miR-206 Promotes Cancer Progression by Targeting Full-Length Neurokinin-1 Receptor in Breast Cancer

Abstract

Substance P plays a pivotal role in human cancer development and progression by binding to its receptor, neurokinin-1. Neurokinin-1 has 2 isoforms: full-length neurokinin-1 and truncated neurokinin-1, the latter lacking the cytoplasmic terminal 96-amino acid residues of the full-length protein. We have identified 3 candidate miR-206 target sites within the 3′-untranslated region of the full-length neurokinin-1 gene from bioinformatics database searches. In the present study, real-time quantitative polymerase chain reaction was performed to quantify the expression of miR-206, and the expression of neurokinin-1 and full-length neurokinin-1 was detected by immunohistochemistry in 82 clinical cases of breast cancer and paired adjacent normal tissues. The miR-206 target gene was demonstrated by using a dual-luciferase reporter assay, quantitative real-time polymerase chain reaction, and Western blotting. Transwell migration and invasion, colony formation, and proliferation assays were performed to evaluate the effects of miR-206 expression on various aspects of breast cancer cell behavior in vitro. We showed that miR-206 expression is upregulated in breast cancer cell lines and breast cancer tissues when compared to that in adjacent normal tissues, and full-length neurokinin-1 expression inversely correlates with Tumor Lymph Node Metastasis (TNM) stage and lymph node metastasis. Western blotting, quantitative real-time polymerase chain reaction, and dual-luciferase reporter assays demonstrated that miR-206 binds the 3′-untranslated region of full-length neurokinin-1 messenger RNA, regulating protein expression. We showed that the overexpression of miR-206 promotes breast cancer cell invasion, migration, proliferation, and colony formation in vitro. The present study furthers the current understanding of the mechanisms underlying breast cancer pathogenesis and may be useful for the development of novel targeted therapies.

miR-206 as a prognostic and sensitivity biomarker for platinum chemotherapy in epithelial ovarian cancer

“…The role of miR-206 in cancers is complicated and controversial. Decreased expression of miR-206 was found in rhabdomyosarcoma [ 26 ], lung cancer [ 28 ], ER + breast cancer [ 29 , 30 ], renal cell carcinoma [ 31 ], ER alpha + endometrioid adenocarcinoma [ 32 ], hepatocellular carcinoma [ 33 , 34 ] and glioma [ 35 ]. Upregulation of miR-206 inhibits the migration, invasion and proliferation of breast cancer [ 30 ], renal cell carcinoma [ 31 ], glioma [ 35 ], and head and neck squamous cell carcinoma [ 31 ], suggesting a tumor suppressor role of miR-206.…”

“…Decreased expression of miR-206 was found in rhabdomyosarcoma [ 26 ], lung cancer [ 28 ], ER + breast cancer [ 29 , 30 ], renal cell carcinoma [ 31 ], ER alpha + endometrioid adenocarcinoma [ 32 ], hepatocellular carcinoma [ 33 , 34 ] and glioma [ 35 ]. Upregulation of miR-206 inhibits the migration, invasion and proliferation of breast cancer [ 30 ], renal cell carcinoma [ 31 ], glioma [ 35 ], and head and neck squamous cell carcinoma [ 31 ], suggesting a tumor suppressor role of miR-206. Increased expression of miR-206 was found in breast cancer [ 30 , 36 ], esophageal carcinoma [ 37 ] and some soft tissue sarcomas [ 38 ], and high miR-206 expression was related to the poor prognosis of breast cancer [ 36 ] and esophageal carcinoma patients [ 37 ].…”

“…Upregulation of miR-206 inhibits the migration, invasion and proliferation of breast cancer [ 30 ], renal cell carcinoma [ 31 ], glioma [ 35 ], and head and neck squamous cell carcinoma [ 31 ], suggesting a tumor suppressor role of miR-206. Increased expression of miR-206 was found in breast cancer [ 30 , 36 ], esophageal carcinoma [ 37 ] and some soft tissue sarcomas [ 38 ], and high miR-206 expression was related to the poor prognosis of breast cancer [ 36 ] and esophageal carcinoma patients [ 37 ]. Upregulation of miR-206 in breast cancer cells promoted the migration, invasion and proliferation of breast cancer cells [ 30 ].…”

The Neurokinin-1 Receptor Antagonist Aprepitant, a New Drug for the Treatment of Hematological Malignancies: Focus on Acute Myeloid Leukemia

“…Lymph node involvement and the cancer stage have been related to the expression of the NK-1R and, in fact, patients with poor prognosis and more advanced and less-differentiated tumors expressed a higher number of NK-1Rs [30,31,35]. This is an important observation, because it means that the NK-1R can be used in cancer as a biomarker and it could be useful for an earlier diagnosis/treatment of the disease [30].…”

“…Regarding the expression of the NK-1R, the study showed that two isoforms of the NK-1R (full-length and truncated) were present in AML cells and, in particular, the truncated form was two-fold higher than the full-length isoform ( Table 1) [23]. In cancer cells, the truncated isoform is up-regulated and the full-length form downregulated and it has been suggested that a low level of the full-length isoform is responsible for the malignant phenotype of cancer cells [35]. However, in healthy cells, the truncated isoform was not expressed, whereas the full-length isoform was higher in AML cells (20-fold in KG-1 and 12-fold in HL-60) when compared to healthy cells (Table 1) [23].…”