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  • Title: BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma.
    Author: Ma J, Zeng S, Zhang Y, Deng G, Qu Y, Guo C, Yin L, Han Y, Cai C, Li Y, Wang G, Bonkovsky HL, Shen H.
    Journal: Cancer Lett; 2017 Dec 28; 411():117-129. PubMed ID: 28987388.
    Abstract:
    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.
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