TRIB2 contributes to cisplatin resistance in small cell lung cancer

Yuanxin Liang, Dong Yu, Roman Perez-Soler, Jim Klostergaard, Yiyu Zou

Research output: Contribution to journalArticle

Abstract

Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype and so far, no favorable therapeutic strategy has been established for chemo-resistant SCLC. Cisplatin is one of the most important components among all standard polychemotherapeutic regimens for SCLC; therefore, this study focused on revealing Cisplatin-resistance mechanism(s) in this disease. Cisplatin-resistant SCLC cells were generated in the NCI-H69 xenograft model in nude mice by continuous intravenous administration of Cisplatin; Cisplatin resistance of the tumor cells was confirmed by in vitro and in vivo tests, and the gene expression profile of the resistant cells was determined using microarray analysis. A significantly higher expression of tribbles pseudokinase 2 (TRIB2) mRNA in the Cisplatin-resistant cells was found compared to parental H69 cells. Further, the Cisplatin-resistance level was decreased when TRIB2 expression was knocked down. The mRNA and protein levels of CCAAT/enhancer binding protein alpha (CEBPA), known to be a transcription factor regulating cell differentiation and a target for degradation by TRIB2, as well as selected cancer stem cell makers in the Cisplatin-resistant cells, were measured. We found that CEBPA protein levels could be upregulated by knocking down the overexpressed TRIB2, which also reversed the Cisplatin-resistance of these cells; further, the Cisplatin-resistant SCLC cells demonstrated certain cancer stem cell-like properties. Similar patterns were also observed in limited human tumor specimens of chemo-resistant SCLC patients: namely, overexpressed TRIB2 and undetected CEBPA proteins. Our study revealed a possible molecular mechanism for Cisplatin-resistant SCLC involving induced TRIB2 overexpression and downregulation of CEBPA protein. We propose that this mechanism is a potential therapeutic target to circumvent chemo-resistance in SCLC.

Original languageEnglish (US)
Pages (from-to)109596-109608
Number of pages13
JournalOncotarget
Volume8
Issue number65
DOIs
StatePublished - Jan 1 2017

Fingerprint

Small Cell Lung Carcinoma
Cisplatin
CCAAT-Enhancer-Binding Protein-alpha
Neoplastic Stem Cells
Proteins
Messenger RNA
Microarray Analysis
Transcriptome
Heterografts
Nude Mice
Intravenous Administration
Cell Differentiation
Lung Neoplasms
Neoplasms
Transcription Factors
Down-Regulation

Keywords

  • CEBPA
  • Cisplatin
  • Resistance
  • Small cell lung cancer
  • TRIB2

ASJC Scopus subject areas

  • Oncology

Cite this

TRIB2 contributes to cisplatin resistance in small cell lung cancer. / Liang, Yuanxin; Yu, Dong; Perez-Soler, Roman; Klostergaard, Jim; Zou, Yiyu.

In: Oncotarget, Vol. 8, No. 65, 01.01.2017, p. 109596-109608.

Research output: Contribution to journalArticle

Liang, Yuanxin ; Yu, Dong ; Perez-Soler, Roman ; Klostergaard, Jim ; Zou, Yiyu. / TRIB2 contributes to cisplatin resistance in small cell lung cancer. In: Oncotarget. 2017 ; Vol. 8, No. 65. pp. 109596-109608.
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abstract = "Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype and so far, no favorable therapeutic strategy has been established for chemo-resistant SCLC. Cisplatin is one of the most important components among all standard polychemotherapeutic regimens for SCLC; therefore, this study focused on revealing Cisplatin-resistance mechanism(s) in this disease. Cisplatin-resistant SCLC cells were generated in the NCI-H69 xenograft model in nude mice by continuous intravenous administration of Cisplatin; Cisplatin resistance of the tumor cells was confirmed by in vitro and in vivo tests, and the gene expression profile of the resistant cells was determined using microarray analysis. A significantly higher expression of tribbles pseudokinase 2 (TRIB2) mRNA in the Cisplatin-resistant cells was found compared to parental H69 cells. Further, the Cisplatin-resistance level was decreased when TRIB2 expression was knocked down. The mRNA and protein levels of CCAAT/enhancer binding protein alpha (CEBPA), known to be a transcription factor regulating cell differentiation and a target for degradation by TRIB2, as well as selected cancer stem cell makers in the Cisplatin-resistant cells, were measured. We found that CEBPA protein levels could be upregulated by knocking down the overexpressed TRIB2, which also reversed the Cisplatin-resistance of these cells; further, the Cisplatin-resistant SCLC cells demonstrated certain cancer stem cell-like properties. Similar patterns were also observed in limited human tumor specimens of chemo-resistant SCLC patients: namely, overexpressed TRIB2 and undetected CEBPA proteins. Our study revealed a possible molecular mechanism for Cisplatin-resistant SCLC involving induced TRIB2 overexpression and downregulation of CEBPA protein. We propose that this mechanism is a potential therapeutic target to circumvent chemo-resistance in SCLC.",
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