SDHB deficiency promotes TGFβ-mediated invasion and metastasis of colorectal cancer through transcriptional repression complex SNAIL1-SMAD3/4.
SDHB deficiency promotes TGFβ-mediated invasion and metastasis of colorectal cancer through transcriptional repression complex SNAIL1-SMAD3/4.
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SDHB缺陷通过转录抑制复合体SNAIL1-SMAD3/4促进TGFbeta介导的结直肠癌侵袭和转移
DOI：
10.1016/j.tranon.2016.09.009
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发表时间：
2016-12
影响因子：
5
通讯作者：
Wu, Guohao
中科院分区：
文献类型：
--
作者：
Wang, Haiyu;Chen, Yusheng;Wu, Guohao
琥珀酸脱氢酶（SDH）是一种异四聚体复合物，其中催化核心SDHB功能丧失突变导致线粒体酶SDH功能障碍，并与癌症形成相关。然而，SDHB 缺失对结直肠癌的影响及其潜在机制尚不清楚。在这项研究中，我们发现人类结直肠癌 (CRC) 样本和 CRC 细胞系中 SDHB 表达均出现一致下降。对 43 名 CRC 患者进行的综合临床分析表明，SDHB 活性降低与淋巴和远处转移的更晚期临床表型之间存在相关性。应用遗传干扰和细胞功能方法，我们发现敲低SDHB通过实现上皮间质转化（EMT）促进细胞迁移和侵袭，而SDHB过表达的逆结果进一步证实了我们的理论。机械探索表明，SDHB 敲低可以激活 TGFβ 信号通路，更准确地说是通过上调紧密连接转录抑制复合物 SNAIL1-SMAD3/SMAD4，从而导致转移增加。总之，通过确定 SNAIL1-SMAD3/SMAD4 对于 SDHB 缺陷的 CRC 细胞中 TGFβ 介导的致瘤能力至关重要，本研究揭示了 SDHB 相关 CRC 未来潜在治疗靶点的关键机械脆弱性。
Succinate dehydrogenase (SDH) is a heterotetrameric complex, among which the catalytic core SDHB loss-of-function mutations lead to mitochondrial enzyme SDH dysfunction and are associated with cancer formation. However, the impact of SDHB loss on colorectal carcinoma and the underlying mechanisms are largely unknown. In this study, we found a coherent decreased SDHB expression both in human colorectal cancer (CRC) samples and CRC cell lines. Combined clinical analysis in a cohort of 43 CRC patients demonstrated a correlation between reduced SDHB activity and a more advanced clinical phenotype regarding lymphatic and distant metastasis. Applying genetic interference and cellular function approaches, we found that knocking down SDHB promoted cell migration and invasion through enabling epithelial-mesenchymal transition (EMT), and inverse results of SDHB overexpression further confirmed our theory. Mechanical exploration revealed that SDHB knockdown could activate TGFβ signaling pathway, more precisely through up-regulation of a tight-junction transcriptional repression complex SNAIL1-SMAD3/SMAD4, thus contributed to the increase in metastasis. In conclusion by identifying SNAIL1-SMAD3/SMAD4 as essential for the TGFβ-mediated tumorigenic capacity in SDHB-deficient CRC cells, this study revealed a critical mechanical vulnerability for potential future therapeutic target of SDHB-associated CRC.
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影响因子：
21.3
作者：
Vincent, Theresa;Neve, Etienne P. A.;Johnson, Jill R.;Kukalev, Alexander;Rojo, Federico;Albanell, Joan;Pietras, Kristian;Virtanen, Ismo;Philipson, Lennart;Leopold, Philip L.;Crystal, Ronald G.;Garcia de Herreros, Antonio;Moustakas, Aristidis;Pettersson, Ralf F.;Fuxe, Jonas
通讯作者：
Fuxe, Jonas
琥珀酸脱氢酶 B 亚基在体外抑制人卵巢癌中的 AMPK-HIF-1α 通路
影响因子：
4
作者：
Chen L;Liu T;Zhang S;Zhou J;Wang Y;Di W
通讯作者：
Di W
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
45.3
作者：
Goldstein, Daniel A.;Ahmad, Bilal B.;Flowers, Christopher R.
通讯作者：
Flowers, Christopher R.
影响因子：
11.5
作者：
Wang, Hui;Shi, Jiaolong;Zhao, Liang
通讯作者：
Zhao, Liang