Tumor Biology

, Volume 37, Issue 2, pp 2127–2136 | Cite as

14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules

  • Kenneth K. Y. Lai
  • Kin Tak Chan
  • Mei Yuk Choi
  • Hector K. Wang
  • Eva Y. M. Fung
  • Ho Yu Lam
  • Winnie Tan
  • Lai Nar Tung
  • Daniel K. H. Tong
  • Raymond W. Y. Sun
  • Nikki P. Lee
  • Simon Law
Original Article


Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC.


14-3-3σ HMGB1 XPA Cisplatin Esophageal squamous cell carcinoma 


Funding support

This project was supported by Small Project Funding, The University of Hong Kong and Special Equipment Grant from the University Grants Committee of the Hong Kong Special Administrative Region, China (SEG_HKU02).

Conflicts of interest



  1. 1.
    Tong DK, Law S, Kwong DL, Wei WI, Ng RW, Wong KH. Current management of cervical esophageal cancer. World J Surg. 2011;35:600–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Law S, Kwong DL, Kwok KF, Wong KH, Chu KM, Sham JS, et al. Improvement in treatment results and long-term survival of patients with esophageal cancer: impact of chemoradiation and change in treatment strategy. Ann Surg. 2003;238:339–47. discussion 47-8.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Law S, Wong J. The current management of esophageal cancer. Adv Surg. 2007;41:93–119.CrossRefPubMedGoogle Scholar
  4. 4.
    Williams CJ, Whitehouse JM. Cis-platinum: a new anticancer agent. Br Med J. 1979;1:1689–91.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Li Y, Wang X, Li J, Ding W. Combination therapy of liposomal paclitaxel and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Eur J Gynaecol Oncol. 2015;36:54–8.PubMedGoogle Scholar
  6. 6.
    Du P, Zhang X, Liu H, Chen L. Lentivirus-Mediated RNAi Silencing Targeting ERCC1 Reverses Cisplatin Resistance in Cisplatin-Resistant Ovarian Carcinoma Cell Line. DNA Cell Biol. 2015;in press.Google Scholar
  7. 7.
    Mishra AK, Dormi SS, Turchi AM, Woods DS, Turchi JJ. Chemical inhibitor targeting the replication protein A-DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer. Biochem Pharmacol. 2015;93:25–33.CrossRefPubMedGoogle Scholar
  8. 8.
    Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015;16:436–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Liu Y, Bernauer AM, Yingling CM, Belinsky SA. HIF1a regulated expression of XPA contributes to cisplatin resistance in lung cancer. Carcinogenesis. 2012;33:1187–92.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    O'Grady S, Finn SP, Cuffe S, Richard DJ, O'Byrne KJ, Barr MP. The role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev. 2014;40:1161–70.CrossRefPubMedGoogle Scholar
  11. 11.
    Chen HH, Chen WC, Liang ZD, Tsai WB, Long Y, Aiba I et al. Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy. Expert Opin Ther Targets. 2015;1-11.Google Scholar
  12. 12.
    Motamedian E, Ghavami G, Sardari S. Investigation on metabolism of cisplatin resistant ovarian cancer using a genome scale metabolic model and microarray data. Iran J Basic Med Sci. 2015;18:267–76.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kang TH, Lindsey-Boltz LA, Reardon JT, Sancar A. Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc Natl Acad Sci U S A. 2010;107:4890–5.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cao B, Shi Q, Wang W. Higher expression of SIRT1 induced resistance of esophageal squamous cell carcinoma cells to cisplatin. J Thorac Dis. 2015;7:711–9.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Imanaka Y, Tsuchiya S, Sato F, Shimada Y, Shimizu K, Tsujimoto G. MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma. J Hum Genet. 2011;56:270–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Yamasaki M, Makino T, Masuzawa T, Kurokawa Y, Miyata H, Takiguchi S, et al. Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma. Br J Cancer. 2011;104:707–13.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chan KT, Choi MY, Lai KK, Tan W, Tung LN, Lam HY, et al. Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma. Oncol Rep. 2014;31:1296–304.PubMedGoogle Scholar
  18. 18.
    Fatima S, Lee NP, Tsang FH, Kolligs FT, Ng IO, Poon RT, et al. Dickkopf 4 (DKK4) acts on Wnt/beta-catenin pathway by influencing beta-catenin in hepatocellular carcinoma. Oncogene. 2012;31:4233–44.CrossRefPubMedGoogle Scholar
  19. 19.
    Hui MK, Chan KW, Luk JM, Lee NP, Chung Y, Cheung LC, et al. Cytoplasmic Forkhead Box M1 (FoxM1) in esophageal squamous cell carcinoma significantly correlates with pathological disease stage. World J Surg. 2012;36:90–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Hui MK, Lai KK, Chan KW, Luk JM, Lee NP, Chung Y, et al. Clinical correlation of nuclear survivin in esophageal squamous cell carcinoma. Med Oncol. 2012;29:3009–16.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Liu LX, Lee NP, Chan VW, Xue W, Zender L, Zhang C, et al. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology. 2009;50:1453–63.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mhawech P. 14-3-3 proteins--an update. Cell Res. 2005;15:228–36.CrossRefPubMedGoogle Scholar
  23. 23.
    Ko S, Kim JY, Jeong J, Lee JE, Yang WI, Jung WH. The role and regulatory mechanism of 14-3-3 sigma in human breast cancer. J Breast Cancer. 2014;17:207–18.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Akahira J, Sugihashi Y, Suzuki T, Ito K, Niikura H, Moriya T, et al. Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation. Clin Cancer Res. 2004;10:2687–93.CrossRefPubMedGoogle Scholar
  25. 25.
    Okumura H, Kita Y, Yokomakura N, Uchikado Y, Setoyama T, Sakurai H, et al. Nuclear expression of 14-3-3 sigma is related to prognosis in patients with esophageal squamous cell carcinoma. Anticancer Res. 2010;30:5175–9.PubMedGoogle Scholar
  26. 26.
    Perathoner A, Pirkebner D, Brandacher G, Spizzo G, Stadlmann S, Obrist P, et al. 14-3-3sigma expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Clin Cancer Res. 2005;11:3274–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Muhlmann G, Ofner D, Zitt M, Muller HM, Maier H, Moser P, et al. 14-3-3 sigma and p53 expression in gastric cancer and its clinical applications. Dis Markers. 2010;29:21–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Laimer K, Blassnig N, Spizzo G, Kloss F, Rasse M, Obrist P, et al. Prognostic significance of 14-3-3sigma expression in oral squamous cell carcinoma (OSCC). Oral Oncol. 2009;45:127–34.CrossRefPubMedGoogle Scholar
  29. 29.
    Han Z, Dimas K, Tian X, Wang Y, Hemmi H, Yamada K, et al. 14-3-3sigma-dependent resistance to cisplatin. Anticancer Res. 2009;29:2009–14.PubMedGoogle Scholar
  30. 30.
    Li Z, Dong Z, Myer D, Yip-Schneider M, Liu J, Cui P, et al. Role of 14-3-3sigma in poor prognosis and in radiation and drug resistance of human pancreatic cancers. BMC Cancer. 2010;10:598.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu Y, Prasad R, Wilson SH. HMGB1: roles in base excision repair and related function. Biochim Biophys Acta. 1799;2010:119–30.Google Scholar
  32. 32.
    Liu Y, Wilson SH. DNA base excision repair: a mechanism of trinucleotide repeat expansion. Trends Biochem Sci. 2012;37:162–72.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Camenisch U, Nageli H. XPA gene, its product and biological roles. Adv Exp Med Biol. 2008;637:28–38.CrossRefPubMedGoogle Scholar
  34. 34.
    Alekseev S, Coin F. Orchestral maneuvers at the damaged sites in nucleotide excision repair. Cell Mol Life Sci. 2015;72:2177–86.CrossRefPubMedGoogle Scholar
  35. 35.
    Lu F, Zhang J, Ji M, Li P, Du Y, Wang H, et al. miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1. Int J Oncol. 2014;45:383–92.PubMedGoogle Scholar
  36. 36.
    Li X, Wang S, Chen Y, Liu G, Yang X. miR-22 targets the 3' UTR of HMGB1 and inhibits the HMGB1-associated autophagy in osteosarcoma cells during chemotherapy. Tumour Biol. 2014;35:6021–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Benzinger A, Muster N, Koch HB, Yates 3rd JR, Hermeking H. Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer. Mol Cell Proteomics. 2005;4:785–95.CrossRefPubMedGoogle Scholar
  38. 38.
    Clocchiatti A, Florean C, Brancolini C. Class IIa HDACs: from important roles in differentiation to possible implications in tumourigenesis. J Cell Mol Med. 2011;15:1833–46.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Neher TM, Shuck SC, Liu JY, Zhang JT, Turchi JJ. Identification of novel small molecule inhibitors of the XPA protein using in silico based screening. ACS Chem Biol. 2010;5:953–65.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Kenneth K. Y. Lai
    • 1
  • Kin Tak Chan
    • 1
  • Mei Yuk Choi
    • 1
  • Hector K. Wang
    • 1
  • Eva Y. M. Fung
    • 2
  • Ho Yu Lam
    • 1
  • Winnie Tan
    • 1
  • Lai Nar Tung
    • 1
  • Daniel K. H. Tong
    • 1
  • Raymond W. Y. Sun
    • 2
    • 3
  • Nikki P. Lee
    • 1
  • Simon Law
    • 1
  1. 1.Department of SurgeryThe University of Hong KongHong KongChina
  2. 2.Department of ChemistryThe University of Hong KongHong KongChina
  3. 3.Department of ChemistryShantou UniversityShantouChina

Personalised recommendations