Decreased lactate dehydrogenase B expression enhances claudin 1-mediated hepatoma cell invasiveness via mitochondrial defects
Decreased lactate dehydrogenase B expression enhances claudin 1-mediated hepatoma cell invasiveness via mitochondrial defects
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DOI：
10.1016/j.yexcr.2011.02.011
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发表时间：
2011-05-01
影响因子：
3.7
通讯作者：
Yoon, Gyesoon
中科院分区：
文献类型：
--
作者：
Kim, June-Hyung;Kim, Ei-Lyoung;Yoon, Gyesoon
有氧乳酸的产生，其最后一步是由乳酸脱氢酶（LDH）执行的，是侵袭性肿瘤发展的典型表型之一。然而，LDH 与癌细胞侵袭性之间的联系的详细机制仍不清楚。这项研究表明，抑制的 LDHB 表达通过线粒体呼吸缺陷诱导紧密连接蛋白claudin-1 (Cln-1)，在肝癌细胞侵袭中发挥关键作用。首先，我们发现所有糖酵解乳酸产量增加的 SNU 人肝癌细胞都具有缺陷的线粒体呼吸活性和 Cln-1 介导的高侵袭活性。在人肝细胞癌组织中也获得了类似的结果。出乎意料的是，乳酸产量的增加是由于 LDHB 下调表达导致 LDH 同工酶转变为 LDH5，而不是 LDHA 诱导，这意味着 LDHB 调节的重要性。其次，LDHB 敲低不仅会在转录水平上触发 Cln-1 诱导，还会引起呼吸损伤。有趣的是，除 KCN 之外的大多数呼吸抑制剂均诱导 Cln-1 表达，尽管鱼藤酮复合物 I 抑制对 Cln-1 诱导最有效。通过敲除复杂 I 亚基之一 NDUFA9，进一步证实了呼吸缺陷介导的 Cln-1 诱导。最后，LDHB 的异位表达减弱了 SNU 354 和 449 细胞的侵袭性，而 LDHB 敲低则显着增强了 Cln-1 诱导的 Chang 细胞的侵袭性。 LDHB 调节增加的侵袭活性可通过敲低 Cln-1 明显逆转。综上所述，我们的结果表明 LDHB 抑制在触发或维持线粒体缺陷中发挥重要作用，然后通过诱导 Cln-1 蛋白促进癌细胞侵袭。 (C) 2011 Elsevier Inc. 保留所有权利。
Aerobic lactate production of which the final step is executed by lactate dehydrogenase (LDH) is one of the typical phenotypes in invasive tumor development. However, detailed mechanism of how LDH links to cancer cell invasiveness remains unclear. This study shows that suppressed LDHB expression plays a critical role in hepatoma cell invasiveness by inducing claudin-1 (Cln-1), a tight junction protein, via mitochondrial respiratory defects. First, we found that all the SNU human hepatoma cells with increased glycolytic lactate production have the defective mitochondrial respiratory activity and the Cln-1-mediated high invasive activity. Similar results were also obtained with human hepatocellular carcinoma tissues. Unexpectedly, the increased lactate production was due to LDH isozyme shifts to LDH5 by LDHB down-expression rather than LDHA induction, implying the importance of LDHB modulation. Second, LDHB knockdown did not only trigger Cln-1 induction at the transcriptional level, but also induced respiratory impairment. Interestingly, most respiratory inhibitors except KCN induced Cln-1 expression although complex I inhibition by rotenone was most effective on Cln-1 induction. Respiratory defect-mediated Cln-1 induction was further confirmed by knockdown of NDUFA9, one of complex I subunits. Finally, ectopic expression of LDHB attenuated the invasiveness of both SNU 354 and 449 cells whereas LDHB knockdown significantly augmented the invasiveness of Chang cells with Cln-1induction. The increased invasive activity by LDHB modulation was clearly reversed by knocking-down Cln-1. Taken together, our results suggest that LDHB suppression plays an important role in triggering or maintaining the mitochondrial defects and then contributes to cancer cell invasiveness by inducing Cln-1 protein. (C) 2011 Elsevier Inc. All rights reserved.