Investigation of the role of cullin 4A overexpression in human liver cancer

Chen,Gang; Zhao,Xiongqi; Tan,Zedan; Wang,Dongdong; Luo,Ding; Zhang,Peiyao; Cao,Jun; Wang,Fan; Liu,Qiyu; Li,Li

doi:10.3892/mmr.2018.9233

Investigation of the role of cullin 4A overexpression in human liver cancer

Authors:
- Gang Chen
- Xiongqi Zhao
- Zedan Tan
- Dongdong Wang
- Ding Luo
- Peiyao Zhang
- Jun Cao
- Fan Wang
- Qiyu Liu
- Li Li
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China
Published online on: June 29, 2018 https://doi.org/10.3892/mmr.2018.9233
Pages: 2531-2540
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cullin 4A (CUL4A) is the major component of cullin‑RING‑based E3 ubiquitin‑protein ligase complexes, which regulate the ubiquitination of target proteins. The overexpression of CUL4A has been associated with the development and progression of various cancer types. However, a detailed understanding of the role of CUL4A in human liver cancer has not been determined by previous studies. In the present study, the association between human liver cancer and CUL4A expression was investigated. The expression of CUL4A in liver cancer tissues and paracancerous tissues of patients was investigated by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemical staining. Overexpression and knockdown of CUL4A were induced with an overexpression vector and small interfering RNA transfection, respectively, in human liver cancer cell lines, and the effects on cell proliferation were analyzed by a Cell Counting Kit‑8 assay to investigate the role of CUL4A in human liver cancer. Cell migration, invasion, apoptosis and the cell cycle were also analyzed following transfection. The results of the present study revealed that the mRNA and protein expression of CUL4A was increased in the liver cancer tissues compared with the paracancerous tissues of 3 patients. Additionally, the results demonstrated that downregulation of CUL4A expression inhibited cell proliferation, migration and invasion, and increased the percentage of cell apoptosis, in HEPG2 and MHCC97‑H cells, while CUL4A overexpression led to the opposite effects. Therefore, the results of the current study indicated that CUL4A may serve an important role in the development and progression of human liver cancer, and highlights the potential of CUL4A as a novel target in the diagnosis and treatment of human liver cancer and potentially other cancer types.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Altekruse SF, Henley SJ, Cucinelli JE and McGlynn KA: Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol. 109:542–553. 2014. View Article : Google Scholar : PubMed/NCBI
3	Tang A, Hallouch O, Chernyak V, Kamaya A and Sirlin CB: Epidemiology of hepatocellular carcinoma: Target population for surveillance and diagnosis. Abdom Radiol (NY). 43:13–25. 2018. View Article : Google Scholar : PubMed/NCBI
4	Xu IM, Lai RK, Lin SH, Tse AP, Chiu DK, Koh HY, Law CT, Wong CM, Cai Z, Wong CC and Ng IO: Transketolase counteracts oxidative stress to drive cancer development. Proc Natl Acad Sci USA. 113:E725–E734. 2016. View Article : Google Scholar : PubMed/NCBI
5	Nishida N and Goel A: Genetic and epigenetic signatures in human hepatocellular carcinoma: A systematic review. Curr Genomics. 12:130–137. 2011. View Article : Google Scholar : PubMed/NCBI
6	Liu M, Jiang L and Guan XY: The genetic and epigenetic alterations in human hepatocellular carcinoma: A recent update. Protein Cell. 5:673–691. 2014. View Article : Google Scholar : PubMed/NCBI
7	Nishida N and Kudo M: Clinical significance of epigenetic alterations in human hepatocellular carcinoma and its association with genetic mutations. Dig Dis. 34:708–713. 2016. View Article : Google Scholar : PubMed/NCBI
8	Yasui K, Arii S, Zhao C, Imoto I, Ueda M, Nagai H, Emi M and Inazawa J: TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas. Hepatology. 35:1476–1484. 2002. View Article : Google Scholar : PubMed/NCBI
9	Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S and Tanaka K: Covalent modification of all members of human cullin family proteins by NEDD8. Oncogene. 18:6829–6834. 1999. View Article : Google Scholar : PubMed/NCBI
10	Sharma P and Nag A: CUL4A ubiquitin ligase: A promising drug target for cancer and other human diseases. Open Biol. 4:1302172014. View Article : Google Scholar : PubMed/NCBI
11	Dohna M, Reincke M, Mincheva A, Allolio B, Solinas-Toldo S and Lichter P: Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications. Genes Chromosomes Cancer. 28:145–152. 2000. View Article : Google Scholar : PubMed/NCBI
12	Xu Y, Wang Y, Ma G, Wang Q and Wei G: CUL4A is overexpressed in human pituitary adenomas and regulates pituitary tumor cell proliferation. J Neurooncol. 116:625–632. 2014. View Article : Google Scholar : PubMed/NCBI
13	Pan Y, Wang B, Yang X, Bai F, Xu Q, Li X, Gao L, Ma C and Liang X: CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition. Sci Rep. 5:170062015. View Article : Google Scholar : PubMed/NCBI
14	Ni W, Zhang Y, Zhan Z, Ye F, Liang Y, Huang J, Chen K, Chen L and Ding Y: A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1. J Hematol Oncol. 10:912017. View Article : Google Scholar : PubMed/NCBI
15	López-Terrada D, Cheung SW, Finegold MJ and Knowles BB: Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol. 40:1512–1515. 2009. View Article : Google Scholar
16	Liu P, Feng Y, Dong D, Liu X, Chen Y, Wang Y and Zhou Y: Enhanced renoprotective efect of IGF-1 modifed human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury. Sci Rep. 6:202872016. View Article : Google Scholar : PubMed/NCBI
17	Liu P, Cai J, Dong D, Chen Y, Liu X, Wang Y and Zhou Y: Effects of SOX2 on proliferation, migration and adhesion of human dental pulp stem cells. PloS One. 10:e01413462015. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Tao S, Liu P, Luo G, de la Vega Rojo M, Chen H, Wu T, Tillotson J, Chapman E and Zhang DD: p97 Negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex. Mol Cell Biol. 37:e00660–e00616. 2017. View Article : Google Scholar : PubMed/NCBI
20	Cai J, Zhang Y, Liu P, Chen S, Wu X, Sun Y, Li A, Huang K, Luo R, Wang L, et al: Generation of tooth-like structures from integration-free human urine induced pluripotent stem cells. Cell Reg (Lond). 2:62013.
21	Liu P, Feng Y, Dong C, Yang D, Li B, Chen X, Zhang Z, Wang Y, Zhou Y and Zhao L: Administration of BMSCs with muscone in rats with gentamicin-induced AKI improves their therapeutic efficacy. PloS One. 9:e971232014. View Article : Google Scholar : PubMed/NCBI
22	Liu P, Feng Y, Dong C, Liu D, Wu X, Wu H, Lv P and Zhou Y: Study on therapeutic action of bone marrow derived mesenchymal stem cell combined with vitamin E against acute kidney injury in rats. Life Sci. 92:829–837. 2013. View Article : Google Scholar : PubMed/NCBI
23	Zhao L, Feng Y, Chen X, Yuan J, Liu X, Chen Y, Zhao Y, Liu P and Li Y: Effects of IGF-1 on neural differentiation of human umbilical cord derived mesenchymal stem cells. Life Sci. 151:93–101. 2016. View Article : Google Scholar : PubMed/NCBI
24	Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, Willbanks A and Sarkar S: EMT and tumor metastasis. Clin Transl Med. 4:62015. View Article : Google Scholar : PubMed/NCBI
25	Jayachandran A, Dhungel B and Steel JC: Epithelial-to-mesenchymal plasticity of cancer stem cells: Therapeutic targets in hepatocellular carcinoma. J Hematol Oncol. 9:742016. View Article : Google Scholar : PubMed/NCBI
26	Panebianco C, Saracino C and Pazienza V: Epithelial-mesenchymal transition: Molecular pathways of hepatitis viruses-induced hepatocellular carcinoma progression. Tumour Biol. 35:7307–7315. 2014. View Article : Google Scholar : PubMed/NCBI
27	Ogunwobi OO and Liu C: Therapeutic and prognostic importance of epithelial-mesenchymal transition in liver cancers: Insights from experimental models. Crit Rev Oncol Hematol. 83:319–328. 2012. View Article : Google Scholar : PubMed/NCBI