miR-143 Overexpression Impairs Growth of Human Colon Carcinoma Xenografts in Mice with Induction of Apoptosis and Inhibition of Proliferation

被引:89
作者
Borralho, Pedro M. [1 ]
Simoes, Andre E. S. [1 ]
Gomes, Sofia E. [1 ]
Lima, Raquel T. [2 ,4 ]
Carvalho, Tania [3 ,5 ]
Ferreira, Duarte M. S. [1 ]
Vasconcelos, Maria H. [2 ,6 ]
Castro, Rui E. [1 ]
Rodrigues, Cecilia M. P. [1 ,7 ]
机构
[1] Univ Lisbon, Fac Pharm, Res Inst Med & Pharmaceut Sci iMed UL, P-1699 Lisbon, Portugal
[2] Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Canc Drug Resistance Grp, Oporto, Portugal
[3] Inst Gulbenkian Ciencias, Oeiras, Portugal
[4] Univ Porto CEQUIMED UP, Ctr Med Chem, Oporto, Portugal
[5] Ctr Lisboa, Inst Portugues Oncol Francisco Gentil, Ctr Invest Patobiol Mol, Lisbon, Portugal
[6] Univ Porto, Fac Pharm, Dept Biol Sci, P-4100 Oporto, Portugal
[7] Univ Lisbon, Fac Pharm, Dept Biochem & Human Biol, P-1699 Lisbon, Portugal
来源
PLOS ONE | 2011年 / 6卷 / 08期
关键词
NF-KAPPA-B; MICRORNA EXPRESSION; DOWN-REGULATION; ERK5; CELLS; ACCUMULATION; PROGRESSION; SIGNATURE; TARGETS; AND-145;
D O I
10.1371/journal.pone.0023787
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: MicroRNAs (miRNAs) are aberrantly expressed in human cancer and involved in the (dys) regulation of cell survival, proliferation, differentiation and death. Specifically, miRNA-143 (miR-143) is down-regulated in human colon cancer. In the present study, we evaluated the role of miR-143 overexpression on the growth of human colon carcinoma cells xenografted in nude mice (immunodeficient mouse strain: N:NIH(s) II-nu/nu). Methodology/Principal Findings: HCT116 cells with stable miR-143 overexpression (Over-143) and control (Empty) cells were subcutaneously injected into the flanks of nude mice, and tumor growth was evaluated over time. Tumors arose, 14 days after tumor cell implantation, and the experiment was ended at 40 days after implantation. miR-143 was confirmed to be significantly overexpressed in Over-143 versus Empty xenografts, by TaqMan(R) Real-time PCR (p<0.05). Importantly, Over-143 xenografts displayed slower tumor growth compared to Empty xenografts from 23 until 40 days in vivo (p<0.05), with final volumes of 928+/-338 and 2512+/-387 mm(3), respectively. Evaluation of apoptotic proteins showed that Over-143 versus Empty xenografts displayed reduced Bcl-2 levels, and increased caspase-3 activation and PARP cleavage (p<0.05). In addition, the incidence of apoptotic tumor cells, assessed by TUNEL, was increased in Over-143 versus Empty xenografts (p<0.01). Finally, Over-143 versus Empty xenografts displayed significantly reduced NF-kappa B activation and ERK5 levels and activation (p<0.05), as well as reduced proliferative index, evaluated by Ki-67 immunohistochemistry (p<0.01). Conclusions: Our results suggest that reduced tumor volume in Over-143 versus Empty xenografts may result from increased apoptosis and decreased proliferation induced by miR-143. This reinforces the relevance of miR-143 in colon cancer, indicating an important role in the control of in vivo tumor progression, and suggesting that miR-143 may constitute a putative novel therapeutic tool for colon cancer treatment that warrants further investigation.
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页数:11
相关论文
共 48 条
[1]   Role of anti-oncomirs miR-143 and-145 in human colorectal tumors [J].
Akao, Y. ;
Nakagawa, Y. ;
Hirata, I. ;
Iio, A. ;
Itoh, T. ;
Kojima, K. ;
Nakashima, R. ;
Kitade, Y. ;
Naoe, T. .
CANCER GENE THERAPY, 2010, 17 (06) :398-408
[2]   Downregulation of microRNAs-143 and-145 in B-cell malignancies [J].
Akao, Yukihiro ;
Nakagawa, Yoshihito ;
Kitade, Yukio ;
Kinoshita, Tomohiro ;
Naoe, Tomoki .
CANCER SCIENCE, 2007, 98 (12) :1914-1920
[3]  
Akao Y, 2006, ONCOL REP, V16, P845
[4]   Role of microRNA-143 in Fas-mediated apoptosis in human T-cell leukemia Jurkat cells [J].
Akao, Yukihiro ;
Nakagawa, Yoshihito ;
Iio, Akio ;
Naoe, Tomoki .
LEUKEMIA RESEARCH, 2009, 33 (11) :1530-1538
[5]   NF-κB and apoptosis in colorectal tumourigenesis [J].
Aranha, M. M. ;
Borralho, P. M. ;
Ravasco, P. ;
da Silva, I. B. Moreira ;
Correia, L. ;
Fernandes, A. ;
Camilo, M. E. ;
Rodrigues, C. M. P. .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2007, 37 (05) :416-424
[6]   MicroRNAs: Genomics, biogenesis, mechanism, and function (Reprinted from Cell, vol 116, pg 281-297, 2004) [J].
Bartel, David P. .
CELL, 2007, 131 (04) :11-29
[7]   Inhibition of Fas expression by RNAi modulates 5-fluorouracil-induced apoptosis in HCT116 cells expressing wild-type p53 [J].
Borralho, Pedro M. ;
da Silva, Isabel B. Moreira ;
Aranha, Marcia M. ;
Albuquerque, Cristina ;
Leitao, Carlos Nobre ;
Steer, Clifford J. ;
Rodrigues, Cecilia M. P. .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2007, 1772 (01) :40-47
[8]   MicroRNA-143 reduces viability and increases sensitivity to 5-fluorouracil in HCT116 human colorectal cancer cells [J].
Borralho, Pedro M. ;
Kren, Betsy T. ;
Castro, Rui E. ;
da Silva, Isabel B. Moreira ;
Steer, Clifford J. ;
Rodrigues, Cecilia M. P. .
FEBS JOURNAL, 2009, 276 (22) :6689-6700
[9]   Gene regulation by microRNAs [J].
Carthew, RW .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2006, 16 (02) :203-208
[10]   MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells [J].
Chan, JA ;
Krichevsky, AM ;
Kosik, KS .
CANCER RESEARCH, 2005, 65 (14) :6029-6033