Abstract
Increasing evidence has emerged to suggest that N-myc downstream-regulated gene 2 (NDRG2) dysregulation participates in a number of tumor biological processes. However, the role of NDRG2 and miRNA-mediated NDRG2 regulation in salivary adenoid cystic carcinoma (SACC) progression remain unknown. Here, we determined that SACC tissues exhibited decreased level of NDRG2, which was associated with poorer rates of overall survival and distant metastasis-free survival. Silencing NDRG2 promoted SACC cell proliferation and metastasis both in vitro and in vivo. MiRNAs have been reported as vital regulators of NDRG2 expression. Based on micronome sequencing of three paired samples of SACC and normal salivary gland tissue and on an online database analysis, miR-130a was identified as a candidate miRNA that potentially regulates NDRG2. We demonstrated that the expression level of NDRG2 was dramatically reduced by exogenous miR-130a. Moreover, a luciferase assay further validated that miR-130a could degrade NDRG2 mRNA by targeting sites in the NDRG2 3′UTR. A rescue experiment suggested that NDRG2 expression could reverse the miR-130a-mediated promotion of cell proliferation and invasion. The expression of miR-130a has been reported to be regulated by certain transcription factors. In the preset study, we verified that the transcription factor MYB acted as the critical driver in SACC-upregulated miR-130a expression directly and induced NDRG2 downregulation in SACC tissues. Additionally, MYB/miR-130a activated the STAT3 and AKT pathways by downregulating NDRG2. These observations suggest that the MYB/miR-130a/NDRG2 axis, which modulates proliferation and metastasis in SACC, provides promising targets for the treatment of SACC.
Highlights
salivary adenoid cystic carcinoma (SACC) is the most common malignancy of the salivary gland, accounting for 30.42% of all salivary malignant tumors in the Chinese population[1]
N-myc downstream-regulated gene 2 (NDRG2) is downregulated in SACC tissue samples, and a low NDRG2 expression level is associated with distant metastasis and poorer survival To determine the expression level of NDRG2 in SACC, we tested the relative mRNA expression of NDRG2 by qRT-PCR in 21 fresh primary SACC human tissues and the corresponding normal salivary glands (NSG)
Kaplan–Meier analyses showed that patients with negative/low levels of NDRG2 were inclined to have poorer overall survival (P = 0.016) and distantmetastasis-free survival (P < 0.0001) rates than those with high NDRG2 levels, but there was no difference in recurrence-free survival between the patients in the two groups (P = 0.76) (Fig. 1c–e)
Summary
SACC is the most common malignancy of the salivary gland, accounting for 30.42% of all salivary malignant tumors in the Chinese population[1]. NDRG2, which is implicated in nervous system diseases and human carcinoma, has recently been reported as a candidate tumor suppressor gene[7]. Official journal of the Cell Death Differentiation Association. Wang et al Cell Death and Disease (2018)9:917. The lack of NDRG2 in T cell leukemia/lymphoma and other malignancies enhances activation of PI3K-AKT and NF-KB signaling through PTEN and NIK phosphorylation[9]. We believe that the clinical significance and exact biological function of NDRG2 in SACC deserve much investigation
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