BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma. (28th December 2017)

• Record Type: Journal Article
• Authors: Ma, Junli; Zeng, Shan; Zhang, Yan; Deng, Ganlu; Qu, Yanling; Guo, Cao; Yin, Ling; Han, Ying; Cai, Changjing; Li, Yiyi; Wang, Guqi; Bonkovsky, Herbert L.; Shen, Hong
• Is Part Of: Cancer letters. Volume 411(2018)
• Page Start: 117
• Page End: 129
• Publication Date: 2017-12-28
• Subjects: Bone morphogenetic protein 4 -- Epithelial-mesenchymal transition -- ELK1 -- Hepatocellular carcinoma -- Oxaliplatin; AFP alpha-fetoprotein -- ANLT adjacent non-tumorous liver tissue -- BMP4 Bone morphogenetic protein 4 -- DCR disease control rate -- EMT epithelial-mesenchymal transition -- HCC hepatocellular carcinoma -- IHC immunohistochemistry -- MMP matrix metalloproteinase -- OS overall survival -- PFS progression free survival -- RFA radiofrequency ablation -- RR Response rate -- siRNA short interfering RNA -- TACE transarterial chemoembolization -- TUNEL TdT-mediated dUTP nick end-labeling; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.09.041
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Research of BMP4 on EMT-regulated OXA sensitivity was performed in HCC specimens, cell lines and a nude mouse model. BMP4 expression was significantly increased in HCC tissue, and was correlated with unfavorable prognosis of HCC patients. BMP4 induces EMT and OXA chemoresistance via MEK/ERK/ELK1 signaling pathway in HCC.