Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma.
Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma.
复制标题
胰岛素样生长因子结合蛋白7在肝细胞癌中起抑制肿瘤的潜在抑制剂。
DOI：
10.1158/1078-0432.ccr-10-2774
复制
发表时间：
2011-11-01
期刊：
影响因子：
--
通讯作者：
Sarkar D
中科院分区：
文献类型：
--
作者：
Chen D;Yoo BK;Santhekadur PK;Gredler R;Bhutia SK;Das SK;Fuller C;Su ZZ;Fisher PB;Sarkar D
肝细胞癌（HCC）是一种高毒性恶性肿瘤，没有有效的治疗方法，因此需要创新和有效的靶向治疗。癌基因星形胶质细胞升高基因-1（AEG-1）在肝癌发生中起着重要作用，并显著下调胰岛素样生长因子结合蛋白-7（IGFBP 7）。本研究的重点是分析IGFBP 7在HCC中的潜在肿瘤抑制功能以及IGFBP 7下调在介导AEG-1功能中的相关性。采用免疫组化、实时荧光定量PCR和ELISA方法检测肝癌组织芯片中IGFBP 7的表达。采用双重荧光原位杂交技术检测IGFBP 7基因座的杂合性缺失。在AEG-1过表达人HCC细胞的背景下建立稳定的IGFBP 7过表达克隆，并分析其体外增殖和衰老以及体内肿瘤发生和血管生成。与正常肝脏和肝细胞相比，IGFBP 7表达在人HCC样品和细胞系中分别显著下调，并且与HCC的阶段和等级负相关。在26%的HCC患者中发现IGFBP 7基因组缺失。IGFBP 7在AEG-1过表达HCC细胞中的强制过表达抑制体外生长并诱导衰老，并且深刻地抑制裸鼠体内生长，这可能是IGFBP 7抑制血管生成的最终结果。目前的研究结果提供了证据，IGFBP 7作为一种新的推定的肝癌肿瘤抑制因子的功能，并建立了IGFBP 7下调可以有效地修改AEG-1功能的推论。因此，IGFBP 7的靶向过表达可能是一种潜在的治疗肝癌的新方法。
Hepatocellular carcinoma (HCC) is a highly virulent malignancy with no effective treatment thus requiring innovative and effective targeted therapies. The oncogene Astrocyte elevated gene-1 (AEG-1) plays a seminal role in hepatocarcinogenesis and profoundly downregulates insulin-like growth factor binding protein-7 (IGFBP7). The present study focuses on analyzing potential tumor suppressor functions of IGFBP7 in HCC and the relevance of IGFBP7 downregulation in mediating AEG-1 function. IGFBP7 expression was detected by immunohistochemistry in HCC tissue microarray and real-time PCR and ELISA in human HCC cell lines. Dual Fluorescence in situ hybridization was performed to detect loss of heterozygosity at IGFBP7 locus. Stable IGFBP7-overexpressing clones were established in the background of AEG-1-overexpressing human HCC cells and were analyzed for in vitro proliferation and senescence and in vivo tumorigenesis and angiogenesis. IGFBP7 expression is significantly downregulated in human HCC samples and cell lines compared to normal liver and hepatocytes, respectively, and inversely correlates with the stages and grades of HCC. Genomic deletion of IGFBP7 was identified in 26% of HCC patients. Forced overexpression of IGFBP7 in AEG-1 overexpressing HCC cells inhibited in vitro growth and induced senescence, and profoundly suppressed in vivo growth in nude mice that might be an end result of inhibition of angiogenesis by IGFBP7. The present findings provide evidence that IGFBP7 functions as a novel putative tumor suppressor for HCC and establish the corollary that IGFBP7 downregulation can effectively modify AEG-1 function. Accordingly, targeted overexpression of IGFBP7 might be a potential novel therapy for HCC.