Junli Ma1, Shan Zeng2, Yan Zhang1, Ganlu Deng1, Yanling Qu1, Cao Guo3, Ling Yin1, Ying Han4, Changjing Cai2, Yiyi Li1, Guqi Wang5, Herbert L Bonkovsky6, Hong Shen7. 1. Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. 2. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. 3. Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. 4. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. 5. School of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA; Whole Pharm Biotechnology Corp., Matthews, NC 28105, USA. 6. School of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA. Electronic address: hbonkovs@wakehealth.edu. 7. Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. Electronic address: hongshen2000@csu.edu.cn.
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.
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.