Limits...
MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer.

Su J, Liang H, Yao W, Wang N, Zhang S, Yan X, Feng H, Pang W, Wang Y, Wang X, Fu Z, Liu Y, Zhao C, Zhang J, Zhang CY, Zen K, Chen X, Wang Y - PLoS ONE (2014)

Bottom Line: We identified specific target sites for miR-143 and miR-145 (miR-143/145) in the 3'-untranslated region (3'-UTR) of the IGF1R gene.These miRNAs are members of a cluster of miRNAs that have been reported to exhibit tumor suppressor activity.We demonstrated that the repression of IGF1R by miR-143/145 suppressed the proliferation of Caco2 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.

ABSTRACT
Insulin-like growth factor 1 receptor (IGF1R) is a transmembrane receptor that is activated by insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors and plays an important role in colorectal cancer etiology and progression. In this study, we used bioinformatic analyses to search for miRNAs that potentially target IGF1R. We identified specific target sites for miR-143 and miR-145 (miR-143/145) in the 3'-untranslated region (3'-UTR) of the IGF1R gene. These miRNAs are members of a cluster of miRNAs that have been reported to exhibit tumor suppressor activity. Consistent with the bioinformatic analyses, we identified an inverse correlation between miR-143/145 levels and IGF1R protein levels in colorectal cancer tissues. By overexpressing miR-143/145 in Caco2, HT29 and SW480 colorectal cancer cells, we experimentally validated that miR-143/145 directly recognizes the 3'-UTR of the IGF1R transcript and regulates IGF1R expression. Furthermore, the biological consequences of the targeting of IGF1R by miR-143/145 were examined by cell proliferation assays in vitro. We demonstrated that the repression of IGF1R by miR-143/145 suppressed the proliferation of Caco2 cells. Taken together, our findings provide evidence for a role of the miR-143/145 cluster as a tumor suppressor in colorectal cancer through the inhibition of IGF1R translation.

Show MeSH

Related in: MedlinePlus

Identification of an inverse correlation between miR-143/145 levels and IGF1R protein levels in human colorectal cancer tissues.(A) Schematic description of the hypothetical duplexes formed by the interactions between the binding sites in the IGF1R 3′-UTR (top) and miR-143/145 (bottom). The predicted free energy value of each hybrid is indicated. The seed recognition sites are denoted, and all nucleotides in these regions are highly conserved across several species, including human, mouse and rat. (B) Quantitative RT-PCR analysis of miR-143 and miR-145 levels in six pairs of colorectal cancer tissue (C) and noncancerous tissue (P) samples. (C and D) Western blot analysis of IGF1R protein levels in six pairs of C and P samples. C: representative image; D: quantitative analysis. *P<0.05; **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4256231&req=5

pone-0114420-g001: Identification of an inverse correlation between miR-143/145 levels and IGF1R protein levels in human colorectal cancer tissues.(A) Schematic description of the hypothetical duplexes formed by the interactions between the binding sites in the IGF1R 3′-UTR (top) and miR-143/145 (bottom). The predicted free energy value of each hybrid is indicated. The seed recognition sites are denoted, and all nucleotides in these regions are highly conserved across several species, including human, mouse and rat. (B) Quantitative RT-PCR analysis of miR-143 and miR-145 levels in six pairs of colorectal cancer tissue (C) and noncancerous tissue (P) samples. (C and D) Western blot analysis of IGF1R protein levels in six pairs of C and P samples. C: representative image; D: quantitative analysis. *P<0.05; **P<0.01.

Mentions: Three computational algorithms, including TargetScan [24] and RNAhydrid [25], were used in combination to identify potential miRNAs that target IGF1R. All three algorithms predicted miR-143 and miR-145 as regulators of IGF1R. The predicted interactions between miR-143/145 and the target sites within the 3′-UTR of IGF1R are illustrated in Figure 1A. One predicted hybridization was observed between both miR-143 and miR-145 and the 3′-UTR of IGF1R. Although the two target sites within the 3′-UTR of IGF1R were near one another, the sites were non-overlapping. There was perfect complementarity between the seed region (the core sequence that encompasses the first 2–8 bases of the mature miRNA) and the cognate targets. The minimum free energy values of the hybridizations between miR-143 and IGF1R and between miR-145 and IGF1R were –19.8 and –24.8 kcal/mol, respectively, which are well within the range of genuine miRNA-target pairs. Furthermore, the miR-143/145 binding sequences in the IGF1R 3′-UTR were highly conserved across species. Thus, miR-143 and miR-145 were selected as candidates for further experimental verification.


MiR-143 and MiR-145 regulate IGF1R to suppress cell proliferation in colorectal cancer.

Su J, Liang H, Yao W, Wang N, Zhang S, Yan X, Feng H, Pang W, Wang Y, Wang X, Fu Z, Liu Y, Zhao C, Zhang J, Zhang CY, Zen K, Chen X, Wang Y - PLoS ONE (2014)

Identification of an inverse correlation between miR-143/145 levels and IGF1R protein levels in human colorectal cancer tissues.(A) Schematic description of the hypothetical duplexes formed by the interactions between the binding sites in the IGF1R 3′-UTR (top) and miR-143/145 (bottom). The predicted free energy value of each hybrid is indicated. The seed recognition sites are denoted, and all nucleotides in these regions are highly conserved across several species, including human, mouse and rat. (B) Quantitative RT-PCR analysis of miR-143 and miR-145 levels in six pairs of colorectal cancer tissue (C) and noncancerous tissue (P) samples. (C and D) Western blot analysis of IGF1R protein levels in six pairs of C and P samples. C: representative image; D: quantitative analysis. *P<0.05; **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256231&req=5

pone-0114420-g001: Identification of an inverse correlation between miR-143/145 levels and IGF1R protein levels in human colorectal cancer tissues.(A) Schematic description of the hypothetical duplexes formed by the interactions between the binding sites in the IGF1R 3′-UTR (top) and miR-143/145 (bottom). The predicted free energy value of each hybrid is indicated. The seed recognition sites are denoted, and all nucleotides in these regions are highly conserved across several species, including human, mouse and rat. (B) Quantitative RT-PCR analysis of miR-143 and miR-145 levels in six pairs of colorectal cancer tissue (C) and noncancerous tissue (P) samples. (C and D) Western blot analysis of IGF1R protein levels in six pairs of C and P samples. C: representative image; D: quantitative analysis. *P<0.05; **P<0.01.
Mentions: Three computational algorithms, including TargetScan [24] and RNAhydrid [25], were used in combination to identify potential miRNAs that target IGF1R. All three algorithms predicted miR-143 and miR-145 as regulators of IGF1R. The predicted interactions between miR-143/145 and the target sites within the 3′-UTR of IGF1R are illustrated in Figure 1A. One predicted hybridization was observed between both miR-143 and miR-145 and the 3′-UTR of IGF1R. Although the two target sites within the 3′-UTR of IGF1R were near one another, the sites were non-overlapping. There was perfect complementarity between the seed region (the core sequence that encompasses the first 2–8 bases of the mature miRNA) and the cognate targets. The minimum free energy values of the hybridizations between miR-143 and IGF1R and between miR-145 and IGF1R were –19.8 and –24.8 kcal/mol, respectively, which are well within the range of genuine miRNA-target pairs. Furthermore, the miR-143/145 binding sequences in the IGF1R 3′-UTR were highly conserved across species. Thus, miR-143 and miR-145 were selected as candidates for further experimental verification.

Bottom Line: We identified specific target sites for miR-143 and miR-145 (miR-143/145) in the 3'-untranslated region (3'-UTR) of the IGF1R gene.These miRNAs are members of a cluster of miRNAs that have been reported to exhibit tumor suppressor activity.We demonstrated that the repression of IGF1R by miR-143/145 suppressed the proliferation of Caco2 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.

ABSTRACT
Insulin-like growth factor 1 receptor (IGF1R) is a transmembrane receptor that is activated by insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors and plays an important role in colorectal cancer etiology and progression. In this study, we used bioinformatic analyses to search for miRNAs that potentially target IGF1R. We identified specific target sites for miR-143 and miR-145 (miR-143/145) in the 3'-untranslated region (3'-UTR) of the IGF1R gene. These miRNAs are members of a cluster of miRNAs that have been reported to exhibit tumor suppressor activity. Consistent with the bioinformatic analyses, we identified an inverse correlation between miR-143/145 levels and IGF1R protein levels in colorectal cancer tissues. By overexpressing miR-143/145 in Caco2, HT29 and SW480 colorectal cancer cells, we experimentally validated that miR-143/145 directly recognizes the 3'-UTR of the IGF1R transcript and regulates IGF1R expression. Furthermore, the biological consequences of the targeting of IGF1R by miR-143/145 were examined by cell proliferation assays in vitro. We demonstrated that the repression of IGF1R by miR-143/145 suppressed the proliferation of Caco2 cells. Taken together, our findings provide evidence for a role of the miR-143/145 cluster as a tumor suppressor in colorectal cancer through the inhibition of IGF1R translation.

Show MeSH
Related in: MedlinePlus