Abstract
BackgroundMicroRNAs (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 FindingsHCT116 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® 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 mm3, 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-κB activation and ERK5 levels and activation (p<0.05), as well as reduced proliferative index, evaluated by Ki-67 immunohistochemistry (p<0.01).ConclusionsOur 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.
Highlights
MicroRNAs are endogenously encoded short non-coding RNAs (20–23 nt), pivotal players in posttranscriptional gene silencing of target mRNAs
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
We evaluated the role of miR-143 overexpression on growth of HCT116 human colon carcinoma cells xenografted in mice, and the putative involvement of apoptosis and proliferation on miR-143 mechanism of action
Summary
MicroRNAs (miRNAs or miRs) are endogenously encoded short non-coding RNAs (20–23 nt), pivotal players in posttranscriptional gene silencing of target mRNAs. MiRNAs are involved in the regulation or fine-tuning of a myriad of crucial biological processes commonly de-regulated in cancer, including cell proliferation, differentiation, cell-cycle and apoptosis, among others [4,5]. It is well known that miRNAs are aberrantly expressed in several forms of human cancer, including colon cancer [6,7,8]. Notwithstanding the fast growth of knowledge on miRNAs, only a small fraction of the molecular signaling circuitry regulated by miRNAs is known in cancer. MicroRNAs (miRNAs) are aberrantly expressed in human cancer and involved in the (dys)regulation of cell survival, proliferation, differentiation and death. 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)
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