Ann Surg Treat Res.  2019 Aug;97(2):83-92. 10.4174/astr.2019.97.2.83.

The Krüppel-like factor (KLF5) as a predictive biomarker in preoperative chemoradiation therapy for rectal cancer

• Kim JY
• Park SG
• Kim KS
• Choi YH
• Kim NK

• KMID: 2455982
• DOI: http://doi.org/10.4174/astr.2019.97.2.83

Abstract

PURPOSE
Preoperative chemoradiation therapy (CRT) has become the standard treatment for patients with locally advanced rectal cancer, 15%-30% of patients still progress while being treated with CRT. The aim of this study was to identify as important biomarker of poor response and evaluate the mechanism associated with CRT resistance.
METHODS
This study included 60 human colon tumour pre-irradiation specimens. Expressions of epidermal growth factor receptor (EGFR), p53, Krüppel-like factor 5 (KLF5), C-ern, Ki67 were assessed and correlated with tumor regression grades and complete remission. We added in vitro study with biomarker which has been identified as important biomarker of poor response to evaluate the mechanism associated with CRT resistance.
RESULTS
Pathologic complete remission (pCR) was achieved by 9 patients (18%). EGFR and KLF5 were significantly associated with pCR (P = 0.048, P = 0.023, respectfully). And multivariate analysis showed high KLF5 intensity was worse factor for pCR (P = 0.012). In vitro study, radiation or chemotherapy therapy stabilized KLF5 protein levels in a time- and dose-depended manner in HCT116 and Caco-2 cells. KLF5 overexpression in HCT116 stable cell line showed significantly better cell viability by increasing cyclinD1 and b-catenin compared to control cells in MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, suggesting that KLF5 mediates cell survival.
CONCLUSION
KLF5 was significantly associated with the presence of KRAS mutations, and KLF5 was an independent poor response predictor of CRT in rectal cancer. Our study is pilot study and more research will be needed in the future.

Keyword

Chemoradiotherapy; KLF5 protein; Prognosis; Rectal neoplasms

MeSH Terms

Caco-2 Cells
Cell Line
Cell Survival
Chemoradiotherapy
Colon
Drug Therapy
Humans
In Vitro Techniques
Multivariate Analysis
Pilot Projects
Polymerase Chain Reaction
Prognosis
Receptor, Epidermal Growth Factor
Rectal Neoplasms*
Receptor, Epidermal Growth Factor

Figure

• 

  Fig. 1 KLF5 and up/down-stream on colon cancer cell line. (A) Western of KLF5 expression depends on KRAS and BRAF mutation. (B) The protein expressed at the downstream of KLF5 with KRAS or without KRAS mutation cell line. KLF, Krüppel-like factor; WT, wild type.

• 

  Fig. 2 The changes of KLF5 expression by stress induction in colon cancer cell line. (A) Radiation therapy, chemotherapy increased KLF5 depends on dose or time regardless KRAS mutation. (B) The changes in protein of KLF5 in SNU-C4 after getting chemoresistance. KLF, Krüppel-like factor; 5-FU, 5-fluorouracil; RT, radiation therapy.

• 

  Fig. 3 The survival analysis with induction of apoptosis signal. (A) Radiation therapy in HCT116 and HCT116 KLF5 OE. (B) HCT116 KLF5 OE shows survival benefits in Cell death signals in MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. KLF, Krüppel-like factor. *P < 0.05.

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