AFAP1L1, a novel associating partner with vinculin, modulates cellular morphology and motility, and promotes the progression of colorectal cancers.
AFAP1L1, a novel associating partner with vinculin, modulates cellular morphology and motility, and promotes the progression of colorectal cancers.
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DOI：
10.1002/cam4.237
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发表时间：
2014-08
期刊：
影响因子：
4
通讯作者：
Toguchida, Junya
中科院分区：
文献类型：
--
作者：
Takahashi, Ryo;Nagayama, Satoshi;Furu, Moritoshi;Kajita, Yoichiro;Jin, YongHui;Kato, Tomohisa;Imoto, Seiya;Sakai, Yoshiharu;Toguchida, Junya
我们先前已经通过基因表达谱确定肌动蛋白相关蛋白1样蛋白(AFAP1L1)是梭形细胞肉瘤的转移预测标志，并通过体外分析证明AFAP1L1参与了细胞侵袭过程。然而，AFAP1L1的确切分子功能尚未完全阐明，AFAP1L1是否可以作为其他恶性肿瘤的预后标志物和/或治疗靶点也是未知的。在本研究中，我们发现AFAP1L1基因在结直肠癌组织中的表达显著高于癌旁正常组织。多因素分析显示AFAP1L1是影响直肠癌复发的独立因素。此外，AFAP1L1的表达水平与直肠癌的淋巴转移状态相结合，为直肠癌术后复发提供了更多的预测信息。转导AFAP1L1的结直肠癌细胞呈圆形，细胞在平板上的运动能力增强，体外对失巢凋亡具有抵抗性。AFAP1L1与纽蛋白一起定位于穿孔虫的环状结构，免疫沉淀实验证明AFAP1L1是纽蛋白的一个新的结合伙伴。转导AFAP1L1的细胞在体内显示肿瘤生长加速，这可能反映了这些表达AFAP1L1的细胞对失巢凋亡的抵抗。此外，局部应用针对AFAP1L1的siRNA显著抑制了移植瘤的体内生长，提示AFAP1L1可能是治疗大肠癌的候选靶点。这些结果表明，AFAP1L1通过调节细胞的形状和运动，并通过抑制失巢凋亡，可能是通过与纽蛋白-包括蛋白质复合体的相互作用，在癌的进展中发挥作用。
We have previously identified actin filament-associated protein 1-like 1 (AFAP1L1) as a metastasis-predicting marker for spindle cell sarcomas by gene expression profiling, and demonstrated that AFAP1L1 is involved in the cell invasion process by in vitro analyses. However, its precise molecular function has not been fully elucidated, and it remains unknown whether AFAP1L1 could be a prognostic marker and/or therapeutic target of other malignancies. In this study, we found a marked elevation of AFAP1L1 gene expression in colorectal cancer (CRC) tissues as compared to the adjacent normal mucosa. Multivariate analysis revealed that AFAP1L1 was an independent and significant factor for the recurrence of rectal cancers. Moreover, the addition of the AFAP1L1 expression level to the lymph node metastasis status provided more predictive information regarding postoperative recurrence in rectal cancers. AFAP1L1-transduced CRC cells exhibited a rounded shape, increased cell motility on planar substrates, and resistance to anoikis in vitro. AFAP1L1 localized to the ringed structure of the invadopodia, together with vinculin, and AFAP1L1 was identified as a novel associating partner of vinculin by immunoprecipitation assay. AFAP1L1-transduced cells showed accelerated tumor growth in vivo, presumably reflecting the anoikis resistance of these AFAP1L1-expressing cells. Furthermore, the local administration of a siRNA against AFAP1L1 significantly suppressed the in vivo tumor growth of xenografts, suggesting that AFAP1L1 might be a candidate therapeutic target for CRCs. These results suggest that AFAP1L1 plays a role in the progression of CRCs by modulating cell shape and motility and by inhibiting anoikis, presumably through interactions with vinculin-including protein complexes.
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