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J Cell Biochem. 2019 Apr;120(4):6035-6045. doi: 10.1002/jcb.27890. Epub 2018 Oct 28.

New insight into BIRC3: A novel prognostic indicator and a potential therapeutic target for liver cancer.

Fu PY1,2, Hu B1,2, Ma XL2,3, Yang ZF1,2, Yu MC1,2, Sun HX1,2, Huang A1,2, Zhang X1,2, Wang J1,2, Hu ZQ1,2, Zhou CH1,2, Tang WG1,2, Ning R1,2, Xu Y1,2, Zhou J1,2,4,5,6.

Author information

1
Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, China.
2
Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
3
Laboratory Medicine Department, Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, China.
4
State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
5
Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
6
Institute of Biomedical Sciences, Fudan University, Shanghai, China.

Abstract

BACKGROUND:

Prognosis of hepatocellular carcinoma (HCC) remains poor due to high recurrence rate and ineffective treatment options, highlighting the need to better understand the mechanism of recurrence and metastasis in HCC.

METHODS:

We first collected messenger RNA (mRNA) expression data from 442 cases of HCC patients from The Cancer Genome Atlas (TCGA) database as well as 251 HCC patients from Zhongshan Hospital during 2009 and 2010 to analyze the expression pattern from tissue microarray (TMA) of baculoviral IAP repeat containing 3 (BIRC3). Then, we used BIRC3 gain-of-function (overexpression) and loss-of-function (knockdown) studies to examine the effect of BIRC3 on HCC cell proliferation and invasion. In addition, we also investigated the undying mechanism by which BIRC3 contributes to HCC tumor progression. Functionally, we also used a BIRC3-specific inhibitor AT-406 in HCC xenograft model to explore the potential therapeutic benefit of targeting BIRC3 in liver cancer.

RESULTS:

BIRC3 serves as a novel prognostic indicator for HCC patients undergoing curative resection. BIRC3 promotes HCC epithelial-mesenchymal transition (EMT), cell migration, and metastasis via upregulating MAP3K7, therefore, inducing ERK1/2 phosphorylation. The specific BIRC3 inhibitor AT-406 can inhibit HCC cell proliferation and reduce pulmonary metastases.

CONCLUSION:

BIRC3 induces tumor proliferation and metastasis in vitro and in vivo. BIRC3 may serve as a novel therapeutic target for liver cancer.

KEYWORDS:

AT-406; BIRC3; liver cancer; targeted therapy

PMID:
30368883
DOI:
10.1002/jcb.27890

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