Regulation of fibulin-2 gene expression by integrin α3β1 contributes to the invasive phenotype of transformed keratinocytes.
Regulation of fibulin-2 gene expression by integrin α3β1 contributes to the invasive phenotype of transformed keratinocytes.
复制标题
DOI：
10.1038/jid.2014.166
复制
发表时间：
2014-09
影响因子：
6.5
通讯作者：
DiPersio, C. Michael
中科院分区：
文献类型：
--
作者：
Missan, Dara S.;Chittur, Sridar V.;DiPersio, C. Michael
层粘连蛋白结合整合素 α3β1 在表皮角质形成细胞中高度表达，调节细胞自主和旁分泌功能，促进伤口愈合和皮肤肿瘤发生。然而，α3β1 在调节基因表达程序（控制永生化或转化角质形成细胞的行为）中的作用仍未得到充分探索。在当前的研究中，我们使用微阵列方法来鉴定永生化角质形成细胞中受 α3β1 调节的基因。 α3β1 反应基因包括几个参与细胞外基质蛋白水解或重塑的基因，包括 fibulin-2 和 SPARC。然而，特定靶基因的α3β1依赖性诱导受到触发永生化的遗传损伤的影响，因为α3β1依赖性fibulin-2表达发生在SV40大T抗原或p53缺失突变永生化的细胞中，而α3β1依赖性SPARC表达仅发生在前一种细胞中。有趣的是，qPCR 阵列没有揭示新鲜分离的原代角质形成细胞中α3β1 依赖性基因表达的强烈模式，表明这种调节是在永生化过程中获得的。用致癌 RasV12 转化的 p53 缺失角质形成细胞保留了 α3β1 依赖性 fibulin-2 表达，并且这些细胞中 RNAi 介导的 fibulin-2 敲低减少了侵袭，尽管其致瘤潜力不高。这些发现表明，永生化/转化角质形成细胞中的 α3β1 在调节 fibulin-2 和其他促进基质重塑和侵袭的基因方面发挥着重要作用。
The laminin-binding integrin α3β1 is highly expressed in epidermal keratinocytes where it regulates both cell-autonomous and paracrine functions that promote wound healing and skin tumorigenesis. However, roles for α3β1 in regulating gene expression programs that control the behaviors of immortalized or transformed keratinocytes remain underexplored. In the current study, we used a microarray approach to identify genes that are regulated by α3β1 in immortalized keratinocytes. α3β1-responsive genes included several that are involved in extracellular matrix proteolysis or remodeling, including fibulin-2 and SPARC. However, α3β1-dependent induction of specific target genes was influenced by the genetic lesion that triggered immortalization, as α3β1-dependent fibulin-2 expression occurred in cells immortalized by either SV40 large T antigen or p53-null mutation, while α3β1-dependent SPARC expression occurred only in the former cells. Interestingly, qPCR arrays did not reveal strong patterns of α3β1-dependent gene expression in freshly isolated primary keratinocytes, suggesting that this regulation is acquired during immortalization. p53-null keratinocytes transformed with oncogenic RasV12 retained α3β1-dependent fibulin-2 expression, and RNAi-mediated knockdown of fibulin-2 in these cells reduced invasion, although not their tumorigenic potential. These findings demonstrate a prominent role for α3β1 in immortalized/transformed keratinocytes in regulating fibulin-2 and other genes that promote matrix remodeling and invasion.
登录
查看更多内容
影响因子：
3.3
作者：
DELWEL, GO;DEMELKER, AA;SONNENBERG, A
通讯作者：
SONNENBERG, A
影响因子：
8
作者：
Briggs, J;Chamboredon, S;Bos, TJ
通讯作者：
Bos, TJ
影响因子：
8
作者：
Chou, Y-T;Wang, H.;Yang, Y-C
通讯作者：
Yang, Y-C
影响因子：
3.7
作者：
Baird, Brandi N.;Schliekelman, Mark J.;Kurie, Jonathan M.
通讯作者：
Kurie, Jonathan M.
影响因子：
6
作者：
Alcendor, Donald J.;Knobel, Susan;Hayward, Gary S.
通讯作者：
Hayward, Gary S.