lin, S.F., Chang, J.G., Abnormal expression of period 1 (PER1) in endometrial carcinoma. J Pathol 206, 111-120. 2005.

Yigzaw, Y., Cartin, L., Pierre, S., Scholich, K., Patel, T.B., The C terminus of sprouty is important for modulation of cellular migration and proliferation. J Biol Chem 276, 22742-22747. 2001.

Yigzaw, Y., Poppleton, H.M., Sreejayan, N., Hassid, A., Patel, T.B., Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of Sprouty. J Biol Chem 278, 284-288. 2003.

Zhu, C.Q., da Cunha Santos, G., Ding, K., Sakurada, A., Cutz, J.C., Liu, N., Zhang, T., Marrano, P., Whitehead, M., Squire, J.A., Kamel-Reid, S., Seymour, L., Shepherd, F.A., Tsao, M.S., Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 26, 4268-4275. 2008.

Zhu, S., Si, M.L., Wu, H., Mo, Y.Y., MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282, 14328-14336. 2007.
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