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首页> 外文期刊>Oncogene >The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-|[kappa]|B signaling pathways
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The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-|[kappa]|B signaling pathways

机译：RASSF8候选肿瘤抑制因子抑制细胞生长并调节Wnt和NF- |κ| B信号通路

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The Ras-assocation domain family (RASSF) of tumor suppressor proteins until recently contained six proteins named RASSF1–6. Recently, four novel family members, RASSF7–10, have been identified by homology searches for RA-domain-containing proteins. These additional RASSF members are divergent and structurally distinct from RASSF1–6, containing an N-terminal RA domain and lacking the Sav/RASSF/Hpo (SARAH) domain. Here, we show that RASSF8 is ubiquitously expressed throughout the murine embryo and in normal human adult tissues. Functionally, RNAi-mediated knockdown of RASSF8 in non-small-cell lung cancer (NSCLC) cell lines, increased anchorage-independent growth in soft agar and enhanced tumor growth in severe combined immunodeficiency (SCID) mice. Furthermore, EdU staining of RASSF8-depleted cells showed growth suppression in a manner dependent on contact inhibition. We show that endogenous RASSF8 is not only found in the nucleus, but is also membrane associated at sites of cell–cell adhesion, co-localizing with the adherens junction (AJ) component β-catenin and binding to E-cadherin. Following RASSF8 depletion in two different lung cancer cell lines using alternative small interfering RNA (siRNA) sequences, we show that AJs are destabilized and E-cadherin is lost from the cell membrane. The AJ components β-catenin and p65 are also lost from sites of cell–cell contact and are relocalized to the nucleus with a concomitant increase in β-catenin-dependent and nuclear factor-κB (NF-κB)-dependent signaling following RASSF8 depletion. RASSF8 may also be required to maintain actin -cytoskeletal organization since immunofluorescence analysis shows a striking disorganization of the actin- cytoskeleton following RASSF8 depletion. Accordingly, scratch wound healing studies show increased cellular migration in RASSF8-deficient cells. These results implicate RASSF8 as a tumor suppressor gene that is essential for maintaining AJs function in epithelial cells and have a role in epithelial cell migration.
机译：直到最近，肿瘤抑制蛋白的Ras缔合域家族（RASSF）才包含六个名为RASSF1-6的蛋白。最近，通过同源搜索包含RA结构域的蛋白质，已经鉴定出四个新的家族成员RASSF7-10。这些额外的RASSF成员与RASSF1–6不同，在结构上有所不同，包含N端RA结构域，并且缺少Sav / RASSF / Hpo（SARAH）域。在这里，我们显示RASSF8在鼠胚胎和正常成人组织中普遍表达。从功能上讲，RNAi介导的非小细胞肺癌（NSCLC）细胞系中RASSF8的敲低，软琼脂中锚定非依赖性生长的增加以及严重的联合免疫缺陷（SCID）小鼠肿瘤生长的增强。此外，对RASSF8耗尽的细胞的EdU染色显示出依赖于接触抑制的生长抑制作用。我们表明，内源性RASSF8不仅存在于细胞核中，而且还存在于细胞-细胞粘附部位的膜上，与粘附连接（AJ）组分β-catenin共定位并与E-cadherin结合。在使用替代性小干扰RNA（siRNA）序列在两种不同的肺癌细胞系中进行RASSF8耗竭后，我们显示出AJ不稳定且E-钙粘蛋白从细胞膜上丢失。 RASSF8耗竭后，AJ成分β-catenin和p65也从细胞与细胞接触的位置丢失，并重新定位到细胞核，伴随β-catenin依赖性和核因子-κB（NF-κB）依赖性的信号传导增加。还可能需要RASSF8来维持肌动蛋白的细胞骨架组织，因为免疫荧光分析显示在RASSF8耗尽后肌动蛋白的细胞骨架显着地分解。因此，从头开始的伤口愈合研究表明在RASSF8缺陷细胞中细胞迁移增加。这些结果暗示RASSF8作为肿瘤抑制基因，对于维持AJs在上皮细胞中的功能至关重要，并在上皮细胞迁移中起作用。

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