Abstract
Screening of the entire let-7 family of microRNAs (miRNA) by in situ hybridization identified let-7g as the only member, the diminished expression of which was significantly associated with lymph node metastasis and poor survival in breast cancer patients. Abrogation of let-7g expression in otherwise nonmetastatic mammary carcinoma cells elicited rapid metastasis from the orthotopic location, through preferential targets, Grb2-associated binding protein 2 (GAB2) and fibronectin 1 (FN1), and consequent activation of p44/42 mitogen-activated protein kinase (MAPK) and specific matrix metalloproteinases. Treatment with estrogen or epidermal growth factor specifically reduced the expression of mature let-7g through activation of p44/42 MAPK and subsequently stimulated expression of GAB2 and FN1, which, in turn, promoted tumor invasion. We thus identify let-7g as a unique member of the let-7 miRNA family that can serve as a prognostic biomarker in breast cancer and also propose a paradigm used by specific signaling molecules via let-7g to cooperatively promote breast cancer invasion and metastasis. Thus, let-7 family members neither possess equivalent clinicopathologic correlation nor function in breast cancer.
Highlights
Introduction microRNAs are small noncoding RNAs ranging in size by 20 to 25 nucleotides. miRNAs posttranscriptionally repress gene expression mostly by recognizing complementary target sites in the 30-untranslated region (30-UTR) of target mRNAs [1,2,3]. miRNAs are involved in the regulation of a continuous biological processes leading to the acquisition of metastatic potential, such as aberrant adhesion, migration, and invasion, and neoangiogenesis [2,3,4]
To define let-7 miRNA species involved in mammary carcinoma progression, we used digoxigeninlabeled locked nucleic acid (LNA)–miRNA probes to detect abundance of 9 mature let-7 miRNAs in archived breast cancer specimens (n 1⁄4 86) and breast tissue specimens from patients with benign breast diseases (n 1⁄4 21) using in situ hybridization [15, 16]
To define the p44/42 mitogenactivated protein kinase (MAPK) downstream molecules that mediate the effect of let-7g, we focused on the gelatinases matrix metalloproteinase (MMP)-2 and MMP-9, which are regulated by the p44/42 MAPK pathway [30,31,32,33], as well as possessing the capacity to degrade type IV collagen and mediate tumor cell invasion [34, 35]
Summary
MicroRNAs (miRNA) are small noncoding RNAs ranging in size by 20 to 25 nucleotides. miRNAs posttranscriptionally repress gene expression mostly by recognizing complementary target sites in the 30-untranslated region (30-UTR) of target mRNAs [1,2,3]. miRNAs are involved in the regulation of a continuous biological processes leading to the acquisition of metastatic potential, such as aberrant adhesion, migration, and invasion, and neoangiogenesis [2,3,4]. MicroRNAs (miRNA) are small noncoding RNAs ranging in size by 20 to 25 nucleotides. A limited number of miRNAs, either upregulated (such as miR-10b, miR-21, miR-373, and miR-520c) or Authors' Affiliations: 1Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China; 2Department of Pathology, Anhui Medical University, Hefei, Anhui; 3State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin; 4Division of Basic Medicine, Wuhan University College of Medicine; 5Overseas Opening Laboratory of Wuhan University College of Medicine, Wuhan, Hubei, PR China; 6Cancer Sciences Institute of Singapore, Center for Life Sciences, Singapore; and 7Department of Breast Surgery, No 2 Affiliated Hospital, Sun-Yat-Sen University, Guangzhou, PR China. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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