Journal
CANCER LETTERS
Volume 411, Issue -, Pages 117-129Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.09.041
Keywords
Bone morphogenetic protein 4; Epithelial-mesenchymal transition; ELK1; Hepatocellular carcinoma; Oxaliplatin
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Funding
- National Nature Science Foundation of China [81772627, 81172470, 81070362, 81372629]
- Nature Science Foundation of Hunan Province [2016JC2037, 2015JC3021]
- US National Institutes of Health [HL 117199]
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Background: Bone morphogenetic protein-4 (BMP4) is a key regulator of epithelial-mesenchymal transition (EMT), which is crucial for cancer cells to acquire chemoresistance. The effects of BMP4 on OXA sensitivity in HCC need to be elucidated. Methods: Functional analysis of BMP4 on EMT-regulated OXA sensitivity was performed in human HCC specimens, in the HCC cell lines HepG2 and HCCLM3, and in a subcutaneous tumor model receiving OXA treatment. The downstream signaling targets of BMP4 in HCC were profiled and confirmed. Results: BMP4 expression was significantly increased in HCC tissue, and was correlated with tumor de-differentiation and unfavorable prognosis. BMP4 promoted HCC EMT and was correlated with OXA resistance. Blocking of BMP4 reversed EMT and increased OXA chemosensitivity in vitro and in vivo. ELK1, a transcription factor involved in EMT, was an important mediator of BMP4-induced OXA resistance in HCC. Blocking of MEK/ERK/ELK1 attenuated BMP4-induced EMT and enhanced OXA sensitivity. Conclusions: BMP4 induces EMT and OXA chemoresistance via MEK/ERK/ELK1 signaling pathway in HCC. BMP4 may be a valuable therapeutic target for HCC patients receiving OXA-based chemotherapy. (c) 2017 Elsevier B.V. All rights reserved.
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