miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans
Pai-Sheng Chen, … , Pan-Chyr Yang, Min-Liang Kuo
Pai-Sheng Chen, … , Pan-Chyr Yang, Min-Liang Kuo
Published August 15, 2011
Citation Information: J Clin Invest. 2011;121(9):3442-3455. https://doi.org/10.1172/JCI45390.
View: Text | PDF | Corrigendum
Research Article

miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans

Abstract

MicroRNAs (miRNAs) influence many biological processes, including cancer. They do so by posttranscriptionally repressing target mRNAs to which they have sequence complementarity. Although it has been postulated that miRNAs can regulate other miRNAs, this has never been shown experimentally to our knowledge. Here, we demonstrate that miR-107 negatively regulates the tumor suppressor miRNA let-7 via a direct interaction. miR-107 was found to be highly expressed in malignant tissue from patients with advanced breast cancer, and its expression was inversely correlated with let-7 expression in tumors and in cancer cell lines. Ectopic expression of miR-107 in human cancer cell lines led to destabilization of mature let-7, increased expression of let-7 targets, and increased malignant phenotypes. In contrast, depletion of endogenous miR-107 dramatically increased the stability of mature let-7 and led to downregulation of let-7 targets. Accordingly, miR-107 expression increased the tumorigenic and metastatic potential of a human breast cancer cell line in mice via inhibition of let-7 and upregulation of let-7 targets. By mutating individual sites within miR-107 and let-7, we found that miR-107 directly interacts with let-7 and that the internal loop of the let-7/miR-107 duplex is critical for repression of let-7 expression. Altogether, we have identified an oncogenic role for miR-107 and provide evidence of a transregulational interaction among miRNAs in human cancer development.

Authors

Pai-Sheng Chen, Jen-Liang Su, Shih-Ting Cha, Woan-Yuh Tarn, Ming-Yang Wang, Hsing-Chih Hsu, Ming-Tsan Lin, Chia-Yu Chu, Kuo-Tai Hua, Chiung-Nien Chen, Tsang-Chih Kuo, King-Jen Chang, Michael Hsiao, Yi-Wen Chang, Jin-Shing Chen, Pan-Chyr Yang, Min-Liang Kuo

×

Figure 3

miR-107 promotes let-7 degradation and antagonizes let-7–suppressed AIG in human cancer cell lines.

Options: View larger image (or click on image) Download as PowerPoint
miR-107 promotes let-7 degradation and antagonizes let-7–suppressed AIG ...
(A) Expression of miR-107 and let-7 in human cancer cell lines. Total RNA (20 μg) was isolated and assayed by Northern blotting with specific probes for let-7a and miR-107. (B) Effect of miR-107 on let-7a expression. Total RNA was isolated from cells transfected with miR-107 antagomir and then assayed by qRT-PCR. U6 was used as an internal control, and the fold change of the let-7a level was normalized with the paired untreated group. (C) An miR-107 antagomir was introduced into H1299 cells in the presence of 1 μg/ml of actinomycin D. Total RNA was isolated and assayed by qRT-PCR for mature let-7a. (D) miR-107 was introduced into A549 cells in the presence of 1 μg/ml of actinomycin D. Total RNA was isolated and mature let-7a was assayed for by qRT-PCR. (E) Forced expression of miR-107 induced the expression of both Ras and HMGA2. H1299 cells were transfected with indicated miRNAs, and Ras and HMGA2 levels were assayed by Western blotting. (F) Dual-luciferase assays were performed to determine the lin-41 expression in the presence of miR-107, let-7a mimics, or antagomirs. (G and H) MiRNA mimics or antagomirs were introduced into MCF-7 or MDA231 cells and effects of miR-107 on colony formation were determined. The indicated miRNAs or antagomirs were transfected into MCF-7 (G, H), MDA-MB-231 (G), and H1299 (H) cells. Soft agar assays were performed over 14 days. *P < 0.05; **P < 0.01; ***P < 0.001. Data are presented as mean ± SD.