MiR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

Xiao-Xiao Lu,Si-Si Hu,Jun Cao,Xiang Liu,Ming-Hua Ge,Yi-Chen Wu,Jing Han,Lian-Lian Hong,Zhi-Qiang Ling,Xiu-Xiu Hou,Pei Li,Lie-Hao Jiang,Xin Zhu

doi:10.1038/labinvest.2015.105

Xiao-Xiao Lu, Si-Si Hu + Show 11 more

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https://doi.org/10.1038/labinvest.2015.105

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Journal: Laboratory Investigation	Publication Date: Dec 1, 2015
Citations: 45	License type: publisher-specific-oa

Affiliation: Zhejiang Cancer Hospital, Zhengzhou University

Abstract

miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis. The suppression of miR-21 in metastatic SACC-LM cells significantly increased the report activity of PDCD4 promoter and the expression of PDCD4 protein. This subsequently resulted in downregulation of the p-STAT3 protein. The level of miR-21 expression positively related to the expression of PDCD4 protein and negatively related to the expression of p-STAT3 protein in SACC specimens, respectively, indicating the potential role of the STAT3-miR-21-PDCD4 pathway in these tumors. Dysregulation of miR-21 has an important role in tumor growth and invasion by targeting PDCD4. Therefore, suppression of miR-21 may provide a potential approach for the treatment of advanced SACC patients.

Highlights

Salivary adenoid cystic carcinoma (SACC) is one of the most common malignancy of the salivary gland, accounting for
A significant overexpression of miR-21 is observed in two SACC cell lines (SACC-83 and SACC-LM) relative to that in normal tissue samples (SACC-83 vs normal salivary gland tissues (NSGs), SACC-LM vs NSGs, both P = 0.002)
These results indicate that miR-21 expression is frequently upregulated in SACC cells, and miR-21 may have a pivotal role in SACC metastasis

Summary

Introduction

Salivary adenoid cystic carcinoma (SACC) is one of the most common malignancy of the salivary gland, accounting for. Laboratory Investigation | Volume 95 December 2015 | www.laboratoryinvestigation.org miR-21 in salivary adenoid cystic carcinoma L-H Jiang et al. Liu et al found that miR-155 facilitates cell cycle progression and promotes invasion in ACC and that the EGFR/NF-κB pathway might participate in mediating the effects of miR-155.16 Mitani et al reported that the overexpression of the miR-17 and miR-20a were significantly associated with poor outcome in SACC.[17] He et al first indicate that miR-181a has an important role in the metastasis of SACC by regulating the MAPK-Snai[2] pathway, and may serve as a novel therapeutic target for SACC.[18] Chen et al employed microarray technology to identify miRNA expression profiles that are involved in the metastatic progression of SACC. The relationship between miRNAs and signaling pathways in SACC is extremely complicated

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Conclusion