Definition of miRNA Signatures of Nodal Metastasis in LCa: miR-449a Targets Notch Genes and Suppresses Cell Migration and Invasion

Abstract

Laryngeal cancer (LCa), a neoplasm of the head and neck region, is a leading cause of death worldwide. Surgical intervention remains the mainstay of LCa treatment, but a crucial point is represented by the possible nodal involvement. Therefore, it is urgently needed to develop biomarkers and therapeutic tools able to drive treatment approaches for LCa. In this study, we investigated deregulated microRNAs (miRNAs) in tissues from LCa patients with either lymph node metastases (N+) or not (NÀ). miRNA expression profiling was performed by a comprehensive PCR array and subsequent validation by RT-qPCR. Results showed a significant decrease of miR-449a expression in N+ compared to NÀ patients, and miR-133b down-modulation in LCa tissues compared to paired normal ones. Receiver operating characteristic (ROC) curve analysis revealed the potential diagnostic power of miR-133b for LCa detection. According to the validation results, we selected miR-449a for further in vitro studies. Ectopic miR-449a expression in the LCa cell line Hep-2 inhibited invasion and motility in vitro, slowed cell proliferation, and induced the downregulation of Notch1 and Notch2 as direct targets of miR-449a. Collectively, this study provides new promising biomarkers for LCa diagnosis and a new opportunity to use miR-449a for the treatment of nodal metastases in LCa patients.

S-Adenosylmethionine Inhibits Cell Growth and Migration of Triple Negative Breast Cancer Cells through Upregulating MiRNA-34c and MiRNA-449a

“…MiRNA-34c and miRNA-449a are downregulated in a wide range of cancers, including human breast cancer suggesting their function as potential tumor suppressors [ 43 , 44 , 45 , 46 , 47 ]. Notably, the up-regulation of miRNA-34 and miRNA-449 has been demonstrated to regulate oncogenic pathways including cell proliferation, metastases and apoptotic pathways [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”

“…Several studies have shown the beneficial effects of the upregulation of miR-449a in cancer [ 49 , 50 , 63 , 64 , 65 , 66 , 67 ]. Very recently it has been demonstrated that up-regulation of miR-449a suppresses the proliferation as well as the migration and invasion of laryngeal carcinoma cells targeting Notch1 and Notch2 down-regulation and it has been suggested that miR-449a, alone or in combination therapy with Notch inhibitors, could be used as a potential tool to treat metastatic laryngeal carcinoma [ 51 ].…”

OTX1 exerts an oncogenic role and is negatively regulated by miR129-5p in laryngeal squamous cell carcinoma

“…Aberrant expression of miR-129-5p has been observed in different types of cancers [27][28][29]. There have widely been reported that microRNAs (miRNAs) are strongly associated with the development and lymph node metastasis of LSCC [30,31]. Our results suggested that miR-129-5p might target and suppress OTX1 in LSCC.…”

Long non‑coding RNA MIAT promotes the proliferation and invasion of laryngeal squamous cell carcinoma cells by sponging microRNA‑613

“…Takeuchi et al ( 33 ) recently reported that a number of microRNAs, including miR-9, miR-10b, miR-21 and miR-132 are aberrantly upregulated in LCa, where they can contribute to the aggressiveness of the LCa. In addition, miR-449a upregulation was found to inhibit cell invasion and motility, suppressed cell proliferation and induced the downregulation of Notch1 and Notch2 in the LCa cell line HEP-2( 34 ). At present, there are no valid prognostic factors that can systematically drive the choice of nodal treatment for LCa.…”