Loss of ARID1A promotes proliferation, migration and invasion via the Akt signaling pathway in NPC
Loss of ARID1A promotes proliferation, migration and invasion via the Akt signaling pathway in NPC
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ARID1A 缺失通过 Akt 信号通路促进 NPC 的增殖、迁移和侵袭
DOI：
10.2147/cmar.s207329
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Xiao, Shengjun
中科院分区：
文献类型：
--
作者：
Yang, Yang;Wang, Xiaoyu;Xiao, Shengjun
背景：富含 AT 的相互作用结构域蛋白 1A (ARID1A) 是开关/蔗糖不可发酵染色质重塑复合物的成员，已观察到该复合物在各种肿瘤中发生突变。据报道，ARID1A 的缺失经常与 PI3K/Akt 通路激活相关。 目的：ARID1A 在鼻咽癌 (NPC) 中的作用迄今为止尚未有报道。本研究的目的是探讨ARID1A在鼻咽癌发生和进展中的临床意义和潜在机制。方法：研究ARID1A在人鼻咽癌组织和细胞系中的表达水平。使用 CCK8、伤口愈合、Transwell 和流式细胞术测定体外评估 ARID1A 敲低对鼻咽癌细胞增殖、迁移和侵袭的影响。通过Western blot检测相关蛋白的表达。结果：在本研究中，ARID1A在鼻咽癌组织和细胞中显着下调。此外，ARID1A 低表达与鼻咽癌患者的侵袭性临床病理特征和较差的生存率显着相关。 siRNA 消除内源性 ARID1A 可促进 CNE1 和 HNE1 细胞的增殖、迁移和侵袭。此外，ARID1A 敲除增加了 NPC 细胞中 Akt 的磷酸化。在 NPC 活检中也观察到高水平的 p-Akt，并且与 ARID1A 下调相关。这些结果意味着 ARID1A 的缺失可以激活 Akt 信号传导。此外，MK-2206（一种高选择性 Akt 抑制剂）部分抑制了 ARID1A 敲低诱导的鼻咽癌细胞增殖、迁移和侵袭。结论：我们的研究结果表明，ARID1A 在调节 Akt 通路中发挥着重要作用，在鼻咽癌中充当肿瘤抑制因子，可能是鼻咽癌治疗的潜在靶点。
Background: AT-rich interactive domain-containing protein 1A (ARID1A) is a member of the switch/sucrose nonfermentable chromatin remodeling complex, which has been observed to be mutated in various tumors. The loss of ARID1A is reported to be frequently associated with PI3K/Akt pathway activation.Objective: The roles of ARID1A in nasopharyngeal carcinoma (NPC) have not been reported until now. The aim of this research was to explore the clinical significance and potential mechanism of ARID1A in NPC development and progression.Methods: ARID1A expression levels were investigated in human NPC tissues and cell lines. The effects of ARID1A knockdown on nasopharyngeal cancer cell proliferation, migration and invasion were evaluated in vitro using CCK8, wound healing, transwell and flow cytometry assays. The expression of relevant proteins was evaluated by Western blot assays.Results: In this study, ARID1A was significantly downregulated in NPC tissues and cells. Furthermore, low ARID1A expression was significantly associated with aggressive clinico-pathological characteristics and poor survival in NPC patients. Depletion of endogenous ARID1A by siRNA promoted proliferation, migration and invasion in CNE1 and HNE1 cells. Additionally, ARID1A knockdown increased the phosphorylation of Akt in NPC cells. High levels of p-Akt were also observed in NPC biopsies and correlated with ARID1A downregulation. These results imply that the loss of ARID1A could activate Akt signaling. In addition, MK-2206 (a highly selective inhibitor of Akt) partially suppressed NPC cell proliferation, migration and invasion, which were induced by ARID1A knockdown.Conclusion: Our findings indicate that ARID1A plays an essential role in modulating the Akt pathway, functions as a tumor suppressor in NPC and may be a potential target for NPC treatment.