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

Abstract

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.

Keywords

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

Notes

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

None

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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

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