Overexpression of AKIP1 promotes angiogenesis and lymphangiogenesis in human esophageal squamous cell carcinoma
Overexpression of AKIP1 promotes angiogenesis and lymphangiogenesis in human esophageal squamous cell carcinoma
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AKIP1 的过表达促进人食管鳞状细胞癌中的血管生成和淋巴管生成。
DOI：
10.1038/onc.2013.559
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发表时间：
2015-01-15
期刊：
影响因子：
8
通讯作者：
Li, J.
中科院分区：
文献类型：
--
作者：
Lin, C.;Song, L.;Li, J.
A-激酶相互作用蛋白1(AKIP1)在乳腺癌和前列腺癌中高表达，提示AKIP1可能是一种有效的致癌蛋白。然而，AKIP1在肿瘤进展中的临床意义和生物学作用在很大程度上仍不清楚。在此，我们报告AKIP1在食管鳞癌(ESCC)细胞系和临床ESCC样本中显著过表达。AKIP1的表达与食管鳞癌的进展和患者较短的生存时间显著相关。此外，我们发现，在体外和体内，过表达AKIP1诱导食管癌血管生成和淋巴管生成，而沉默AKIP1则减少ESCC血管生成和淋巴管生成。此外，我们还证明了AKIP1通过与其启动子相互作用，通过与多种转录因子，包括SP1、AP2和核因子-kappa B(NF-kappa B)的协同作用，在转录水平上上调血管内皮生长因子-C(VEGF-C)。重要的是，AKIP1和VEGF-C的水平在一组人ESCC以及在非小细胞肺癌、肝细胞癌和卵巢癌中被观察到显著的相关性。因此，这些发现表明AKIP1在食管癌血管生成和淋巴管生成中起重要作用，并揭示了肿瘤中VEGF-C上调的新机制。
A-kinase-interacting protein 1 (AKIP1) is found to be overexpressed in breast and prostate cancers, suggesting that AKIP1 might act as a potent oncogenic protein. However, the clinical significance and biological role of AKIP1 in cancer progression remain largely unknown. Herein, we report that AKIP1 is markedly overexpressed in esophageal squamous cell carcinoma (ESCC) cell lines and clinical ESCC samples. AKIP1 expression significantly correlates with ESCC progression and patients' shorter survival time. Furthermore, we find that overexpressing AKIP1 induces, whereas silencing AKIP1 reduces, ESCC angiogenesis and lymphangiogenesis both in vitro and in vivo. Moreover, we demonstrate that AKIP1 transcriptionally upregulates vascular endothelial growth factor-C (VEGF-C) via interaction with its promoter through cooperation with multiple transcriptional factors, including SP1, AP2 and nuclear factor-kappa B (NF-kappa B). Importantly, significant correlation between levels of AKIP1 and VEGF-C is observed in a cohort of human ESCC, as well as in non-small cell lung cancer, hepatocellular carcinoma and ovarian cancer. Hence, these findings indicate an important role for AKIP1 in ESCC angiogenesis and lymphangiogenesis, and uncover a novel mechanism for the upregulation of VEGF-C in cancers.