Abstract
BackgroundAbnormal activation of STAT3 and miR-21 plays a vital role in progression and invasion of solid tumors. The cyclin-dependent kinase 5 (CDK5) is reported to contribute to cancer metastasis by regulating epithelial-mesenchymal transition (EMT). However, the role of STAT3/miR-21 axis and CDK5 in head and neck squamous cell carcinoma remains unclear.MethodsWe measured the expression of miR-21, CDK5 and EMT markers in 60 HNSCC tumor samples. We used Immunohistochemistry and in situ hybridization assay to examine the role of STAT3/miR-21 axis and CDK5 activation in the invasiveness of HNSCC. The clinical survival relevance was analyzed by Kaplan-Meier analysis and univariate/multivariate COX regression model. Multiple approaches including scratch, transwell chamber assay and other molecular biology techniques were used to validate the anti-invasion effect of targeting miR-21 in Tca8113 and Hep-2 cell lines in vitro. Furthermore, whether miR-21 depletion inhibits HNSCC invasion in vivo was confirmed in Tca8113 xenograft tumor model.ResultsThe expression of miR-21 and CDK5 were significantly correlated with lymph node metastasis in HNSCC. Hep-2 and Tca8113 cell lines showed co-overexpression of miR-21 and CDK5. WP1066 or asON-miR-21 treatment depleted miR-21 and CDK5 expression and significantly inhibited migration or invasion in Hep-2 and Tca8113 cells. The expression levels of CDK5/p35, N-cadherin, vimentin, β-catenin were inhibited while E-cadherin level was increased by miR-21 depletion in vitro and in vivo. Conversely, ectopic CDK5 overexpression significantly induced tumor cell motility and EMT. Moreover, ectopic CDK5 overexpression in Hep-2 and Tca8113 cells rescued the observed phenotype after miR-21 silencing or WP1066 treatment.ConclusionsmiR-21 cooperates with CDK5 to promote EMT and invasion in HNSCC. This finding suggests that CDK5 may be an important cofactor for targeting when designing metastasis-blocking therapy by targeting STAT3/miR-21 axis with STAT3 inhibitor or miR-21 antisense oligonucleotide. This is the first demonstration of the novel role of STAT3/miR-21 axis and CDK5/CDK5R1 (p35) in metastasis of HNSCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0487-x) contains supplementary material, which is available to authorized users.
Highlights
Abnormal activation of Signal transducers and activators of transcription 3 (STAT3) and miR-21 plays a vital role in progression and invasion of solid tumors
Conclusions: miR-21 cooperates with cyclin-dependent kinase 5 (CDK5) to promote epithelial-mesenchymal transition (EMT) and invasion in Head and neck squamous cell carcinoma (HNSCC). This finding suggests that CDK5 may be an important cofactor for targeting when designing metastasis-blocking therapy by targeting STAT3/miR-21 axis with STAT3 inhibitor or miR-21 antisense oligonucleotide
This is the first demonstration of the novel role of STAT3/ miR-21 axis and CDK5/CDK5R1 (p35) in metastasis of HNSCC
Summary
Abnormal activation of STAT3 and miR-21 plays a vital role in progression and invasion of solid tumors. The role of STAT3/miR-21 axis and CDK5 in head and neck squamous cell carcinoma remains unclear. Epithelial mesenchymal transition (EMT) is considered as a vital process of metastasis, and it may significantly contribute to the progression of HNSCC [3,4,5]. MiR-21 has been demonstrated as a key regulator of biological behaviors of cancer cells, including apoptosis [10], proliferation [12], EMT [13], migration and invasion [14]. Luo et al found that STAT3/miR-21 activation by IL-6 was associated with arsenite-induced EMT of human bronchial epithelial (HBE) cells [15]. Our previous research suggested that inhibition of STAT3/miR21 axis with WP1066, a small-molecule STAT3 inhibitor, suppressed HNSCC cell growth and sensitized cells to cisplatin [16, 17]
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