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31 July 2017 : Laboratory Research  

Regenerating Family Member 4 (Reg4) Enhances 5-Fluorouracil Resistance of Gastric Cancer Through Activating MAPK/Erk/Bim Signaling Pathway

Jiaoyue Jin1BE, Hang Lv2CG, Junzhou Wu1CD, Dan Li1BC, Kaiyan Chen1BF, Fanrong Zhang1BF, Jing Han3B, Jianguo Feng1CD, Nan Zhang1F, Herbert Yu4F, Dan Su1AG, Lisha Ying1A*

DOI: 10.12659/MSM.903134

Med Sci Monit 2017; 23:3715-3721

Abstract

BACKGROUND: Reg4, a member of the Reg multigene family, is highly upregulated in many gastrointestinal cancers including gastric cancer (GC). The enhanced expression of Reg4 is associated with the resistance of GC to 5-fluorouracil (5-FU), while the underlying mechanism is not clear. The aim of the present study was to explore the resistant mechanism underlying 5-FU resistance.

MATERIAL AND METHODS: Reg4 expression was assessed by Western blot analysis for SGC-7901, BGC-823, AGS, MKN28, and MKN45. Synthetic short single strand RNA oligonucleotides and Flag-Reg4 plasmid were used to investigate the biological function of Reg4 in vitro. The cell viability assay was performed by MTT. Flow cytometry was carried out to measure the apoptosis caused by 5-FU. Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) was used to examine the expression of 5-FU metabolism related enzymes. The effect of Reg4 on intracellular signaling was evaluated by Western blot.

RESULTS: Western blot analysis of 5 GC cells showed that Reg4 was low or null in SGC-7901 and BGC-823, while high in AGS, MKN28, and MKN45. Over-expression of flag-Reg4 in SGC-7901 led to an increase in cell viability and lower apoptosis with 5-FU treatment. In contrast, siRNA knockdown of Reg4 enhanced 5-FU induced apoptosis. However, over-expression or knockdown of Reg4 had no significant influence on the expression of 5-FU metabolic enzymes. Further investigation revealed that Reg4 could activate Erk1/2-Bim-caspase3 cascade.

CONCLUSIONS: Reg4 inhibited apoptosis through regulating MAPK/Erk/Bim signaling pathway and thereby enhanced the resistance of GC to 5-FU.

Keywords: Fluorouracil, Stomach Neoplasms

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750