Gankyrin is essential for hypoxia enhanced metastatic potential in breast cancer cells

Gao,Liucun; Xie,Huahong; Dong,Lihou; Zou,Jia; Fu,Jie; Gao,Xin; Ou,Lun; Xiang,Shensi; Song,Haifeng

doi:10.3892/mmr.2013.1860

Gankyrin is essential for hypoxia enhanced metastatic potential in breast cancer cells

Authors:
- Liucun Gao
- Huahong Xie
- Lihou Dong
- Jia Zou
- Jie Fu
- Xin Gao
- Lun Ou
- Shensi Xiang
- Haifeng Song
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Affiliations: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, P.R. China, State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
Published online on: December 12, 2013 https://doi.org/10.3892/mmr.2013.1860
Pages: 1032-1036

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Abstract

Hypoxia, a critical regulator of tumor growth and metastasis, induces the transcriptional activation of several pathways involved in proliferation, migration and invasion. Gankyrin was found to be overexpressed, and also promoted the metastasis in breast cancer cells, which is also involved in the regulation of hypoxia inducible factor‑1 and hypoxia‑inducible factor‑1α. The present study showed that gankyrin mRNA and protein expression were increased under hypoxic conditions in the BT474 breast cancer cell line, accompanied with increased ability of cell migration and invasion. Lentivirus‑mediated siRNA targeting gankyrin was transfected into BT474 cells. Wound‑healing and transwell experiments showed that gankyrin deletion abrogated the increased migration and invasion of BT474 cells due to hypoxia. In addition, E‑cadherin was found to be involved in the gankyrin induced invasion of breast cancer cells due to hypoxia. The present study indicated that gankyrin deletion abrogated the increased metastatic potential of breast cancer cells under hypoxic conditions partly through regulating E‑cadherin, suggesting that an improved understanding of gankyrin may offer a potential therapeutic target for the treatment of human breast cancer metastasis.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Onozuka HK, Tsuchihara K and Esumi H: Hypoglycemic/hypoxic condition in vitro mimicking the tumor microenvironment markedly reduced the efficacy of anticancer drugs. Cancer Sci. 102:975–982. 2011.PubMed/NCBI
3	Louie E, Nik S, Chen JS, et al: Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res. 12:R942010. View Article : Google Scholar : PubMed/NCBI
4	Pouysségur J, Dayan F and Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 441:437–443. 2006.PubMed/NCBI
5	Harris AL: Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI
6	Krzywda S, Brzozowski AM, Higashitsuji H, et al: The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53. J Biol Chem. 279:1541–1545. 2004. View Article : Google Scholar : PubMed/NCBI
7	Lozano G and Zambetti GP: Gankyrin: an intriguing name for a novel regulator of p53 and RB. Cancer Cell. 8:3–4. 2005. View Article : Google Scholar : PubMed/NCBI
8	Higashitsuji H, Higashitsuji H, Itoh K, et al: The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell. 8:75–87. 2005. View Article : Google Scholar : PubMed/NCBI
9	Fu XY, Wang HY, Tan L, Liu SQ, Cao HF and Wu MC: Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance. World J Gastroenterol. 8:638–643. 2002.PubMed/NCBI
10	Ortiz CM, Ito T, Tanaka E, et al: Gankyrin oncoprotein overexpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance. Int J Cancer. 122:325–332. 2008. View Article : Google Scholar
11	Tang S, Yang G, Meng Y, et al: Overexpression of a novel gene gankyrin correlates with the malignant phenotype of colorectal cancer. Cancer Biol Ther. 9:88–95. 2010. View Article : Google Scholar : PubMed/NCBI
12	Meng Y, He L, Guo X, et al: Gankyrin promotes the proliferation of human pancreatic cancer. Cancer Lett. 297:9–17. 2010. View Article : Google Scholar : PubMed/NCBI
13	Li J, Knobloch TJ, Kresty LA, et al: Gankyrin, a biomarker for epithelial carcinogenesis, is overexpressed in human oral cancer. Anticancer Res. 31:2683–2692. 2011.PubMed/NCBI
14	Kim YH, Kim JH, Choi YW, et al: Gankyrin is frequently overexpressed in breast cancer and is associated with ErbB2 expression. Exp Mol Pathol. 94:360–365. 2012. View Article : Google Scholar : PubMed/NCBI
15	Zhen C, Chen L, Zhao Q, et al: Gankyrin promotes breast cancer cell metastasis by regulating Rac1 activity. Oncogene. 32:3452–3460. 2013. View Article : Google Scholar : PubMed/NCBI
16	Liu Y, Higashitsuji H, Higashitsuji H, et al: Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1. Biochem Biophys Res Commun. 432:22–27. 2013. View Article : Google Scholar : PubMed/NCBI
17	Liu N, Zhang G, Bi F, et al: RhoC is essential for the metastasis of gastric cancer. J Mol Med (Berl). 85:1149–1156. 2007. View Article : Google Scholar : PubMed/NCBI
18	Yang G, Tang SQ, Huang DS, Wang JW, Liu Y and Wang JY: Aplastic anemia transformed into acute myeloblastic leukemia M1 8 years later: a case report. Zhonghua Er Ke Za Zhi. 43:2212005.(In Chinese).
19	Fu J, Chen Y, Cao J, et al: p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1alpha pathways. Hepatology. 53:181–192. 2011. View Article : Google Scholar
20	Chen J, Imanaka N, Chen J and Griffin JD: Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer. 102:351–360. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zhu J, Sun L, Lin S, et al: BlyS is up-regulated by hypoxia and promotes migration of human breast cancer cells. J Exp Clin Cancer Res. 31:312012. View Article : Google Scholar : PubMed/NCBI
22	Dong LW, Yang GZ, Pan YF, et al: The oncoprotein p28GANK establishes a positive feedback loop in beta-catenin signaling. Cell Res. 21:1248–1261. 2011. View Article : Google Scholar : PubMed/NCBI