High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma
High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma
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DOI：
10.1111/j.1349-7006.2006.00322.x
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发表时间：
2006-11-01
期刊：
影响因子：
5.7
通讯作者：
Tsuneyoshi, Masazumi
中科院分区：
文献类型：
--
作者：
Aishima, Shinichi;Basaki, Yuji;Tsuneyoshi, Masazumi
胰岛素样生长因子结合蛋白-3 （IGFBP-3）调节多种类型癌细胞的细胞增殖。然而，igf - igfbp -3信号如何参与肝细胞癌（HCC）的生长和进展尚不清楚。本研究的目的是评估IGFBP-3在HCC中的作用。IGF的1型受体（IGF- 1r）在7个品系中有不同水平的表达，但IGF- 2r未表达。在这7个细胞系中，外源添加IGF-I或IGF-II能以剂量依赖的方式刺激HAK-1B、KIM-1、KYN-2和HepG2细胞的生长，但HAK-1A、KYN-1和KYN-3细胞系没有生长。外源添加IGFBP-3可明显阻断IGF-I和igf - ii对KYN-2和HepG2细胞的生长刺激，对KIM-1和HAK-1B细胞的生长有中度刺激，但对KYN-1、KYN-3和HAK-1A细胞的生长无影响。IGF-I增强了KYN-2细胞中IGF-1R、Akt和Erk1/2的磷酸化，同时使用IGFBP-3阻断了IGF-I的所有类型的激活。相反，在KYN-3细胞中没有检测到IGF-I的这种激活。IGFBP-3也抑制igf -i诱导的KYN-2细胞的侵袭。此外，我们可以观察到IGFBP-3在KYN-3细胞中有明显的表达，而在其他6个细胞系中没有。此外，IGFBP-3表达的降低与肿瘤大小、组织学分化、囊膜侵袭和门静脉侵袭有显著相关性，而IGF-1R表达的降低与肿瘤大小、组织学分化、囊膜侵袭和门静脉侵袭无显著相关性。IGFBP-3低表达与生存率低独立相关。IGFBP-3可能是一个具有内在重要性的分子靶点，对进一步开发新的HCC治疗策略具有重要意义。
Insulin-like growth factor binding protein-3 (IGFBP-3) modulates cell proliferation of various cancer cell types. However, it remains unclear how IGF-IGFBP-3-signaling is involved in growth and progression of hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the role of IGFBP-3 in HCC. Type 1 receptor for IGF (IGF-1R) was expressed at various levels in the seven lines examined, but IGF-2R was not expressed. Of the seven lines, the growth of HAK-1B, KIM-1, KYN-2 and HepG2 cells was stimulated in a dose-dependent manner by the exogenous addition of IGF-I or IGF-II, but the HAK-1A, KYN-1 and KYN-3 cell lines showed no growth. Exogenous addition of IGFBP-3 markedly blocked IGF-I and IGF-II-stimulated cell growth of KYN-2 and HepG2 cells, and moderately stimulated that of KIM-1 and HAK-1B cells, but no growth of the KYN-1, KYN-3 and HAK-1A cell lines was observed. IGF-I enhanced the phosphorylation of IGF-1R, Akt and Erk1/2 in KYN-2 cells, and coadministration of IGFBP-3 blocked all types of activation by IGF-I investigated here. In contrast, no such activation by IGF-I was detected in KYN-3 cells. IGFBP-3 also suppressed IGF-I-induced cell invasion by KYN-2 cells. Moreover, we were able to observe the apparent expression of IGFBP-3 in KYN-3 cells, but not in the other six cell lines. Furthermore reduced expression of IGFBP-3, but not that of IGF-1R, was significantly correlated with tumor size, histological differentiation, capsular invasion and portal venous invasion. Low expression of IGFBP-3 was independently associated with poor survival. IGFBP-3 could be a molecular target of intrinsic importance for further development of novel therapeutic strategy against HCC.