Enhanced production of CTGF and IL-11 from highly metastatic hepatoma cells under hypoxic conditions: an implication of hepatocellular carcinoma metastasis to bone
Enhanced production of CTGF and IL-11 from highly metastatic hepatoma cells under hypoxic conditions: an implication of hepatocellular carcinoma metastasis to bone
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低氧条件下高度转移性肝癌细胞 CTGF 和 IL-11 的产生增强：肝细胞癌骨转移的暗示
DOI：
10.1007/s00432-012-1370-4
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发表时间：
2013-04-01
影响因子：
3.6
通讯作者：
Zeng, Zhao-Chong
中科院分区：
文献类型：
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作者：
Gao, Ya-Bo;Xiang, Zuo-Lin;Zeng, Zhao-Chong
目的肝细胞癌 (HCC) 骨特异性转移 (BM) 的生物学基础尚不清楚。本研究的目的是通过 BM 进一步阐明 HCC 的分子和细胞机制。方法通过定量实时聚合酶链反应检测从 127 例福尔马林固定、石蜡包埋的 HCC 标本中提取的 RNA 中结缔组织生长因子 (CTGF) 和白细胞介素 11 (IL-11) 的表达。在体外建立细胞缺氧模型，以研究 CTGF 和骨保护素 (OPG) 的表达以及在缺氧诱导的肿瘤侵袭性中的作用。结果 BM 中的平均 CTGF 表达量比非转移性样品高 3.63 倍，并且在 62.5% (10/16) 的 BM 样品中检测到 IL-11 表达，而在非转移性样品中仅检测到 18.9% (21/111) 的 IL-11 表达。那些。高度转移的 HCC 细胞系往往表现出 CTGF 和 IL-11 的强表达，但 OPG 的表达较低。 HCC 97L 细胞的缺氧刺激使 CTGF mRNA 水平在 1.5 小时内增加了 2.80 倍，并且这些细胞中的缺氧诱导因子 1α mRNA 水平可以通过重组 CTGF 蛋白刺激而增加。此外，低氧条件下也会诱导OPG和基质金属蛋白酶-2和-9水平。结论瘤内CTGF或IL-11的表达水平是HCC患者BM发生的独立预后因素。肿瘤缺氧增强了 CTGF 的表达，从而启动侵袭性血管生成级联反应并增强许多缺氧相关基因的表达。 OPG 的细胞释放可能在肿瘤细胞存活中发挥作用。缺氧诱导的肝癌细胞级联反应可能有助于体内侵袭和转移。
PurposeThe biology underlying bone-specific metastasis (BM) of hepatocellular carcinoma (HCC) is poorly understood. The goal of the present study is to further elucidate the molecular and cellular mechanisms underlying HCC with BM.MethodsThe expression of connective tissue growth factor (CTGF) and interleukin-11 (IL-11) in RNA extracted from 127 formalin-fixed, paraffin-embedded HCC specimens was examined by quantitative real-time polymerase chain reaction. A cellular hypoxic model was established in vitro to investigate CTGF and osteoprotegerin (OPG) expression and roles in hypoxia-induced tumor aggressiveness.ResultsThe mean CTGF expression in BM versus non-metastatic samples was 3.63-times higher, and IL-11 expression was detected in 62.5 % (10/16) of BM samples versus only in 18.9 % (21/111) of the non-metastatic ones. Highly metastatic HCC cell lines tended to show strong expression of CTGF and IL-11, but low expression of OPG. Hypoxic stimulation of HCC 97L cells increased the level of CTGF mRNA by 2.80-fold within 1.5 h, and hypoxia-inducible factor-1α mRNA levels in these cells could be increased by stimulation with recombinant CTGF protein. Furthermore, OPG and matrix metalloproteinase-2 and -9 levels were also induced under hypoxic conditions.ConclusionsExpression levels of intratumoral CTGF or IL-11 were independent prognostic factors for the development of BM in HCC patients. Tumor hypoxia enhanced the expression of CTGF, which initiates the invasive angiogenesis cascade and enhances expression of many hypoxia-associated genes. Cellular release of OPG may play a role in tumor cell survival. The hypoxia-induced cascade in HCC cells may contribute to invasion and metastasis in vivo.