DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.
DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.
复制标题
DIAPH3通过激活硒蛋白TrxR1介导的抗氧化作用促进胰腺癌进展。
DOI：
10.1111/jcmm.16196
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发表时间：
2021-03
影响因子：
5.3
通讯作者：
Lou W
中科院分区：
文献类型：
--
作者：
Rong Y;Gao J;Kuang T;Chen J;Li JA;Huang Y;Xin H;Fang Y;Han X;Sun LQ;Deng YZ;Li Z;Lou W
胰腺癌是一种高度恶性的消化道肿瘤，诊断和治疗困难。大约90%的病例来自腺上皮的导管腺癌。近年来，该病的发病率和死亡率显著增加。它的5年生存率<1%，是恶性肿瘤中最严重的肿瘤之一。胰腺癌早期诊断率低，手术死亡率高，治愈率低。硒代氨基酸代谢产生的硒化合物可通过消耗细胞内的NADPH，促进大量氧化应激及随后的解折叠反应和内质网应激，最终导致细胞凋亡、坏死或坏死性细胞死亡。在本研究中，我们首先鉴定出DIAPH3是胰腺癌患者组织中高表达的蛋白质，并通过过表达和干扰实验证实DIAPH3促进胰腺癌细胞的增殖、非贴壁生长和侵袭。其次，生物信息学数据挖掘表明，与DIAPH3相互作用的潜在蛋白参与硒氨基酸代谢调控。硒可以被掺入硒蛋白合成中，如TrxR1和GPX4，它们分别直接还原氢过氧化物或抵抗铁凋亡。我们随后的验证证实了DIAPH3促进硒含量，并与硒蛋白RPL 6相互作用，RPL 6是一种参与硒氨基酸代谢的核糖体蛋白亚基。此外，我们验证了DIAPH3可以通过上调TrxR1表达来下调细胞ROS水平。最后，裸鼠异种移植模型实验结果表明DIAPH3敲低可以降低体内肿瘤生长和TrxR1表达以及ROS水平。总的来说，我们的观察表明DIAPH3可以通过激活硒蛋白TrxR1介导的抗氧化作用促进胰腺癌进展。
Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5‐year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early‐stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage‐independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down‐regulate cellular ROS level via up‐regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1‐mediated antioxidant effects.
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