PEA15 promotes liver metastasis of colorectal cancer by upregulating the ERK/MAPK signaling pathway Retraction in /10.3892/or.2023.8574

Tang,Bo; Liang,Wenjin; Liao,Yong; Li,Zeming; Wang,Yan; Yan,Chao

doi:10.3892/or.2018.6825

PEA15 promotes liver metastasis of colorectal cancer by upregulating the ERK/MAPK signaling pathway

Retraction in: /10.3892/or.2023.8574

Authors:
- Bo Tang
- Wenjin Liang
- Yong Liao
- Zeming Li
- Yan Wang
- Chao Yan
View Affiliations

Affiliations: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China, Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi 541004, P.R. China
Published online on: October 25, 2018 https://doi.org/10.3892/or.2018.6825
Pages: 43-56
Copyright: © Tang 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

Liver metastasis is one of the major causes of death in patients with colorectal cancer, and although treatment has improved recently, the long‑term survival rate of patients has not improved significantly. In the present study, we used immunohistochemistry to determine that phosphoprotein enriched in astrocytes‑15 kDa (PEA15) was highly expressed in colorectal cancer tissues and liver metastatic cancer tissues. It was also highly expressed in metastatic colorectal cancer patients compared to non‑metastatic patients. Through clinicopathological data of patients with liver metastasis of colorectal cancer, we found that high expression of PEA15 was positively correlated with TNM staging, liver metastasis and poor prognosis of colorectal cancer patients. Using confocal immunofluorescence microscopy, western blotting and cell proliferation, migration and invasion assays, we also determined that PEA15 could promote cancer cell proliferation in vitro and in vivo, epithelial mesenchymal transition (EMT) and the characteristics of cancer stem cells in vitro, thus promoting the abilities of invasion and migration. In addition, we revealed that PEA15 promoted the liver metastasis of colorectal cancer cells in a xenograft tumor metastasis model. In addition, concerning the mechanism, we used gene chip analysis to determine that PEA15 upregulated the ERK/MAPK signaling pathway in colorectal cancer cells. Therefore, we concluded that PEA15 may be a potential biomarker for liver metastasis of colorectal cancer therapy. Collectively, PEA15 promoted the development of liver metastasis of colorectal cancer through the ERK/MAPK signaling pathway.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
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	Wu Z, Wei D, Gao W, Xu Y, Hu Z, Ma Z, Gao C, Zhu X and Li Q: TPO-induced metabolic reprogramming drives liver metastasis of colorectal cancer CD110+ tumor-initiating cells. Cell Stem Cell. 17:47–59. 2015. View Article : Google Scholar : PubMed/NCBI
4	Renault F, Formstecher E, Callebaut I, Junier MP and Chneiweiss H: The multifunctional protein PEA-15 is involved in the control of apoptosis and cell cycle in astrocytes. Biochem Pharmacol. 66:1581–1588. 2003. View Article : Google Scholar : PubMed/NCBI
5	Danziger N, Yokoyama M, Jay T, Cordier J, Glowinski J and Chneiweiss H: Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate. J Neurochem. 64:1016–1025. 1995. View Article : Google Scholar : PubMed/NCBI
6	Farina B, Doti N, Pirone L, Malgieri G, Pedone EM, Ruvo M and Fattorusso R: Molecular basis of the PED/PEA15 interaction with the C-terminal fragment of phospholipase D1 revealed by NMR spectroscopy. Biochim Biophys Acta. 1834:1572–1580. 2013. View Article : Google Scholar : PubMed/NCBI
7	Nagarajan A, Dogra SK, Liu AY, Green MR and Wajapeyee N: PEA15 regulates the DNA damage-induced cell cycle checkpoint and oncogene-directed transformation. Mol Cell Biol. 34:2264–2282. 2014. View Article : Google Scholar : PubMed/NCBI
8	Fiory F, Formisano P, Perruolo G and Beguinot F: Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism. Am J Physiol Endocrinol Metab. 297:E592–E601. 2009. View Article : Google Scholar : PubMed/NCBI
9	Mace PD, Wallez Y, Egger MF, Dobaczewska MK, Robinson H, Pasquale EB and Riedl SJ: Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Nat Commun. 4:16812013. View Article : Google Scholar : PubMed/NCBI
10	Quintavalle C, Hindupur SK, Quagliata L, Pallante P, Nigro C, Condorelli G, Andersen JB, Tagscherer KE, Roth W, Beguinot F, et al: Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib. Cell Death Dis. 8:e31382017. View Article : Google Scholar : PubMed/NCBI
11	Zanca C, Garofalo M, Quintavalle C, Romano G, Acunzo M, Ragno P, Montuori N, Incoronato M, Tornillo L, Baumhoer D, et al: PED is overexpressed and mediates TRAIL resistance in human non-small cell lung cancer. J Cell Mol Med. 12:2416–2426. 2008. View Article : Google Scholar : PubMed/NCBI
12	Shin M, Lee KE, Yang EG, Jeon H and Song HK: PEA-15 facilitates EGFR dephosphorylation via ERK sequestration at increased ER-PM contacts in TNBC cells. FEBS Lett. 589:1033–1039. 2015. View Article : Google Scholar : PubMed/NCBI
13	Bartholomeusz C, Rosen D, Wei C, Kazansky A, Yamasaki F, Takahashi T, Itamochi H, Kondo S, Liu J and Ueno NT: PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival. Cancer Res. 68:9302–9310. 2008. View Article : Google Scholar : PubMed/NCBI
14	Pinato DJ, Tan TM, Toussi ST, Ramachandran R, Martin N, Meeran K, Ngo N, Dina R and Sharma R: An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: Correlation with tumour phenotype and survival outcomes. Br J Cancer. 110:115–122. 2014. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression date using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Method. 25:402–408. 2001. View Article : Google Scholar
16	Li F and Mahato RI: RNA interference for improving the outcome of islet transplantation. Adv Drug Deliv Rev. 63:47–68. 2011. View Article : Google Scholar : PubMed/NCBI
17	Sotelo J, Esposito D, Duhagon MA, Banfield K, Mehalko J, Liao H, Stephens RM, Harris TJ, Munroe DJ and Wu X: Long-range enhancers on 8q24 regulate c-Myc. Proc Natl Acad Sci USA. 107:3001–3005. 2010. View Article : Google Scholar : PubMed/NCBI
18	Urosevic J, Garcia-Albéniz X, Planet E, Real S, Céspedes MV, Guiu M, Fernandez E, Bellmunt A, Gawrzak S, Pavlovic M, et al: Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH. Nat Cell Biol. 16:685–694. 2014. View Article : Google Scholar : PubMed/NCBI
19	Loboda A, Nebozhyn MV, Watters JW, Buser CA, Shaw PM, Huang PS, Van't Veer L, Tollenaar RA, Jackson DB, Agrawal D, et al: EMT is the dominant program in human colon cancer. BMC Med Genomics. 4:92011. View Article : Google Scholar : PubMed/NCBI
20	Formisano P, Ragno P, Pesapane A, Alfano D, Alberobello AT, Rea VE, Giusto R, Rossi FW, Beguinot F, Rossi G and Montuori N: PED/PEA-15 interacts with the 67 kD laminin receptor and regulates cell adhesion, migration, proliferation and apoptosis. J Cell Mol Med. 16:1435–1446. 2012. View Article : Google Scholar : PubMed/NCBI
21	Mor A and Philips MR: Compartmentalized Ras/MAPK signaling. Annu Rev Immunol. 24:771–800. 2006. View Article : Google Scholar : PubMed/NCBI
22	Fang JY and Richardson BC: The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 6:322–327. 2005. View Article : Google Scholar : PubMed/NCBI
23	Gu Y, Wang Q, Guo K, Qin W, Liao W, Wang S, Ding Y and Lin J: TUSC3 promotes colorectal cancer progression and epithelial-mesenchymal transition (EMT) through WNT/β-catenin and MAPK signalling. J Pathol. 239:60–71. 2016. View Article : Google Scholar : PubMed/NCBI
24	Lee J, Bartholomeusz C, Krishnamurthy S, Liu P, Saso H, Lafortune TA, Hortobagyi GN and Ueno NT: PEA-15 unphosphorylated at both serine 104 and serine 116 inhibits ovarian cancer cell tumorigenicity and progression through blocking β-catenin. Oncogenesis. 1:e222012. View Article : Google Scholar : PubMed/NCBI
25	Sulzmaier F, Opoku-Ansah J and Ramos JW: Phosphorylation is the switch that turns PEA-15 from tumor suppressor to tumor promoter. Small GTPases. 3:173–177. 2012. View Article : Google Scholar : PubMed/NCBI
26	Eckert A, Böck BC, Tagscherer KE, Haas TL, Grund K, Sykora J, Herold-Mende C, Ehemann V, Hollstein M, Chneiweiss H, et al: The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway. Oncogene. 27:1155–1166. 2008. View Article : Google Scholar : PubMed/NCBI
27	Li X, Iomini C, Hyink D and Wilson PD: PRKX critically regulates endothelial cell proliferation, migration, and vascular-like structure formation. Dev Biol. 356:475–485. 2011. View Article : Google Scholar : PubMed/NCBI