HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas
HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas
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HDGF 相关蛋白 3 是肝细胞癌中锚定非依赖性存活和化疗耐药所必需的
DOI：
10.1136/gutjnl-2011-300781
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发表时间：
2013-03-01
期刊：
影响因子：
24.5
通讯作者：
Yu, Long
中科院分区：
文献类型：
--
作者：
Xiao, Qianyi;Qu, Kai;Yu, Long
目的肝癌源性生长因子（HDGF）相关蛋白（HRPs）由6个成员组成，其特征是一个保守的has结构域。在家族成员中，HDGF是第一个被确定为有丝分裂因子，并在肝细胞癌发病中发挥重要作用。本研究的目的是研究hdgf相关蛋白-3 (HRP-3)， HRP家族的另一成员在肝细胞癌（HCC）中的相关性。设计采用定量逆转录酶PCR、western blot和免疫组织化学方法检测肝细胞癌组织中HRP-3的表达。体外和体内研究了HCC细胞系中HRP-3过表达和下调的生物学后果。结果肝细胞癌组织中HRP-3 mRNA和蛋白的表达高度上调。虽然小干扰rna敲低HRP-3不能影响HCC细胞的锚定依赖性生长，但在体外抑制肝癌细胞的锚定依赖性生长和体内抑制异种移植物肿瘤的生长。此外，敲低HRP-3被证明使HCC细胞对anoikis敏感。此外，HRP-3特异性激活细胞外信号调节激酶（ERK）通路，而不影响c-Jun n -末端激酶（JNK）、p38、AKT和转录信号换能器和激活因子3 （STAT3）。重要的是，ERK通路的抑制降低了hrp -3介导的肝癌细胞免受疾病的保护。最后，研究表明，敲低HRP-3可促进多种化疗药物诱导的HCC细胞凋亡。结论HRP-3在HCC的发病过程中发挥着重要作用，可能成为HCC治疗药物开发的新的预后标志物和分子靶点。
Objective Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of six members and are characterised by a conserved HATH domain. Among the family members, HDGF was the first to be identified as a mitogenic factor and shown to play an important role in hepatocellular carcinoma pathogenesis. The aim of the present study is to examine the relevance of HDGF-related protein-3 (HRP-3), another member of the HRP family in hepatocellular carcinoma (HCC). Design HRP-3 expression in HCC tissues was measured by quantitative reverse transcriptase PCR, western blot and immunohistochemistry analysis. The biological consequences of overexpression and knockdown of HRP-3 in HCC cell lines were studied in vitro and in vivo. Results Expression of HRP-3 mRNA and protein was shown to be highly upregulated in HCC tissues. While knockdown of HRP-3 by small interference RNAs failed to affect anchorage-dependent growth of HCC cells, it inhibited anchorage-independent growth of HCC cells in vitro and xenograft tumour growth in vivo. Further, knockdown of HRP-3 was shown to sensitise HCC cells to anoikis. Moreover, HRP-3 specifically activated the extracellular-signal-regulated kinase (ERK) pathway without affecting c-Jun N-terminal kinase (JNK), p38, AKT and signal transducer and activator of transcription 3 (STAT3). Importantly, inhibition of the ERK pathway diminished HRP-3-mediated protection of HCC cells from anoikis. Finally, knockdown of HRP-3 was shown to enhance apoptosis of HCC cells induced by multiple chemotherapeutic drugs. Conclusion These findings indicate that HRP-3 plays an essential role in HCC pathogenesis and suggest that it may serve as a novel prognostic marker and molecular target for development of drugs for treatment of HCC.