The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma
The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma
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DOI：
10.1038/onc.2016.71
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发表时间：
2016-10-06
期刊：
影响因子：
8
通讯作者：
Inazawa, J.
中科院分区：
文献类型：
--
作者：
Muramatsu, T.;Kozaki, K-I;Inazawa, J.
转移是导致癌症预后不良的关键因素，但转移的潜在机制仍然知之甚少。为了探讨口腔鳞癌细胞系HOC 313的转移机制，我们建立了一个高转移细胞亚系HOC 313-LM，并在HOC 313-LM的19p13.2-p13.13特异性扩增区域内鉴定了脱氧羟腐胺赖氨酸合成酶（DHPS）为转移相关基因。DHPS介导的羟腐胺赖氨酸修饰的真核生物翻译因子5A促进了RhoA的翻译，导致RhoA信号通路的激活，不仅导致体外癌细胞的运动性、侵袭和转移增加，而且导致体内肿瘤生长增加。此外，使用DHPS抑制剂N1-Guanyl-1，7-diaminoheptane，导致体内肿瘤形成显著减少。在食管鳞状细胞癌（ESCC）患者中，DHPS在ESCC肿瘤中的过表达与更差的无复发生存率显著相关，并与远处转移相关。在羟腐胺赖氨酸级联反应中这些分子机制的阐明提示了SCC中新的治疗靶点的机会。
Metastasis is a critical factor contributing to poor prognosis in cancer, but the underlying mechanisms of metastasis are still poorly understood. We established a highly metastatic cell subline (HOC313-LM) derived from an oral squamous cell carcinoma cell line (HOC313) for uncovering the mechanisms of metastasis, and identified deoxyhypusine synthase (DHPS) as a metastasis-associated gene within the specific amplification at 19p13.2-p13.13 in HOC313-LM. DHPS-mediated hypusine-modification of eukaryotic translation factor 5A facilitated the translation of RhoA, resulting in the activation of the RhoA signaling pathway and leading to not only increased cell motility, invasion and metastasis of cancer cells in vitro, but also increased tumor growth in vivo. Moreover, the use of N1-Guanyl-1,7-diaminoheptane, a DHPS inhibitor, resulted in a significant decrease in tumor formation in vivo. In patients with esophageal squamous cell carcinoma (ESCC), overexpression of DHPS in ESCC tumors was significantly associated with worse recurrence-free survival, and correlated with distant metastasis. The elucidation of these molecular mechanisms within the hypusine cascade suggests opportunities for novel therapeutic targets in SCC.