Association between RNF2+P‑AKT expression in pretreatment biopsy specimens, and poor survival following radiotherapy in patients with esophageal squamous cell carcinoma

Li,Qiaofang; Li,Shuguang; Yang,Xingxiao; Zhang,Xueyuan; Song,Chunyang; Zhu,Shuchai

doi:10.3892/ol.2019.10727

Association between RNF2+P‑AKT expression in pretreatment biopsy specimens, and poor survival following radiotherapy in patients with esophageal squamous cell carcinoma

Authors:
- Qiaofang Li
- Shuguang Li
- Xingxiao Yang
- Xueyuan Zhang
- Chunyang Song
- Shuchai Zhu
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Affiliations: Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, Department of Infectious Disease, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
Published online on: August 7, 2019 https://doi.org/10.3892/ol.2019.10727
Pages: 3734-3742
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The protein expression levels of Ring finger protein 2 (RNF2) and phosphor‑protein kinase B (P‑AKT) were determined in esophageal squamous cell carcinoma (ESCC) tissues, and the association between patient clinicopathological characteristics and survival time following definitive intensity‑modulated radiotherapy was assessed. Cancerous biopsy tissues were collected from patients with ESCC at The Fourth Affiliated Hospital of Hebei Medical University between January 2010 and December 2013. Of these 99 cases, 83 were used to analyze the protein expression level of RNF2 (89.2% positive), 85 for P‑AKT (65.9% positive) and 80 for RNF2+P‑AKT protein expression levels (62.5% both positive). The expression levels of RNF2 protein in ESCC were associated with tumor volume (P=0.024), whilst those of P‑AKT and RNF2+PAKT were associated with sex (P=0.041 and P=0.003, respectively). There were no significant differences in overall survival (OS) or progression‑free survival (PFS) rate between the RNF2‑ and the RNF2+‑+++ groups (P=0.134 and P=0.366, respectively), or between the P‑AKT‑ group and P‑AKT+‑+++ group (P=0.468; P=0.580, respectively). The 1‑, 3‑ and 5‑year OS rates were 68.0, 28.0, and 20.0%, and 86.7, 53.3, and 31.1%, in the RNF2/P‑AKT+ group and Other group, respectively (χ2=4.205; P=0.040). Multivariate analysis revealed that age, T stage and RNF2+P‑AKT expression were independent prognostic factors for ESCC (P=0.010, P=0.008 and P=0.010, respectively). The expression of RNF2+P‑AKT combined was an independent prognostic factor affecting survival rate, and therefore presents a potential prognostic indicator for patients with ESCC, treated with definitive radiotherapy.

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1	Global Burden of Disease Cancer Collaboration, ; Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, Maclntyre MF, Allen C, Hansen G, Woodbrook R, et al: The global burden of cancer 2013. JAMA Oncol. 1:505–527. 2015. View Article : Google Scholar : PubMed/NCBI
2	Pennathur A, Gibson MK, Jobe BA and Luketich JD: Oesophageal carcinoma. Lancet. 381:400–412. 2013. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD and Jemal A: Cancer Statistics. 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
4	Otte AP and Kwaks TH: Gene repression by Polycomb group protein complexes: A distinct complex for every occasion? Curr Opin Genet Dev. 13:448–454. 2003. View Article : Google Scholar : PubMed/NCBI
5	Levine SS, Weiss A, Erdjument-Bromage H, Shao Z, Tempst P and Kingston RE: The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol Cell Biol. 22:6070–6078. 2002. View Article : Google Scholar : PubMed/NCBI
6	Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P and Reinberg D: Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16:2893–2905. 2002. View Article : Google Scholar : PubMed/NCBI
7	Bentley ML, Corn JE, Dong KC, Phung Q, Cheung TK and Cochran AG: Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex. EMBO J. 30:3285–3297. 2011. View Article : Google Scholar : PubMed/NCBI
8	Buchwald G, van der Stoop P, Weichenrieder O, Perrakis A, van Lohuizen M and Sixma TK: Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b. EMBO J. 25:2465–2474. 2006. View Article : Google Scholar : PubMed/NCBI
9	Li Z, Cao R, Wang M, Myers MP, Zhang Y and Xu RM: Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. J Biol Chem. 281:20643–20649. 2006. View Article : Google Scholar : PubMed/NCBI
10	Ruan ZP, Xu R, Lv Y, Tian T, Wang WJ, Guo H and Nan KJ: Bmi1 knockdown inhibits hepatocarcinogenesis. Int J Oncol. 42:261–268. 2013. View Article : Google Scholar : PubMed/NCBI
11	Song W, Tao K, Li H, Jin C, Song Z, Li J, Shi H, Li X, Dang Z and Dou K: Bmi-1 is related to proliferation, survival and poor prognosis in pancreatic cancer. Cancer Sci. 101:1754–1760. 2010. View Article : Google Scholar : PubMed/NCBI
12	Sánchez-Beato M, Sánchez E, González-Carreró J, Morente M, Díez A, Sánchez-Verde L, Martín MC, Cigudosa JC, Vidal M and Piris MA: Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays. Mod Pathol. 19:684–694. 2006. View Article : Google Scholar : PubMed/NCBI
13	Bosch A, Panoutsopoulou K, Corominas JM, Gimeno R, Moreno-Bueno G, Martín-Caballero J, Morales S, Lobato T, Martínez-Romero C, Farias EF, et al: The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells. Oncotarget. 5:2065–2076. 2014. View Article : Google Scholar : PubMed/NCBI
14	Su WJ, Fang JS, Cheng F, Liu C, Zhou F and Zhang J: RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development. Proc Natl Acad Sci USA. 110:1720–1725. 2013. View Article : Google Scholar : PubMed/NCBI
15	Yang XX, Ma M, Sang MX, Wang XX, Song H, Liu ZK and Zhu SC: Radiosensitization of esophageal carcinoma cells by knockdown of RNF2 expression. Int J Oncol. 48:1985–1996. 2016. View Article : Google Scholar : PubMed/NCBI
16	Yang XX, Ma M, Sang MX, Zhang XY, Liu ZK, Song H and Zhu SC: BMI-1 suppression increases the radiosensitivity of oesophageal carcinoma via the PI3K/Akt signaling pathway. Oncol Rep. 39:667–678. 2018.PubMed/NCBI
17	Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC Cancer Staging Mamal. 7th. Springer-Verlag; New York, NY: pp. 103–15. 2009
18	Masunaga R, Kohno H, Dhar DK, Ohno S, Shibakita M, Kinugasa S, Yoshimura H, Tachibana M, Kubota H and Nagasue N: Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res. 6:4064–4068. 2000.PubMed/NCBI
19	Wu D, Ding Y, Wang S, Zhang Q and Liu L: Increased expression of high mobility group box 1 (HMGB1) is associated with progression and poor prognosis in human nasopharyngeal carcinoma. J Pathol. 216:167–175. 2008. View Article : Google Scholar : PubMed/NCBI
20	Chen J, Xu H, Zou X, Wang J, Zhu Y, Chen H, Shen B, Deng X, Zhou A, Chin YE, et al: Snail recruits Ring1B to mediate transcriptional repression and cell migration in pancreatic cancer cells. Cancer Res. 74:4353–4363. 2014. View Article : Google Scholar : PubMed/NCBI
21	Chen S, Chen J, Zhan Q, Zhu Y, Chen H, Deng X, Hou Z, Shen B, Chen Y and Peng C: H2AK119Ub1 and H3K27Me3 in molecular staging for survival prediction of patients with pancreatic ductal adenocarcinoma. Oncotarget. 5:10421–10433. 2014.PubMed/NCBI
22	Rai K, Akdemir KC, Kwong LN, Fiziev P, Wu CJ, Keung EZ, Sharma S, Samant NS, Williams M, Axelrad JB, et al: Dual Roles of RNF2 in melanoma progression. Cancer Discov. 5:1314–1327. 2015. View Article : Google Scholar : PubMed/NCBI
23	van der Stoop P, Boutsma EA, Hulsman D, Noback S, Heimerikx M, Kerkhoven RM, Voncken JW, Wessels LF and van Lohuizen M: Ubiquitin E3 ligase Ring1b/Rnf2 of polycomb repressive complex 1 contributes to stable maintenance of mouse embryonic stem cells. PLoS One. 3:e22352008. View Article : Google Scholar : PubMed/NCBI
24	van der Velden YU, Wang L, Querol Cano L and Haramis AP: The polycomb group protein ring1b/rnf2 is specifically required for craniofacial development. PLoS One. 8:e739972013. View Article : Google Scholar : PubMed/NCBI
25	Zhang XJ, Yu HY, Cai YJ and Ke M: Lycium barbarum polysaccharides inhibit proliferation and migration of bladder cancer cell lines BIU87 by suppressing Pi3K/AKT pathway. Oncotarget. 8:5936–5942. 2017.PubMed/NCBI
26	Bussink J, van der Kogel AJ and Kaanders JH: Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol. 9:288–296. 2008. View Article : Google Scholar : PubMed/NCBI
27	Deng R, Tang J, Ma JG, Chen SP, Xia LP, Zhou WJ, Li DD, Feng GK, Zeng YX and Zhu XF: PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation. Oncogene. 30:944–955. 2011. View Article : Google Scholar : PubMed/NCBI
28	Zhang Y, Zheng L, Ding Y, Li Q, Wang R, Liu T, Sun Q, Yang H, Peng S, Wang W and Chen L: MiR-20a induces cell radioresistance by activating the PTEN/PI3K/Akt signaling pathway in hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 92:1132–1140. 2015. View Article : Google Scholar : PubMed/NCBI
29	Yoshioka A, Miyata H, Doki Y, Yasuda T, Yamasaki M, Motoori M, Okada K, Matsuyama J, Makari Y, Sohma I, et al: The activation of Akt during preoperative chemotherapy for esophageal cancer correlates with poor prognosis. Oncol Rep. 19:1099–1107. 2008.PubMed/NCBI
30	Schmitz KJ, Otterbach F, Callies R, Levkau B, Hölscher M, Hoffmann O, Grabellus F, Kimmig R, Schmid KW and Baba HA: Prognostic relevance of activated Akt kinase in node-negative breast cancer: A clinicopathological study of 99 cases. Mod Pathol. 17:15–21. 2004. View Article : Google Scholar : PubMed/NCBI
31	Wang L, Liu JL, Yu L, Liu XX, Wu HM, Lei FY, Wu S and Wang X: Downregulated miR-495 [Corrected] inhibits the G1-S Phase transition by targeting Bmi-1 in breast cancer. Medicine (Baltimore). 94:e7182015. View Article : Google Scholar : PubMed/NCBI
32	Jin M, Zhang T, Liu C, Badeaux MA, Liu B, Liu R, Jeter C, Chen X, Vlassov AV and Tang DG: miRNA-128 suppresses prostate cancer by inhibiting BMI-1 to inhibit tumor-initiating cells. Cancer Res. 74:4183–4195. 2014. View Article : Google Scholar : PubMed/NCBI
33	Yang F, Lv LZ, Cai QC and Jiang Y: Potential roles of EZH2, Bmi-1 and miR-203 in cell proliferation and invasion in hepatocellular carcinoma cell line Hep3B. World J Gastroenterol. 21:13268–13276. 2015. View Article : Google Scholar : PubMed/NCBI
34	Richly H, Aloia L and Di Croce L: Roles of the Polycomb group proteins in stem cells and cancer. Cell Death Dis. 2:e2042011. View Article : Google Scholar : PubMed/NCBI
35	Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS and Zhang Y: Role of histone H2A ubiquitination in Polycomb silencing. Nature. 431:873–878. 2004. View Article : Google Scholar : PubMed/NCBI
36	Rao PS, Satelli A, Zhang S, Srivastava SK, Srivenugopal KS and Rao US: RNF2 is the target for phosphorylation by the p38 MAPK and ERK signaling pathways. Proteomics. 9:2776–2787. 2009. View Article : Google Scholar : PubMed/NCBI
37	Shi HY and Zhu SC: Radiosensitization of esophageal cancer cells ECA109 by knockdown of H2AX. Thorac Cancer. 4:254–263. 2013. View Article : Google Scholar : PubMed/NCBI
38	Ohtsubo M, Yasunaga S, Ohno Y, Tsumura M, Okada S, Ishikawa N, Shirao K, Kikuchi A, Nishitani H, Kobayashi M and Takihara Y: Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity. Proc Natl Acad Sci USA. 105:10396–10401. 2008. View Article : Google Scholar : PubMed/NCBI
39	Sen N, Satija YK and Das S: PGC-1α, a key modulator of p53, promotes cell survival upon metabolic stress. Mol Cell. 44:621–634. 2011. View Article : Google Scholar : PubMed/NCBI
40	Ben-Saadon R, Zaaroor D, Ziv T and Ciechanover A: The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity. Mol Cell. 24:701–711. 2006. View Article : Google Scholar : PubMed/NCBI