MicroRNA miR-24 Enhances Tumor Invasion and Metastasis by Targeting PTPN9 and PTPRF to Promote EGF Signaling

Abstract

SummaryMicroRNAs are known to play regulatory roles in gene expression associated with cancer development. We analyzed levels of the microRNA miR-24 in patients with breast carcinoma and found that miR-24 was higher in breast carcinoma samples than in benign breast tissues. We generated constructs expressing miR-24 and studied its functions using both in vitro and in vivo techniques. We found that the ectopic expression of miR-24 promoted breast cancer cell invasion and migration. In vivo experiments in mice indicated that the expression of miR-24 enhanced tumor growth, invasion into local tissues, metastasis to lung tissues and decreased overall mouse survival. In the miR-24-expressing cells and tumors, EGFR was highly phosphorylated, whereas expression of the phosphatases tyrosine-protein phosphatase non-receptor type 9 (PTPN9) and receptor-type tyrosine-protein phosphatase F (PTPRF) were repressed. We confirmed that miR-24 could directly target both PTPN9 and PTPRF. Consistent with this, we found that the levels of phosphorylated epidermal growth factor receptor (pEGFR) were higher whereas the levels of PTPN9 and PTPRF were lower in the patients with metastatic breast carcinoma. Ectopic expression of PTPN9 and PTPRF decreased pEGFR levels, cell invasion, migration and tumor metastasis. Furthermore, we found that MMP2, MMP11, pErk, and ADAM15 were upregulated, whereas TIMP2 was downregulated; all of which supported the roles of miR-24 in tumor invasion and metastasis. Our results suggest that miR-24 plays a key role in breast cancer invasion and metastasis. miR-24 could potentially be a target for cancer intervention.

Reciprocal regulation of miRNAs and piRNAs in embryonic development

“…cDNA synthesis was performed with miScript Reverse Transcription Kit (Qiagen), using 1 μg RNA as template as described. 34 PCRs were performed with miScriptSYBR GreenPCR Kit (Qiagen) using 1 μl cDNA as templates. Mouse U6 was used as a real-time PCR control.…”

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

“…miR-24: miR-24 was identified as a miR with increased expression in BC tissue compared to benign breast tissue (66). Ectopic expression promotes invasion and migration of the BC cells 4T1 and MT-1 (66).…”

“…Ectopic expression promotes invasion and migration of the BC cells 4T1 and MT-1 (66). miR-24 transfected MT-1 cells promote increased tumor growth and formation of lung metastases after tail vein injection (66).…”

“…Ectopic expression promotes invasion and migration of the BC cells 4T1 and MT-1 (66). miR-24 transfected MT-1 cells promote increased tumor growth and formation of lung metastases after tail vein injection (66). Protein tyrosine phosphatase non-receptor 9 (PTPN9) and protein tyrosine phosphatase receptor F (PTPRF) (67,68) have been identifed as direct targets of miR-24 (66) resulting in up-regulation of phosphorylated epidermal growth factor receptor (pEGFR).…”

“…Protein tyrosine phosphatase non-receptor 9 (PTPN9) and protein tyrosine phosphatase receptor F (PTPRF) (67,68) have been identifed as direct targets of miR-24 (66) resulting in up-regulation of phosphorylated epidermal growth factor receptor (pEGFR). miR-24 promotes the increased expression of downstream effectors such as MMP-2, MMP-11 and a disintegrin and metalloprotease 15 (ADAM15), mediators of cell invasion, migration and metastasis (66). pEGFR was found to be more abundant in BC tissues than in normal breast tissue and immuno-histochemistry (IHC) revealed that PTPN9 and PTPRF gave rise to much weaker signals in tumor tissues than in normal breast tissue (66).…”