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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

RETRACTED ARTICLE: Up-regulation of CDK16 by multiple mechanisms in hepatocellular carcinoma promotes tumor progression

Authors: Yitao Wang, Xian Qin, Tao Guo, Pengpeng Liu, Ping Wu, Zhisu Liu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

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Abstract

Background

Hepatocellular carcinoma (HCC) remains difficult to cure due to lack of effective treatment and the molecular mechanisms are complex and not completely understood. In this study, We investigated the role of CDK16 in tumor progression of HCC.

Methods

We interrogated the expression level of CDK16 by polymerase chain reaction and immunohistochemistry(IHC) and studied its clinical significance. The functional role of CDK16 on HCC was studied via gain and loss of function in vitro and in vivo. Luciferase reporter assay and Chromatin immunoprecipitation(ChIP) assay were performed to investigate the transcriptional and post-transcriptional mechanisms involved in the regulation of CDK16.

Results

CDK16 expression was significantly up-regulated in HCC and higher expression of CDK16 was positively correlated with aggressive clinicopathological phenotype and poorer survival rates. Functionally, knockdown of CDK16 suppressed proliferation in vitro and in vivo. Inactivation of CDK16 also induced apoptosis and cell cycle arrest. Most importantly, CDK16 promoted epithelial mesenchymal transition and tumor invasion by activating β-catenin signaling. In addition, We identified E2F1 as a positive transcriptional regulator of CDK16. Moreover, down regulation of miR-125b-5p enhanced CDK16 expression at post-transcriptional level.

Conclusion

We provided the first evidence that CDK16 is an bona fide oncogene in HCC, and multiple activating mechanisms at transcriptional and posttranscriptional levels together contributes to CDK16 up-regulation in HCC.
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Literature
1.
Mortality GBD. Causes of death C: global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388:1459–544.CrossRef
2.
Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27:1485–91.CrossRef
3.
White DL, Thrift AP, Kanwal F, Davila J, El-Serag HB. Incidence of Hepatocellular carcinoma in all 50 United States, from 2000 through 2012. Gastroenterology. 2017;152:812–20.CrossRef
4.
5.
de Martel C, Maucort-Boulch D, Plummer M, Franceschi S. World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma. Hepatology (Baltimore, Md). 2015;62:1190–200.CrossRef
6.
Parikh ND, Marshall VD, Singal AG, Nathan H, Lok AS, Balkrishnan R, Shahinian V. Survival and cost-effectiveness of sorafenib therapy in advanced hepatocellular carcinoma: an analysis of the SEER-Medicare database. Hepatology (Baltimore, Md). 2017;65:122–33.CrossRef
7.
Cole AR. PCTK proteins: the forgotten brain kinases? Neurosignals. 2009;17:288–97.CrossRef
8.
Le Bouffant F, Le Minter P, Traiffort E, Ruat M, Sladeczek F. Multiple subcellular localizations of PCTAIRE-1 in brain. Mol Cell Neurosci. 2000;16:388–95.CrossRef
9.
Palmer KJ, Konkel JE, Stephens DJ. PCTAIRE protein kinases interact directly with the COPII complex and modulate secretory cargo transport. J Cell Sci. 2005;118:3839–47.CrossRef
10.
Mikolcevic P, Sigl R, Rauch V, Hess MW, Pfaller K, Barisic M, Pelliniemi LJ, Boesl M, Geley S: Cyclin-dependent kinase 16/PCTAIRE kinase 1 is activated by cyclin Y and is essential for spermatogenesis. Mol Cell Biol. 2012;32:868–879.CrossRef
11.
Liu Y, Cheng K, Gong K, Fu AK, Ip NY. Pctaire1 phosphorylates N-ethylmaleimide-sensitive fusion protein: implications in the regulation of its hexamerization and exocytosis. J Biol Chem. 2006;281:9852–8.CrossRef
12.
Iwano S, Satou A, Matsumura S, Sugiyama N, Ishihama Y, Toyoshima F. PCTK1 regulates integrin-dependent spindle orientation via protein kinase a regulatory subunit KAP0 and myosin X. Mol Cell Biol. 2015;35:1197–208.CrossRef
13.
Graeser R, Gannon J, Poon RY, Dubois T, Aitken A, Hunt T. Regulation of the CDK-related protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells. J Cell Sci. 2002;115:3479–90.
14.
Chen XY, Gu XT, Saiyin H, Wan B, Zhang YJ, Li J, Wang YL, Gao R, Wang YF, Dong WP, Najjar SM, Zhang CY, Ding HF, Liu JO, Yu L. Brain-selective kinase 2 (BRSK2) phosphorylation on PCTAIRE1 negatively regulates glucose-stimulated insulin secretion in pancreatic beta-cells. J Biol Chem. 2012;287:30368–75.CrossRef
15.
Besset V, Rhee K, Wolgemuth DJ. The cellular distribution and kinase activity of the Cdk family member Pctaire1 in the adult mouse brain and testis suggest functions in differentiation. Cell Growth Differ. 1999;10:173–81.
16.
Shimizu K, Uematsu A, Imai Y, Sawasaki T. Pctaire1/Cdk16 promotes skeletal myogenesis by inducing myoblast migration and fusion. FEBS Lett. 2014;588:3030–7.CrossRef
17.
Yanagi T, Krajewska M, Matsuzawa S, Reed JC. PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells. Cancer Res. 2014;74:5795–807.CrossRef
18.
Cwiek P, Leni Z, Salm F, Dimitrova V, Styp-Rekowska B, Chiriano G, Carroll M, Holand K, Djonov V, Scapozza L, Guiry P, Arcaro A. RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification. Oncotarget. 2015;6:116–29.CrossRef
19.
Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–23.CrossRef
20.
Yanagi T, Reed JC, Matsuzawa S. PCTAIRE1 regulates p27 stability, apoptosis and tumor growth in malignant melanoma. Oncoscience. 2014;1:624–33.CrossRef
21.
Gan WJ, Wang JR, Zhu XL, He XS, Guo PD, Zhang S, Li XM, Li JM, Wu H. RARgamma-induced E-cadherin downregulation promotes hepatocellular carcinoma invasion and metastasis. J Exp Clin Cancer Res. 2016;35:164.CrossRef
22.
Yoshida GJ. Emerging role of epithelial-mesenchymal transition in hepatic cancer. J Exp Clin Cancer Res. 2016;35:141.CrossRef
23.
Zhang Y, Zeng S, Ma J, Deng G, Qu Y, Guo C, Shen H. Nestin overexpression in hepatocellular carcinoma associates with epithelial-mesenchymal transition and chemoresistance. J Exp Clin Cancer Res. 2016;35:111.CrossRef
24.
Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J, Song C, Cheung YS, Lai PB, Cheng SH, Ng MH, Huang A, Ko BC. SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3beta/beta-catenin signaling. Hepatology (Baltimore, Md). 2013;57:2287–98.CrossRef
25.
Zhao J, Ou B, Han D, Wang P, Zong Y, Zhu C, Liu D, Zheng M, Sun J, Feng H, Lu A. Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/elk-1/snail and AKT/GSK3beta/beta-catenin pathways. Mol Cancer. 2017;16:70.CrossRef
26.
Tang B, Tang F, Wang Z, Qi G, Liang X, Li B, Yuan S, Liu J, Yu S, He S. Overexpression of CTNND1 in hepatocellular carcinoma promotes carcinous characters through activation of Wnt/beta-catenin signaling. J Exp Clin Cancer Res. 2016;35:82.CrossRef
27.
Mathelier A, Fornes O, Arenillas DJ, Chen CY, Denay G, Lee J, Shi W, Shyr C, Tan G, Worsley-Hunt R, Zhang AW, Parcy F, Lenhard B, Sandelin A, Wasserman WW. JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 2016;44:D110–5.CrossRef
28.
Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18:333–4.CrossRef
29.
Kent LN, Bae S, Tsai SY, Tang X, Srivastava A, Koivisto C, Martin CK, Ridolfi E, Miller GC, Zorko SM, Plevris E, Hadjiyannis Y, Perez M, Nolan E, Kladney R, Westendorp B, de Bruin A, Fernandez S, Rosol TJ, Pohar KS, Pipas JM, Leone G. Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. J Clin Invest. 2017;127:830–42.CrossRef
30.
Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.CrossRef
31.
Zhou JN, Zeng Q, Wang HY, Zhang B, Li ST, Nan X, Cao N, Fu CJ, Yan XL, Jia YL, Wang JX, Zhao AH, Li ZW, Li YH, Xie XY, Zhang XM, Dong Y, Xu YC, He LJ, Yue W, Pei XT. MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4. Hepatology (Baltimore, Md). 2015;62:801–15.CrossRef
32.
33.
Zi Z, Zhang Z, Li Q, An W, Zeng L, Gao D, Yang Y, Zhu X, Zeng R, Shum WW, Wu J. CCNYL1, but not CCNY, cooperates with CDK16 to regulate spermatogenesis in mouse. PLoS Genet. 2015;11:e1005485.CrossRef
34.
Tang X, Guilherme A, Chakladar A, Powelka AM, Konda S, Virbasius JV, Nicoloro SM, Straubhaar J, Czech MP. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci U S A. 2006;103:2087–92.CrossRef
35.
Taneera J, Fadista J, Ahlqvist E, Zhang M, Wierup N, Renstrom E, Groop L. Expression profiling of cell cycle genes in human pancreatic islets with and without type 2 diabetes. Mol Cell Endocrinol. 2013;375:35–42.CrossRef
36.
Sauer K, Weigmann K, Sigrist S, Lehner CF. Novel members of the cdc2-related kinase family in drosophila: cdk4/6, cdk5, PFTAIRE, and PITSLRE kinase. Mol Biol Cell. 1996;7:1759–69.CrossRef
37.
Rhee K, Wolgemuth DJ. Cdk family genes are expressed not only in dividing but also in terminally differentiated mouse germ cells, suggesting their possible function during both cell division and differentiation. Dev Dyn. 1995;204:406–20.CrossRef
38.
Yanagi T, Shi R, Aza-Blanc P, Reed JC, Matsuzawa S. PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines. PLoS One. 2015;10:e0119404.CrossRef
39.
Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7:re8.CrossRef
40.
Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8:1398–406.CrossRef
41.
Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58.CrossRef
42.
Hua H, Li M, Luo T, Yin Y, Jiang Y. Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci. 2011;68:3853–68.CrossRef
43.
Shats I, Deng M, Davidovich A, Zhang C, Kwon JS, Manandhar D, Gordan R, Yao G, You L. Expression level is a key determinant of E2F1-mediated cell fate. Cell Death Differ. 2017;24:626–37.CrossRef
44.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.CrossRef
45.
Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, Ogata H, Karin M, Struhl K, Hadzopoulou-Cladaras M, Iliopoulos D. An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell. 2011;147:1233–47.CrossRef
Metadata
Title
RETRACTED ARTICLE: Up-regulation of CDK16 by multiple mechanisms in hepatocellular carcinoma promotes tumor progression
Authors
Yitao Wang
Xian Qin
Tao Guo
Pengpeng Liu
Ping Wu
Zhisu Liu
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0569-2

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