C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis

  • Authors:
    • Hui Shi
    • Yinting Mao
    • Qianqian Ju
    • Yingcheng Wu
    • Wen Bai
    • Peiwen Wang
    • Yudong Zhang
    • Maorong Jiang
  • View Affiliations

  • Published online on: April 12, 2018     https://doi.org/10.3892/ijo.2018.4367
  • Pages: 167-176
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

C-terminal binding protein‑2 (CtBP2) is a transcriptional co-repressor that is associated with tumorigenesis and tumor progression. It has been reported to predict a poor prognosis in several human cancers, including esophageal squamous cell carcinoma (ESCC). The present study aimed to investigate the involvement of CtBP2 in the cisplatin (DDP) resistance of the ECA109 ESCC cell line and its effect on the expression of apoptosis-associated proteins. Constructed recombinant lentiviruses were used for the knockdown or overexpression of CtBP2 in ECA109 cells, and the expression of CtBP2 was measured using reverse transcription-quantitative polymerase chain reaction and western blotting following transfection. MTT assays, Hoechst 33342 staining and flow cytometry (FCM) were applied to detect the influence of CtBP2 on the DDP-induced viability and apoptosis of the transfected ECA109 cells. In addition, the levels of apoptosis-associated proteins, including p53, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and activated caspase-3 were investigated in the transfected ECA109 cells. Stable ECA109 cells with CtBP2 overexpression or knockdown were successfully established. The results of the MTT, Hoechst 33342 and FCM assays demonstrated that overexpression of CtBP2 attenuated the reduction of cell viability and inhibited the cell apoptosis induced by DDP. Furthermore, the western blotting results indicated that CtBP2 overexpression inhibited the DDP-induced apoptosis of ECA109 cells via the reduction of p53, activated caspase-3 and Bax expression, and promotion of Bcl‑2 expression. Therefore, the present study indicated that CtBP2 reduced the susceptibility of ECA109 cells to DDP by regulating the expression of apoptosis-related proteins, suggesting that it may be a promising therapeutic target in ESCC in the future.

References

1 

Wakatsuki K, Matsumoto S, Migita K, Ito M, Kunishige T, Nakade H, Nakatani M, Kitano M, Takano M, Obayashi C, et al: Usefulness of computed tomography density of a tumor in predicting the response of advanced esophageal cancer to preoperative chemotherapy. Surgery. 162:823–835. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Servagi-Vernat S, Créhange G, Bonnetain F, Mertens C, Brain E and Bosset JF: Chemoradiation in elderly esophageal cancer patients: Rationale and design of a phase I/II multicenter study (OSAGE). BMC Cancer. 17:4832017. View Article : Google Scholar : PubMed/NCBI

3 

Canto MI, Abrams J, Kunzli H, Weusten B, Komatsu Y, Jobe BA and Lightdale CJ: Nitrous oxide cryotherapy for treatment of esophageal squamous cell neoplasia: Initial multicenter international experience with a novel portable cryoballoon ablation system (with video). Gastrointest Endosc. 87:574–581. 2018. View Article : Google Scholar

4 

Pennathur A, Gibson MK, Jobe BA and Luketich JD: Oesophageal carcinoma. Lancet. 381:400–412. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Li Y, Wu X, Li L, Liu Y, Xu C, Su D and Liu Z: The E3 ligase HECTD3 promotes esophageal squamous cell carcinoma (ESCC) growth and cell survival through targeting and inhibiting caspase-9 activation. Cancer Lett. 404:44–52. 2017. View Article : Google Scholar : PubMed/NCBI

6 

Kjaer DW, Larsson H, Svendsen LB and Jensen LS: Changes in treatment and outcome of oesophageal cancer in Denmark between 2004 and 2013. Br J Surg. 104:1338–1345. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Martin-Richard M, Díaz Beveridge R, Arrazubi V, Alsina M, Galan Guzmán M, Custodio AB, Gómez C, Muñoz FL, Pazo R and Rivera F: SEOM Clinical Guideline for the diagnosis and treatment of esophageal cancer (2016). Clin Transl Oncol. 18:1179–1186. 2016. View Article : Google Scholar : PubMed/NCBI

8 

Sohda M and Kuwano H: Current status and future prospects for esophageal cancer treatment. Ann Thorac Cardiovasc Surg. 23:1–11. 2017. View Article : Google Scholar :

9 

Arnold M, Laversanne M, Brown LM, Devesa SS and Bray F: Predicting the future burden of esophageal cancer by histological subtype: International trends in incidence up to 2030. Am J Gastroenterol. 112:1247–1255. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Palumbo Júnior A, Da Costa NM, Esposito F, Fusco A and Pinto LF: High Mobility Group A proteins in esophageal carcinomas. Cell Cycle. 15:2410–2413. 2016. View Article : Google Scholar : PubMed/NCBI

11 

Pan F, Mao H, Bu F, Tong X, Li J, Zhang S, Liu X, Wang L, Wu L, Chen R, et al: Sp1-mediated transcriptional activation of miR-205 promotes radioresistance in esophageal squamous cell carcinoma. Oncotarget. 8:5735–5752. 2017.

12 

Sugihara H, Ishimoto T, Miyake K, Izumi D, Baba Y, Yoshida N, Watanabe M and Baba H: Noncoding RNA expression aberration is associated with cancer progression and is a potential biomarker in esophageal aquamous cell carcinoma. Int J Mol Sci. 16:27824–27834. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Goense L, van Rossum PS, Kandioler D, Ruurda JP, Goh KL, Luyer MD, Krasna MJ and van Hillegersberg R: Stage-directed individualized therapy in esophageal cancer. Ann N Y Acad Sci. 1381:50–65. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Cleary JM, Mamon HJ, Szymonifka J, Bueno R, Choi N, Donahue DM, Fidias PM, Gaissert HA, Jaklitsch MT, Kulke MH, et al: Neoadjuvant irinotecan, cisplatin, and concurrent radiation therapy with celecoxib for patients with locally advanced esophageal cancer. BMC Cancer. 16:4682016. View Article : Google Scholar : PubMed/NCBI

15 

Phatak P, Byrnes KA, Mansour D, Liu L, Cao S, Li R, Rao JN, Turner DJ, Wang JY and Donahue JM: Overexpression of miR-214-3p in esophageal squamous cancer cells enhances sensitivity to cisplatin by targeting survivin directly and indirectly through CUG-BP1. Oncogene. 35:2087–2097. 2016. View Article : Google Scholar :

16 

Wu Y and Jiang M: The revolution of lung cancer treatment: from vaccines, to immune checkpoint inhibitors, to chimeric antigen receptor T therapy. Biotarget. 1:72017. View Article : Google Scholar

17 

Liu T, Li R, Zhao H, Deng J, Long Y, Shuai MT, Li Q, Gu H, Chen YQ and Leng AM: eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma. Oncotarget. 7:66851–66864. 2016.PubMed/NCBI

18 

Komatsu S, Ichikawa D, Kawaguchi T, Miyamae M, Okajima W, Ohashi T, Imamura T, Kiuchi J, Konishi H, Shiozaki A, et al: Circulating miR-21 as an independent predictive biomarker for chemoresistance in esophageal squamous cell carcinoma. Am J Cancer Res. 6:1511–1523. 2016.PubMed/NCBI

19 

Sumner ET, Chawla AT, Cororaton AD, Koblinski JE, Kovi RC, Love IM, Szomju BB, Korwar S, Ellis KC and Grossman SR: Transforming activity and therapeutic targeting of C-terminal-binding protein 2 in Apc-mutated neoplasia. Oncogene. 36:4810–4816. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Dai F, Xuan Y, Jin JJ, Yu S, Long ZW, Cai H, Liu XW, Zhou Y, Wang YN, Chen Z, et al: CtBP2 overexpression promotes tumor cell proliferation and invasion in gastric cancer and is associated with poor prognosis. Oncotarget. 8:28736–28749. 2017.PubMed/NCBI

21 

Riku M, Inaguma S, Ito H, Tsunoda T, Ikeda H and Kasai K: Down-regulation of the zinc-finger homeobox protein TSHZ2 releases GLI1 from the nuclear repressor complex to restore its transcriptional activity during mammary tumorigenesis. Oncotarget. 7:5690–5701. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Zheng X, Song T, Dou C, Jia Y and Liu Q: CtBP2 is an independent prognostic marker that promotes GLI1 induced epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget. 6:3752–3769. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Zhang C, Li S, Qiao B, Yang K, Liu R, Ma B, Liu Y, Zhang Z and Xu Y: CtBP2 overexpression is associated with tumorigenesis and poor clinical outcome of prostate cancer. Arch Med Sci. 11:1318–1323. 2015. View Article : Google Scholar

24 

Yang X, Sun Y, Li H, Shao Y, Zhao D, Yu W and Fu J: C-terminal binding protein-2 promotes cell proliferation and migration in breast cancer via suppression of p16INK4A. Oncotarget. 8:26154–26168. 2017.PubMed/NCBI

25 

Frietze S, O'Geen H, Littlepage LE, Simion C, Sweeney CA, Farnham PJ and Krig SR: Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with ERalpha. BMC Genomics. 15:5202014. View Article : Google Scholar : PubMed/NCBI

26 

May T, Yang J, Shoni M, Liu S, He H, Gali R, Ng SK, Crum C, Berkowitz RS and Ng SW: BRCA1 expression is epigenetically repressed in sporadic ovarian cancer cells by overexpression of C-terminal binding protein 2. Neoplasia. 15:600–608. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Guan C, Shi H, Wang H, Zhang J, Ni W, Chen B, Hou S, Yang X, Shen A and Ni R: CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A. J Cell Biochem. 114:1343–1354. 2013. View Article : Google Scholar

28 

Zhang J, Zhu J, Yang L, Guan C, Ni R, Wang Y, Ji L and Tian Y: Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression. Tumour Biol. 36:6701–6714. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Birts CN, Harding R, Soosaipillai G, Halder T, Azim-Araghi A, Darley M, Cutress RI, Bateman AC and Blaydes JP: Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance. Biol Cell. 103:1–19. 2010. View Article : Google Scholar : PubMed/NCBI

30 

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

31 

Ansari S, Chen C, Hasani-Sadrabadi MM, Yu B, Zadeh HH, Wu BM and Moshaverinia A: Hydrogel elasticity and microarchitecture regulate dental-derived mesenchymal stem cell-host immune system cross-talk. Acta Biomater. 60:181–189. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Mihaly SR, Sakamachi Y, Ninomiya-Tsuji J and Morioka S: Noncanocial cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFβ-activated kinase 1. Sci Rep. 7:29182017. View Article : Google Scholar

33 

Luna C, Mendoza N, Casao A, Pérez-Pé R, Cebrián-Pérez JA and Muiño-Blanco T: c-Jun N-terminal kinase and p38 mitogen-activated protein kinase pathways link capacitation with apoptosis and seminal plasma proteins protect sperm by interfering with both routes. Biol Reprod. 96:800–815. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Whiteside TL: Stimulatory role of exosomes in the context of therapeutic anti-cancer vaccines. Biotarget. 1:52017. View Article : Google Scholar

35 

Kwon D, Yun JY, Keam B, Kim YT and Jeon YK: Prognostic implications ofFGFR1andMYCstatus in esophageal squamous cell carcinoma. World J Gastroenterol. 22:9803–9812. 2016. View Article : Google Scholar : PubMed/NCBI

36 

Chen P, Zhang JY, Sha BB, Ma YE, Hu T, Ma YC, Sun H, Shi JX, Dong ZM and Li P: Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450. Oncotarget. 8:27471–27480. 2017.PubMed/NCBI

37 

Zhang HF, Wu C, Alshareef A, Gupta N, Zhao Q, Xu XE, Jiao JW, Li EM, Xu LY and Lai R: The PI3K/AKT/c-MYC axis promotes the acquisition of cancer stem-like features in esophageal squamous cell carcinoma. Stem Cells. 34:2040–2051. 2016. View Article : Google Scholar : PubMed/NCBI

38 

Konishi H, Fujiwara H, Shiozaki A, Shoda K, Kosuga T, Kubota T, Okamoto K and Otsuji E: Effects of neoadjuvant 5-fluorouracil and cisplatin therapy in patients with clinical stage II/III esophageal squamous cell carcinoma. Anticancer Res. 38:1017–1023. 2018.PubMed/NCBI

39 

Liu B, Wang C, Chen P, Cheng B and Cheng Y: RACKI induces chemotherapy resistance in esophageal carcinoma by upregulating the PI3K/AKT pathway and Bcl-2 expression. Onco Targets Ther. 11:211–220. 2018. View Article : Google Scholar : PubMed/NCBI

40 

Veena MS, Wilken R, Zheng JY, Gholkar A, Venkatesan N, Vira D, Ahmed S, Basak SK, Dalgard CL, Ravichandran S, et al: p16 protein and gigaxonin are associated with the ubiquitination of NFκB in cisplatin-induced senescence of cancer cells. J Biol Chem. 289:34921–34937. 2014. View Article : Google Scholar : PubMed/NCBI

41 

Geiger JL, Lazim AF, Walsh FJ, Foote RL, Moore EJ, Okuno SH, Olsen KD, Kasperbauer JL, Price DL, Garces YI, et al: Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck squamous cell carcinoma. Oral Oncol. 50:311–318. 2014. View Article : Google Scholar : PubMed/NCBI

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APA
Shi, H., Mao, Y., Ju, Q., Wu, Y., Bai, W., Wang, P. ... Jiang, M. (2018). C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis. International Journal of Oncology, 53, 167-176. https://doi.org/10.3892/ijo.2018.4367
MLA
Shi, H., Mao, Y., Ju, Q., Wu, Y., Bai, W., Wang, P., Zhang, Y., Jiang, M."C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis". International Journal of Oncology 53.1 (2018): 167-176.
Chicago
Shi, H., Mao, Y., Ju, Q., Wu, Y., Bai, W., Wang, P., Zhang, Y., Jiang, M."C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis". International Journal of Oncology 53, no. 1 (2018): 167-176. https://doi.org/10.3892/ijo.2018.4367