14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules.
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.
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Kenneth K Y
KK
Lai
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Kin Tak
KT
Chan
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Mei Yuk
MY
Choi
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Hector K
HK
Wang
Department of Chemistry, The University of Hong Kong, Hong Kong, China.
Eva Y M
EY
Fung
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Ho Yu
HY
Lam
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Winnie
W
Tan
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Lai Nar
LN
Tung
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Daniel K H
DK
Tong
Department of Chemistry, The University of Hong Kong, Hong Kong, China.|Department of Chemistry, Shantou University, Shantou, Guangdong, China.
Raymond W Y
RW
Sun
Department of Surgery, The University of Hong Kong, Hong Kong, China. nikkilee@hku.hk.
Nikki P
NP
Lee
Department of Surgery, The University of Hong Kong, Hong Kong, China. slaw@hku.hk.
Simon
S
Law
D048948:14-3-3 Proteins / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004938:Esophageal Neoplasms / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D005095:Exoribonucleases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D016133:Polymerase Chain Reaction; D059467:Transcriptome; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D005095:Exoribonucleases; C413442:SFN protein, human; D002945:Cisplatin
14-3-3σ; Cisplatin; Esophageal squamous cell carcinoma; HMGB1; XPA