Loss of AF-6/afadin induces cell invasion, suppresses the formation of glandular structures and might be a predictive marker of resistance to chemotherapy in endometrial cancer.
Loss of AF-6/afadin induces cell invasion, suppresses the formation of glandular structures and might be a predictive marker of resistance to chemotherapy in endometrial cancer.
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DOI：
10.1186/s12885-015-1286-x
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发表时间：
2015-04-12
期刊：
影响因子：
3.8
通讯作者：
Kitawaki J
中科院分区：
文献类型：
--
作者：
Yamamoto T;Mori T;Sawada M;Matsushima H;Ito F;Akiyama M;Kitawaki J
AF-6/afadin 在粘附连接的形成中起着重要作用。在乳腺癌和结肠癌中，AF-6/afadin 的缺失会诱导细胞迁移和细胞侵袭。我们的目的是阐明 AF-6/afadin 在人类子宫内膜癌中的作用。通过 3 维培养研究子宫内膜癌细胞系的形态学和 AF-6/afadin 表达。我们使用 Matrigel 侵袭测定来证明 AF-6/afadin 敲低诱导的侵袭能力。进行细胞增殖测定以评估 AF-6/afadin 敲低诱导的对阿霉素、紫杉醇和顺铂的化疗耐药性。通过子宫内膜癌组织中的免疫组织化学分析确定 AF-6/afadin 表达与临床病理状态之间的关联。研究前获得了所有患者的知情同意。强烈表达 AF-6/afadin 的石川细胞 3 维培养物中的大多数细胞团显示出圆形腺样结构。相比之下，HEC1A 和 AN3CA 细胞（均弱表达 AF-6/afadin）的 3 维培养物中的细胞团分别显示出不规则的腺样结构和无腺样结构的杂乱集落。 AF-6/afadin 敲除导致 3 维培养物中腺样结构数量减少，细胞侵袭增强，并且在高 AF-6/afadin 表达的子宫内膜癌细胞系中 ERK1/2 和 Src 磷酸化增强。 MAPK/ERK 激酶 (MEK) (U0126) 和 Src (SU6656) 抑制剂抑制 AF-6/afadin 敲低诱导的侵袭能力。 AF-6/afadin 敲除可诱导 Ishikawa 细胞（而非 HEC1A）对阿霉素、紫杉醇和顺铂产生化疗耐药性。免疫组织化学分析显示AF-6/afadin表达与子宫肌层浸润和高组织学分级显着相关。 AF-6/afadin 调节细胞形态和侵袭性。侵袭能力部分通过 ERK 和 Src 途径调节。这些途径的抑制剂可能是抑制子宫内膜癌子宫肌层侵袭的分子靶向药物。 AF-6/afadin 可能是对不典型增生或无子宫肌层浸润的 1 级子宫内膜样腺癌患者进行保留生育治疗的有用选择标记。 AF-6/afadin 敲除诱导化学耐药性，尤其是对顺铂的耐药性。因此，AF-6/afadin 的缺失可能是顺铂化疗耐药的预测标志。
AF-6/afadin plays an important role in the formation of adherence junctions. In breast and colon cancer, loss of AF-6/afadin induces cell migration and cell invasion. We aimed to elucidate the role of AF-6/afadin in human endometrial cancer. Morphology and AF-6/afadin expression in endometrial cancer cell lines was investigated by 3-dimensional culture. We used Matrigel invasion assay to demonstrate AF-6/afadin knockdown induced invasive capability. Cell proliferation assay was performed to estimate chemoresistance to doxorubicin, paclitaxel and cisplatin induced by AF-6/afadin knockdown. The associations between AF-6/afadin expression and clinicopathological status were determined by immunohistochemical analysis in endometrial cancer tissues. Informed consent was obtained from all patients before the study. The majority of cell clumps in 3-dimensional cultures of Ishikawa cells that strongly expressed AF-6/afadin showed round gland-like structures. In contrast, the cell clumps in 3-dimensional cultures of HEC1A and AN3CA cells—both weakly expressing AF-6/afadin—showed irregular gland-like structures and disorganized colonies with no gland-like structures, respectively. AF-6/afadin knockdown resulted in reduced number of gland-like structures in 3-dimensional cultures and enhancement of cell invasion and phosphorylation of ERK1/2 and Src in the highly AF-6/afadin-expressing endometrial cancer cell line. Inhibitors of MAPK/ERK kinase (MEK) (U0126) and Src (SU6656) suppressed the AF-6/afadin knockdown-induced invasive capability. AF-6/afadin knockdown induced chemoresistance to doxorubicin, paclitaxel and cisplatin in Ishikawa cells, not in HEC1A. Immunohistochemical analysis showed that AF-6/afadin expression was significantly associated with myometrial invasion and high histological grade. AF-6/afadin regulates cell morphology and invasiveness. Invasive capability is partly regulated through the ERK and Src pathway. The inhibitors to these pathways might be molecular-targeted drugs which suppress myometrial invasion in endometrial cancer. AF-6/afadin could be a useful selection marker for fertility-sparing therapy for patients with atypical hyperplasia or grade 1 endometrioid adenocarcinoma with no myometrial invasion. AF-6/afadin knockdown induced chemoresistance especially to cisplatin. Therefore, loss of AF-6/afadin might be a predictive marker of chemoresistance to cisplatin.
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DOI：
10.1111/j.1349-7006.2000.tb00958.x
发表时间：
2000-04-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Sugimura, M;Kobayashi, K;Kudo, R
通讯作者：
Kudo, R
影响因子：
11.5
作者：
Mell, LK;Meyer, JJ;Mundt, AJ
通讯作者：
Mundt, AJ
Afadin：一种新型的肌动蛋白结合蛋白，其中一个PDZ结构域位于基于钙粘蛋白的细胞到细胞粘附连接处。
影响因子：
7.8
作者：
Mandai, K;Nakanishi, H;Satoh, A;Obaishi, H;Wada, M;Nishioka, H;Itoh, M;Mizoguchi, A;Aoki, T;Fujimoto, T;Matsuda, Y;Tsukita, S;Takai, Y
通讯作者：
Takai, Y
影响因子：
3.6
作者：
Chen, Ting;Wang, Changyuan;Liu, Kexin
通讯作者：
Liu, Kexin
影响因子：
4
作者：
Miyata, Muneaki;Ogita, Hisakazu;Takai, Yoshimi
通讯作者：
Takai, Yoshimi