UBE2C induces EMT through Wnt/β‑catenin and PI3K/Akt signaling pathways by regulating phosphorylation levels of Aurora-A

Wang,Rui; Song,Yue; Liu,Xi; Wang,Qixue; Wang,Yunfei; Li,Liwei; Kang,Chunsheng; Zhang,Qingyu

doi:10.3892/ijo.2017.3880

UBE2C induces EMT through Wnt/β‑catenin and PI3K/Akt signaling pathways by regulating phosphorylation levels of Aurora-A

Authors:
- Rui Wang
- Yue Song
- Xi Liu
- Qixue Wang
- Yunfei Wang
- Liwei Li
- Chunsheng Kang
- Qingyu Zhang
View Affiliations

Affiliations: Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
Published online on: February 17, 2017 https://doi.org/10.3892/ijo.2017.3880
Pages: 1116-1126
Copyright: © Wang 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

The ubiquitin-conjugating enzyme 2C (UBE2C) is the key component in the ubiquitin proteasome system (UPS) by partnering with the anaphase‑promoting complex (APC/C). A high UBE2C protein expression level has been reported in various types of human tumors. However, little is known about the precise mechanism by which UBE2C expression is downregulated in gastric cancer. We found in MGC‑803 and SGC‑7901 gastric cancer cells UBE2C‑deficient G2/M phase arrest in the cell cycle and subsequently decreased gastric adenocarcinoma tumorigenesis. In the previous study, we identified Aurora-A (AURKA) as the hub gene of the gastric cancer linkage network based genome‑wide association study (eGWAS). Furthermore, knockdown of UBE2C using siRNA markedly reduced the level of phosphorylation AURKA (p‑AURKA) via Wnt/β‑catenin and PI3K/Akt signaling pathways suppressed the occurrence and development of gastric cancer. Additionally, the expression of E‑cadherin was up‑regulated and N-cadherin was downregulated in response to UBE2C knockdown and inhibits epithelial-mesenchymal transition (EMT). Collectively, our data suggest that the activity of AURKA might be regulated by UBE2C through regulating the activity of APC/C. UBE2C may be a new marker in the diagnosis of gastric cancer and may be a potential therapeutic target for the treatment of gastric adenocarcinoma.

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
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Yang L: Incidence and mortality of gastric cancer in China. World J Gastroenterol. 12:17–20. 2006. View Article : Google Scholar : PubMed/NCBI
4	Tamura G: Genetic and epigenetic alterations of tumor suppressor and tumor-related genes in gastric cancer. Histol Histopathol. 17:323–329. 2002.PubMed/NCBI
5	Zhong JL and Huang CZ: Ubiquitin proteasome system research in gastrointestinal cancer. World J Gastrointest Oncol. 8:198–206. 2016. View Article : Google Scholar : PubMed/NCBI
6	Hao Z, Zhang H and Cowell J: Ubiquitin-conjugating enzyme UBE2C: Molecular biology, role in tumorigenesis, and potential as a biomarker. Tumour Biol. 33:723–730. 2012. View Article : Google Scholar
7	Xie C, Powell C, Yao M, Wu J and Dong Q: Ubiquitin-conjugating enzyme E2C: A potential cancer biomarker. Int J Biochem Cell Biol. 47:113–117. 2014. View Article : Google Scholar
8	Wagner KW, Sapinoso LM, El-Rifai W, Frierson HF, Butz N, Mestan J, Hofmann F, Deveraux QL and Hampton GM: Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin. Oncogene. 23:6621–6629. 2004. View Article : Google Scholar : PubMed/NCBI
9	Wing SS and Jain P: Molecular cloning, expression and characterization of a ubiquitin conjugation enzyme (E2_17kB) highly expressed in rat testis. Biochem J. 305:125–132. 1995. View Article : Google Scholar
10	Jiang L, Huang CG, Lu YC, Luo C, Hu GH, Liu HM, Chen JX and Han HX: Expression of ubiquitin-conjugating enzyme E2C/UbcH10 in astrocytic tumors. Brain Res. 1201:161–166. 2008. View Article : Google Scholar : PubMed/NCBI
11	Chou CP, Huang NC, Jhuang SJ, Pan HB, Peng NJ, Cheng JT, Chen CF, Chen JJ and Chang TH: Ubiquitin-conjugating enzyme UBE2C is highly expressed in breast microcalcification lesions. PLoS One. 9:e939342014. View Article : Google Scholar : PubMed/NCBI
12	Perrotta I, Bruno L, Maltese L, Russo E, Donato A and Donato G: Immunohistochemical analysis of the ubiquitin-conjugating enzyme UbcH10 in lung cancer: A useful tool for diagnosis and therapy. J Histochem Cytochem. 60:359–365. 2012. View Article : Google Scholar : PubMed/NCBI
13	Pallante P, Malapelle U, Berlingieri MT, Bellevicine C, Sepe R, Federico A, Rocco D, Galgani M, Chiariotti L, Sanchez-Cespedes M, et al: UbcH10 overexpression in human lung carcinomas and its correlation with EGFR and p53 mutational status. Eur J Cancer. 49:1117–1126. 2013. View Article : Google Scholar
14	Pallante P, Berlingieri MT, Troncone G, Kruhoffer M, Orntoft TF, Viglietto G, Caleo A, Migliaccio I, Decaussin-Petrucci M, Santoro M, et al: UbcH10 overexpression may represent a marker of anaplastic thyroid carcinomas. Br J Cancer. 93:464–471. 2005. View Article : Google Scholar : PubMed/NCBI
15	Lin J, Raoof DA, Wang Z, Lin MY, Thomas DG, Greenson JK, Giordano TJ, Orringer MB, Chang AC, Beer DG, et al: Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma. Neoplasia. 8:1062–1071. 2006. View Article : Google Scholar
16	Ieta K, Ojima E, Tanaka F, Nakamura Y, Haraguchi N, Mimori K, Inoue H, Kuwano H and Mori M: Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression. Int J Cancer. 121:33–38. 2007. View Article : Google Scholar : PubMed/NCBI
17	Bavi P, Uddin S, Ahmed M, Jehan Z, Bu R, Abubaker J, Sultana M, Al-Sanea N, Abduljabbar A, Ashari LH, et al: Bortezomib stabilizes mitotic cyclins and prevents cell cycle progression via inhibition of UBE2C in colorectal carcinoma. Am J Pathol. 178:2109–2120. 2011. View Article : Google Scholar : PubMed/NCBI
18	Li SZ, Song Y, Zhang HH, Jin BX, Liu Y, Liu WB, Zhang XD and Du RL: UbcH10 overexpression increases carcinogenesis and blocks ALLN susceptibility in colorectal cancer. Sci Rep. 4:69102014. View Article : Google Scholar : PubMed/NCBI
19	Chen S, Chen Y, Hu C, Jing H, Cao Y and Liu X: Association of clinicopathological features with UbcH10 expression in colorectal cancer. J Cancer Res Clin Oncol. 136:419–426. 2010. View Article : Google Scholar
20	van Ree JH, Jeganathan KB, Malureanu L and van Deursen JM: Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. J Cell Biol. 188:83–100. 2010. View Article : Google Scholar : PubMed/NCBI
21	Fukasawa K: Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer. 7:911–924. 2007. View Article : Google Scholar : PubMed/NCBI
22	Hu N, Wang Z, Song X, Wei L, Kim BS, Freedman ND, Baek J, Burdette L, Chang J, Chung C, et al: Genome-wide association study of gastric adenocarcinoma in Asia: A comparison of associations between cardia and non-cardia tumours. Gut. 65:1611–1618. 2016. View Article : Google Scholar
23	Oh S and Oh S: Epidemiological and genome-wide association study of gastritis or gastric ulcer in korean populations. Genomics Inform. 12:127–133. 2014. View Article : Google Scholar : PubMed/NCBI
24	Saeki N, Ono H, Sakamoto H and Yoshida T: Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study. Cancer Sci. 104:1–8. 2013. View Article : Google Scholar
25	Liu X, Li Z, Song Y, Wang R, Han L, Wang Q, Jiang K, Kang C and Zhang Q: AURKA induces EMT by regulating histone modification through Wnt/β-catenin and PI3K/Akt signaling pathway in gastric cancer. Oncotarget. 7:33152–33164. 2016.PubMed/NCBI
26	Mahankali M, Henkels KM, Gomez-Cambronero J and Speranza F: A non-mitotic role for Aurora kinase A as a direct activator of cell migration upon interaction with PLD, FAK and Src. J Cell Sci. 128:516–526. 2015. View Article : Google Scholar :
27	Do TV, Xiao F, Bickel LE, Klein-Szanto AJ, Pathak HB, Hua X, Howe C, O'Brien SW, Maglaty M, Ecsedy JA, et al: Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion. Oncogene. 33:539–549. 2014. View Article : Google Scholar
28	Tong T, Zhong Y, Kong J, Dong L, Song Y, Fu M, Liu Z, Wang M, Guo L, Lu S, et al: Overexpression of Aurora-A contributes to malignant development of human esophageal squamous cell carcinoma. Clin Cancer Res. 21:7304–7310. 2004. View Article : Google Scholar
29	Zhang Y, Han T, Wei G and Wang Y: Inhibition of microRNA-17/20a suppresses cell proliferation in gastric cancer by modulating UBE2C expression. Oncol Rep. 33:2529–2536. 2015.PubMed/NCBI
30	Shuliang S, Lei C, Guangwu J and Changjie L: Involvement of ubiquitin-conjugating enzyme E2C in proliferation and invasion of prostate carcinoma cells. Oncol Res. 21:121–127. 2013. View Article : Google Scholar
31	Rape M, Reddy SK and Kirschner MW: The processivity of multiubiquitination by the APC determines the order of substrate degradation. Cell. 124:89–103. 2006. View Article : Google Scholar : PubMed/NCBI
32	Alfieri C, Chang L, Zhang Z, Yang J, Maslen S, Skehel M and Barford D: Molecular basis of APC/C regulation by the spindle assembly checkpoint. Nature. 536:431–436. 2016. View Article : Google Scholar : PubMed/NCBI
33	Garvanska DH, Larsen MS and Nilsson J: Synergistic inhibition of the APC/C by the removal of APC15 in HCT116 cells lacking UBE2C. Biol Open. 5:1441–1448. 2016. View Article : Google Scholar : PubMed/NCBI
34	Vasiljevic A, Champier J, Figarella-Branger D, Wierinckx A, Jouvet A and Fevre-Montange M: Molecular characterization of central neurocytomas: Potential markers for tumor typing and progression. Neuropathology. 33:149–161. 2013. View Article : Google Scholar
35	Gheldof A and Berx G: Cadherins and epithelial-to-mesenchymal transition. Prog Mol Biol Transl Sci. 116:317–336. 2013. View Article : Google Scholar : PubMed/NCBI
36	Dar AA, Belkhiri A and El-Rifai W: The aurora kinase A regulates GSK-3β in gastric cancer cells. Oncogene. 28:866–875. 2009. View Article : Google Scholar
37	Radice GL: N-cadherin-mediated adhesion and signaling from development to disease: Lessons from mice. Prog Mol Biol Transl Sci. 116:263–289. 2013. View Article : Google Scholar : PubMed/NCBI
38	Lee JY and Kong G: Roles and epigenetic regulation of epithelial-mesenchymal transition and its transcription factors in cancer initiation and progression. Cellular and molecular life sciences. Cell Mol Life Sci. 73:4643–4660. 2016. View Article : Google Scholar : PubMed/NCBI
39	Phillips S and Kuperwasser C: SLUG: Critical regulator of epithelial cell identity in breast development and cancer. Cell Adhes Migr. 8:578–587. 2014. View Article : Google Scholar
40	Zhang P, Hu P, Shen H, Yu J, Liu Q and Du J: Prognostic role of Twist or Snail in various carcinomas: A systematic review and meta-analysis. Eur J Clin Invest. 44:1072–1094. 2014. View Article : Google Scholar : PubMed/NCBI