Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Targeting STAT3/miR-21 axis inhibits epithelial-mesenchymal transition via regulating CDK5 in head and neck squamous cell carcinoma

Authors: Shan-Shan Sun, Xuan Zhou, Yuan-Yuan Huang, Ling-Ping Kong, Mei Mei, Wen-Yu Guo, Ming-Hui Zhao, Yu Ren, Qiang Shen, Lun Zhang

Published in: Molecular Cancer | Issue 1/2015

Login to get access

Abstract

Background

Abnormal 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.

Methods

We 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.

Results

The 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.

Conclusions

miR-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.
Appendix
Available only for authorised users
Literature
1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.PubMedCrossRef
2.
Ries LAG, John L. Young J, Keel GE, Eisner MP, Lin YD, Horner M-JD. Cancer Survival Among Adults: U.S. SEER Program, 1988-2001, Patient and Tumor Characteristics. Natl Cancer Inst SEER Program NIH. 2007:07-6215.
3.
4.
Chaw SY, Majeed AA, Dalley AJ, Chan A, Stein S, Farah CS. Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation. Oral Oncol. 2012;48(10):997–1006.PubMedCrossRef
5.
Zhang S, Zhou X, Wang B, Zhang KL, Liu S, Yue K, et al. Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma. Oral Oncol. 2014;50(9):809–17.PubMedCrossRef
6.
Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26(19):2799–803.PubMedCrossRef
7.
Yan LX, Wu QN, Zhang Y, Li YY, Liao DZ, Hou JH, et al. Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth. Breast Cancer Res. 2011;13(1):R2.
8.
Huang TH, Wu FT, Loeb GB, Hsu R, Heidersbach A, Brincat A, et al. Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion. J Biol Chem. 2009;284(27):18515–24.PubMedPubMedCentralCrossRef
9.
Danielsson K, Wahlin YB, Gu X, Boldrup L, Nylander K. Altered expression of miR-21, miR-125b, and miR-203 indicates a role for these microRNAs in oral lichen planus. J Oral Pathol Med. 2012;41(1):90–5.PubMedCrossRef
10.
Zhou XA, Zhang JX, Jia QA, Ren Y, Wang YY, Shi L, et al. Reduction of miR-21 induces glioma cell apoptosis via activating caspase 9 and 3. Oncol Rep. 2010;24(1):195–201.PubMed
11.
Fukushima Y, Iinuma H, Tsukamoto M, Matsuda K, Hashiguchi Y. Clinical significance of microRNA-21 as a biomarker in each Dukes’ stage of colorectal cancer. Oncol Rep. 2015;33(2):573–82.PubMed
12.
Zhou X, Ren Y, Moore L, Mei M, You YP, Xu P, et al. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest. 2010;90(2):144–55.PubMedCrossRef
13.
Wang T, Zhang L, Shi C, Sun H, Wang J, Li R, et al. TGF-beta-induced miR-21 negatively regulates the antiproliferative activity but has no effect on EMT of TGF-beta in HaCaT cells. Int J Biochem Cell Biol. 2012;44(2):366–76.PubMedCrossRef
14.
Han M, Liu M, Wang Y, Mo Z, Bi X, Liu Z, et al. Re-expression of miR-21 contributes to migration and invasion by inducing epithelial-mesenchymal transition consistent with cancer stem cell characteristics in MCF-7 cells. Mol Cell Biochem. 2012;363(1-2):427–36.PubMedCrossRef
15.
Luo F, Xu Y, Ling M, Zhao Y, Xu W, Liang X, et al. Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells. Toxicol Appl Pharmacol. 2013;273(1):27–34.PubMedCrossRef
16.
Zhou X, Ren Y, Liu A, Han L, Zhang K, Li S, et al. STAT3 inhibitor WP1066 attenuates miRNA-21 to suppress human oral squamous cell carcinoma growth in vitro and in vivo. Oncol Rep. 2014;31(5):2173–80.PubMed
17.
Zhou X, Ren Y, Liu A, Jin R, Jiang Q, Huang Y, et al. WP1066 sensitizes oral squamous cell carcinoma cells to cisplatin by targeting STAT3/miR-21 axis. Sci Rep. 2014;4:7461.PubMedPubMedCentralCrossRef
18.
Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, et al. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res. 2010;70(11):4460–9.PubMedPubMedCentralCrossRef
19.
Strock CJ, Park JI, Nakakura EK, Bova GS, Isaacs JT, Ball DW, et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res. 2006;66(15):7509–15.PubMedCrossRef
20.
Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V, et al. The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell. 2013;24(4):499–511.PubMedCrossRef
21.
Demelash A, Rudrabhatla P, Pant HC, Wang X, Amin ND, McWhite CD, et al. Achaete-scute homologue-1 (ASH1) stimulates migration of lung cancer cells through Cdk5/p35 pathway. Mol Biol Cell. 2012;23(15):2856–66.PubMedPubMedCentralCrossRef
22.
Edge SB, Compton CC. The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4.PubMedCrossRef
23.
Sanchez-Tillo E, de Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A. beta-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc Natl Acad Sci U S A. 2011;108(48):19204–9.PubMedPubMedCentralCrossRef
24.
Zhang B, Yang Y, Shi XT, Liao WY, Chen M, Cheng ASL, et al. Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-beta/beta-catenin signaling and epithelial-mesenchymal transition. Cancer Lett. 2015;356(2):704–12.PubMedCrossRef
25.
Zeng T, Peng LF, Chao CH, Fu B, Wang GX, Wang YB, et al. miR-451 inhibits invasion and proliferation of bladder cancer by regulating EMT. Int J Clin Exp Patho. 2014;7(11):7653–62.
26.
Lim BJ, Jung SS, Choi SY, Lee CS. Expression of metastasis-associated molecules in non-small cell lung cancer and their prognostic significance. Mol Med Rep. 2010;3(1):43–9.PubMed
27.
Han ML, Liu MR, Wang YM, Chen X, Xu JL, Sun Y, et al. Antagonism of miR-21 Reverses Epithelial-Mesenchymal Transition and Cancer Stem Cell Phenotype through AKT/ERK1/2 Inactivation by Targeting PTEN. PloS one. 2012;7(6):e39520.
28.
Bao LL, Yan Y, Xu C, Ji WD, Shen SW, Xu GY, et al. MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. Cancer Lett. 2013;337(2):226–36.PubMedCrossRef
29.
Luo F, Ji J, Liu Y, Xu Y, Zheng G, Jing JF, et al. MicroRNA-21, up-regulated by arsenite, directs the epithelial-mesenchymal transition and enhances the invasive potential of transformed human bronchial epithelial cells by targeting PDCD4. Toxicol Lett. 2015;232(1):301–9.CrossRef
30.
Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Proliferat. 2003;36(3):131–49.CrossRef
31.
32.
Schuman EM, Murase S. Cadherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic beta-catenin-cadherin interactions. Philos T Roy Soc B. 2003;358(1432):749–56.CrossRef
33.
Kwon YT, Gupta A, Zhou Y, Nikolic M, Tsai LH. Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase. Curr Biol. 2000;10(7):363–72.PubMedCrossRef
34.
Liebl J, Weitensteiner SB, Vereb G, Takacs L, Furst R, Vollmar AM, et al. Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis. J Biol Chem. 2010;285(46):35932–43.PubMedPubMedCentralCrossRef
35.
Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS, et al. MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol. 2008;28(17):5369–80.PubMedPubMedCentralCrossRef
36.
Shi Z, Zhang J, Qian X, Han L, Zhang K, Chen L, et al. AC1MMYR2, an inhibitor of dicer-mediated biogenesis of Oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression. Cancer Res. 2013;73(17):5519–31.PubMedCrossRef
37.
Li BS, Ma W, Jaffe H, Zheng Y, Takahashi S, Zhang L, et al. Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem. 2003;278(37):35702–9.PubMedCrossRef
38.
Daval M, Gurlo T, Costes S, Huang CJ, Butler PC. Cyclin-dependent kinase 5 promotes pancreatic beta-cell survival via Fak-Akt signaling pathways. Diabetes. 2011;60(4):1186–97.PubMedPubMedCentralCrossRef
39.
Ren Y, Zhou X, Yang JJ, Liu X, Zhao XH, Wang QX, et al. AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR-21/CDK5 axis. Cancer Lett. 2015;362(2):174–82.PubMedCrossRef
Metadata
Title
Targeting STAT3/miR-21 axis inhibits epithelial-mesenchymal transition via regulating CDK5 in head and neck squamous cell carcinoma
Authors
Shan-Shan Sun
Xuan Zhou
Yuan-Yuan Huang
Ling-Ping Kong
Mei Mei
Wen-Yu Guo
Ming-Hui Zhao
Yu Ren
Qiang Shen
Lun Zhang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0487-x

Other articles of this Issue 1/2015

Molecular Cancer 1/2015 Go to the issue

Research

COSMC knockdown mediated aberrant O-glycosylation promotes oncogenic properties in pancreatic cancer

Research

A conserved region within interferon regulatory factor 5 controls breast cancer cell migration through a cytoplasmic and transcription-independent mechanism

Research

MicroRNA-223 delivered by platelet-derived microvesicles promotes lung cancer cell invasion via targeting tumor suppressor EPB41L3

Research

Biological characteristics of a new human glioma cell line transformed into A2B5+ stem cells

Research

The pseudokinase SgK223 promotes invasion of pancreatic ductal epithelial cells through JAK1/Stat3 signaling

Research

Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits