The Tumor Suppressor BCL7B Functions in the Wnt Signaling Pathway.
The Tumor Suppressor BCL7B Functions in the Wnt Signaling Pathway.
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DOI：
10.1371/journal.pgen.1004921
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发表时间：
2015-01
期刊：
影响因子：
4.5
通讯作者：
Mitani S
中科院分区：
文献类型：
--
作者：
Uehara T;Kage-Nakadai E;Yoshina S;Imae R;Mitani S
人类BCL7基因家族由BCL7A、BCL7B和BCL7C组成。多项临床研究报道BCL7家族参与癌症的发生、进展和发展。其中，BCL7B位于染色体7q11.23，是Williams-Beuren综合征患者缺失的基因之一。尽管一些研究表明 Williams-Beuren 综合征患者发生的恶性疾病与 BCL7B 的畸变有关，但对该基因在细胞水平上的功能知之甚少。本研究以秀丽隐杆线虫中BCL7基因家族的唯一同源物bcl-7为研究对象，并分析了bcl-7缺失突变体。结果，我们发现bcl-7是上皮接缝细胞不对称分化所必需的，上皮接缝细胞具有干细胞的自我更新特性，并通过WNT途径进行不对称分裂。秀丽隐杆线虫中受 WNT 通路调节的远端细胞发育在 bcl-7 敲除突变体中也受到影响。有趣的是，bcl-7 突变体表现出核增大，让人想起恶性细胞的退行性特征。此外，在 KATOIII 人胃癌细胞中，BCL7B 敲低可诱导细胞核增大，促进多核表型并抑制细胞死亡。此外，本研究表明BCL7B负向调节Wnt信号通路，正向调节细胞凋亡通路。综上所述，我们的数据表明 BCL7B/BCL-7 在维持细胞核结构方面具有一定作用，并参与多种途径的调节，包括 Wnt 和细胞凋亡。这项研究可能暗示 BCL7B 缺陷存在罹患恶性肿瘤的风险，例如 Williams-Beuren 综合征。 BCL7B 是人类 BCL7 基因家族的成员，在 Williams-Beuren 综合征患者中被删除。尽管一些临床研究表明，Williams-Beuren 综合征患者发生的恶性疾病与 BCL7B 的畸变有关，但对该基因的生理功能知之甚少。在这里，我们发现bcl-7是秀丽隐杆线虫BCL7基因家族的唯一同源物，它至少通过Wnt途径调节体细胞“干样”接缝细胞的不对称细胞分化，并促进细胞凋亡途径。此外，bcl-7 缺失突变体在表皮和生殖细胞中显示出增大的细胞核。此外，在 KATOIII 人胃癌细胞中，BCL7B 敲低会诱导细胞核增大（如在秀丽隐杆线虫中观察到的那样），并促进多核表型，这两种情况都让人想起恶性疾病。 BCL7B 还负向调节 Wnt 信号通路并正向调节细胞凋亡通路，与秀丽隐杆线虫类似。总而言之，这项研究可能为了解 BCL7 家族在细胞分化和恶性肿瘤中的功能打开大门。
Human BCL7 gene family consists of BCL7A, BCL7B, and BCL7C. A number of clinical studies have reported that BCL7 family is involved in cancer incidence, progression, and development. Among them, BCL7B, located on chromosome 7q11.23, is one of the deleted genes in patients with Williams-Beuren syndrome. Although several studies have suggested that malignant diseases occurring in patients with Williams-Beuren syndrome are associated with aberrations in BCL7B, little is known regarding the function of this gene at the cellular level. In this study, we focused on bcl-7, which is the only homolog of BCL7 gene family in Caenorhabditis elegans, and analyzed bcl-7 deletion mutants. As a result, we found that bcl-7 is required for the asymmetric differentiation of epithelial seam cells, which have self-renewal properties as stem cells and divide asymmetrically through the WNT pathway. Distal tip cell development, which is regulated by the WNT pathway in Caenorhabditis elegans, was also affected in bcl-7-knockout mutants. Interestingly, bcl-7 mutants exhibited nuclear enlargement, reminiscent of the anaplastic features of malignant cells. Furthermore, in KATOIII human gastric cancer cells, BCL7B knockdown induced nuclear enlargement, promoted the multinuclei phenotype and suppressed cell death. In addition, this study showed that BCL7B negatively regulates the Wnt-signaling pathway and positively regulates the apoptotic pathway. Taken together, our data indicate that BCL7B/BCL-7 has some roles in maintaining the structure of nuclei and is involved in the modulation of multiple pathways, including Wnt and apoptosis. This study may implicate a risk of malignancies with BCL7B-deficiency, such as Williams-Beuren syndrome. BCL7B, a member of the human BCL7 gene family, is deleted in patients with Williams-Beuren syndrome. Although several clinical studies have suggested that malignant diseases occurring in patients with Williams-Beuren syndrome are associated with aberrations in BCL7B, little is known regarding the physiological function of this gene. Here, we show that bcl-7, the only homolog of BCL7 gene family in Caenorhabditis elegans, regulates asymmetric cell differentiation in somatic “stem-like” seam cells through at least the Wnt pathway and promotes the apoptotic pathway. In addition, bcl-7 deletion mutants show enlarged nuclei in epidermis and germ cells. Furthermore, in KATOIII human gastric cancer cells, BCL7B knockdown induces nuclear enlargement, as observed in Caenorhabditis elegans, and promotes the multinucleated phenotype, both of which are reminiscent of malignant diseases. BCL7B also negatively regulates the Wnt-signaling pathway and positively regulates the apoptotic pathway, similar to Caenorhabditis elegans. Altogether, this study may open the door for understanding the function of BCL7 family in cell differentiation and malignancies.
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DOI：
10.1006/bbrc.2000.2260
发表时间：
2000-03-05
影响因子：
3.1
作者：
Gengyo-Ando, K;Mitani, S
通讯作者：
Mitani, S
影响因子：
64.5
作者：
FISHEL, R;LESCOE, MK;KOLODNER, R
通讯作者：
KOLODNER, R
影响因子：
56.9
作者：
AMBROS, V;HORVITZ, HR
通讯作者：
HORVITZ, HR
影响因子：
29.4
作者：
Curia MC;De Iure S;De Lellis L;Veschi S;Mammarella S;White MJ;Bartlett J;Di Iorio A;Amatetti C;Lombardo M;Di Gregorio P;Battista P;Mariani-Costantini R;Williams SM;Cama A
通讯作者：
Cama A
影响因子：
2.7
作者：
Chesney, Michael A.;Lam, Ngan;Morgan, Dyan E.;Phillips, Bryan T.;Kimble, Judith
通讯作者：
Kimble, Judith