PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells
PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells
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PUM1 敲低通过激活胰腺癌细胞中的 PERK/eIF2/ATF4 信号通路来防止肿瘤进展
DOI：
10.1038/s41419-019-1839-z
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发表时间：
2019-08-08
影响因子：
9
通讯作者：
Bie, Ping
中科院分区：
文献类型：
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作者：
Dai, Haisu;Shen, Kaicheng;Bie, Ping
胰腺导管腺癌（PDAC）是一种预后极差的恶性肿瘤。因此，充分了解其发生、发展的分子机制具有重要意义。据报道，Pumilio RNA 结合家族成员 1 (PUM1) 在卵巢癌和非小细胞肺癌中发挥癌基因的作用。然而，其在PDAC中的作用和机制尚未完全阐明。在这里，我们发现 PDAC 组织中的 PUM1 蛋白水平高于邻近组织，并且 PUM1 水平与 TNM 分期和总生存时间显着相关，表明 PUM1 高表达与 PDAC 患者不良预后之间存在相关性。体外和体内实验表明，PUM1 敲低可抑制 MIA PaCa-2 和 PANC-1 细胞的增殖、迁移、侵袭和上皮间质转化 (EMT)，并促进细胞凋亡。通过cDNA微阵列和ingenuity信号通路分析，我们发现elF2信号通路的激活与PUM1的敲低显着相关。 PUM1 敲低细胞中 eF2 信号通路关键成分、p-PERK、p-EIF2A 和 ATF4 水平的增加进一步证实了这些结果。我们还发现PDAC组织中PUM1水平与p-PERK水平呈显着负相关，并且PERK过表达抑制细胞增殖、迁移、侵袭和EMT，并在体外促进细胞凋亡。此外，PERK抑制剂减轻了PUM1敲低对细胞增殖、凋亡、迁移、侵袭和EMT的影响。综上所述，我们的结果表明，PUM1 敲低可抑制细胞生长、侵袭和转移，并通过激活 PDAC 细胞中的 PERK/elF2/ATF4 信号通路促进细胞凋亡。 PUM1 可能是开发治疗 PDAC 的药物和新治疗策略的潜在靶点。
Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with very poor prognosis. Therefore, it is important to fully understand the molecular mechanism underlying its occurrence and development. Pumilio RNA-binding family member 1 (PUM1) has been reported to function as an oncogene in ovarian cancer and nonsmall cell lung cancer. However, its role and mechanism in PDAC have not been fully illuminated. Here, we found that the PUM1 protein levels were higher in PDAC tissues than in adjacent tissues and that PUM1 levels were significantly associated with TNM stage and overall survival time, indicating a correlation between high PUM1 expression and poor prognosis in patients with PDAC. In vitro and in vivo assays showed that PUM1 knockdown inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), and promoted apoptosis in MIA PaCa-2 and PANC-1 cells. Through cDNA microarrays and ingenuity pathway analysis, we found that the activation of the elF2 signaling pathway significantly correlated with PUM1 knockdown. These results were further confirmed by the increased levels of key components of the elF2 signaling pathway, p-PERK, p-EIF2A, and ATF4 in PUM1 knockdown cells. We also found that PUM1 levels have a significant negative correlation with p-PERK levels in PDAC tissues and that PERK overexpression inhibited cell proliferation, migration, invasion, and EMT, and promoted apoptosis in vitro. Moreover, a PERK inhibitor alleviated the effects of PUM1 knockdown on cell proliferation, apoptosis, migration, invasion, and EMT. Taken together, our results revealed that PUM1 knockdown suppressed cell growth, invasion, and metastasis, and promoted apoptosis by activating the PERK/elF2/ATF4 signaling pathway in PDAC cells. PUM1 could be a potential target to develop pharmaceuticals and novel therapeutic strategies for the treatment of PDAC.