SIPA1 promotes invasion and migration in human oral squamous cell carcinoma by ITGB1 and MMP7
SIPA1 promotes invasion and migration in human oral squamous cell carcinoma by ITGB1 and MMP7
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DOI：
10.1016/j.yexcr.2017.02.026
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发表时间：
2017-03-15
影响因子：
3.7
通讯作者：
Uzawa, Katsuhiro
中科院分区：
文献类型：
--
作者：
Takahara, Toshikazu;Kasamatsu, Atsushi;Uzawa, Katsuhiro
信号诱导增殖相关蛋白1 （SIPA1）是一种已知的GTPase激活蛋白。SIPA1过表达与乳腺癌和前列腺癌的转移进展有关；然而，SIPA1与口腔鳞状细胞癌（OSCC）的相关性尚不清楚。本研究的目的是研究SIPA1在OSCC中的表达及其功能机制。采用定量逆转录聚合酶链反应、Western blot和免疫组织化学分析SIPA1 mRNA和蛋白的表达。SIPA1在体外和体内的表达均显著上调。此外，SIPA1表达与局部淋巴结转移相关。接下来，我们利用SIPA1敲低（shSIPA1）细胞评估了与肿瘤转移相关的细胞功能，并分析了SIPA1的下游分子，即含溴结构域蛋白4（BRD4）、整合素β (ITGB1)和基质金属蛋白酶7 （MMP7）。shSIPA1细胞的侵袭和迁移能力下降，但细胞粘附能力保持在较高水平。此外，ITGB1在shSIPA1细胞中的表达高于对照细胞，而MMP7的表达低于对照细胞。本研究首次证实SIPA1通过调控ITGB1和MMP7促进肿瘤转移。因此，SIPA1可能成为OSCC淋巴结转移患者新的治疗靶点。
Signal-induced proliferation-associated protein 1 (SIPA1) is known to be a GTPase activating protein. Overexpressed SIPA1 is related to metastatic progression in breast and prostate cancers; however, the relevance of SIPA1 in oral squamous cell carcinoma (OSCC) is still unknown. The aim of this study was to examine SIPA1 expression and its functional mechanisms in OSCC. SIPA1 mRNA and protein expressions were analyzed by quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry. The expressions of SIPA1 were up-regulated significantly in vitro and in vivo. Moreover, SIPA1 expression was correlated with regional lymph node metastasis. We next assessed the cellular functions associated with tumoral metastasis using SIPA1 knockdown (shSIPA1) cells and analyzed the downstream molecules of SIPA1, i.e., bromodomain containing protein 4(BRD4), integrin betal (ITGB1), and matrix metalloproteinase 7 (MMP7). The shSIPA1 cells showed decreased invasiveness and migratory activities, however cellular adhesion ability was maintained at a high level. In addition, ITGB1 expression was greater in shSIPA1 cells, whereas MMP7 expression was lower than in control cells. This research is the first to establish that SIPA1 promotes cancer metastasis by regulating the ITGB1 and MMP7. Therefore, SIPA1 might be a novel therapeutic target for patients with lymph node metastasis of OSCC.