Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival.
Hypoxia-induced oxidative stress promotes MUC4 degradation via autophagy to enhance pancreatic cancer cells survival.
复制标题
缺氧诱导的氧化应激会通过自噬促进MUC4降解，从而增强胰腺癌细胞的存活。
作者：
据报道，胰腺癌（PC）和相关的肿瘤前病变是缺氧的，主要是由于PC的血管减少。虽然在癌性条件下缺氧的存在与致癌蛋白（MUC 1）的过表达有关，但许多新出现的报道也表明缺氧的生长抑制作用。尽管被认为是PC中最高差异表达和确定的致癌蛋白，但MUC 4在微环境应激方面的调节尚未确定。在此，我们首次报道了在缺氧条件下，PC中MUC 4蛋白的稳定性以缺氧诱导因子1α（HIF-1α）非依赖性方式受到严重影响。从机制上讲，我们已经证明，缺氧介导的诱导活性氧（ROS）促进自噬通过抑制pAkt/mTORC 1途径，自噬的中央调节器之一。免疫组织荧光分析显示，在原发性胰腺肿瘤（n = 25）中，8-羟基鸟苷（8-OHG）和MUC 4之间存在显著的负相关性（P值= 0.017）。此外，我们发现PC组织中MUC 4和LAMP 1/LC 3（微管相关蛋白1A/1B-轻链3）之间存在明显的共定位，并且还观察到它们的表达模式呈负相关，这表明自噬率高的区域MUC 4表达较少。我们还发现，缺氧和ROS对总体细胞生长和活力具有负面影响，这在MUC 4存在下被部分地但显著地（P < 0.05）挽救。总之，缺氧介导的氧化应激诱导PC中的自噬，导致MUC 4降解以提高存活率，这可能是通过向应激细胞提供所需的代谢产物。
Pancreatic cancer (PC) and associated pre-neoplastic lesions have been reported to be hypoxic, primarily due to hypovascular nature of PC. Though the presence of hypoxia under cancerous condition has been associated with the overexpression of oncogenic proteins (MUC1), multiple emerging reports have also indicated the growth inhibitory effects of hypoxia. In spite of being recognized as the top-most differentially expressed and established oncogenic protein in PC, MUC4 regulation in terms of micro-environmental stress has not been determined. Herein, for the first time, we are reporting that MUC4 protein stability is drastically affected in PC, under hypoxic condition in a hypoxia inducible factor 1α (HIF-1α)-independent manner. Mechanistically, we have demonstrated that hypoxia-mediated induction of reactive oxygen species (ROS) promotes autophagy by inhibiting pAkt/ mTORC1 pathway, one of the central regulators of autophagy. Immunohistofluorescence analyses revealed significant negative correlation (P-value = 0.017) between 8-hydroxy guanosine (8-OHG) and MUC4 in primary pancreatic tumors (n = 25). Moreover, we found pronounced colocalization between MUC4 and LAMP1/LC3 (microtubule-associated protein 1A/1B-light chain 3) in PC tissues and also observed their negative relationship in their expression pattern, suggesting that areas with high autophagy rate had less MUC4 expression. We also found that hypoxia and ROS have negative impact on overall cell growth and viability, which was partially, though significantly (P < 0.05), rescued in the presence of MUC4. Altogether, hypoxia-mediated oxidative stress induces autophagy in PC, leading to the MUC4 degradation to enhance survival, possibly by offering required metabolites to stressed cells.
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影响因子：
8
作者：
Blanco FF;Jimbo M;Wulfkuhle J;Gallagher I;Deng J;Enyenihi L;Meisner-Kober N;Londin E;Rigoutsos I;Sawicki JA;Risbud MV;Witkiewicz AK;McCue PA;Jiang W;Rui H;Yeo CJ;Petricoin E;Winter JM;Brody JR
通讯作者：
Brody JR
影响因子：
--
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通讯作者：
Reindl, Katie M
影响因子：
6.3
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Hinoda, Y;Ikematsu, Y;Yonezawa, S
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Yonezawa, S
影响因子：
11.2
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Kamphorst JJ;Nofal M;Commisso C;Hackett SR;Lu W;Grabocka E;Vander Heiden MG;Miller G;Drebin JA;Bar-Sagi D;Thompson CB;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
5.4
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Gupta D;Lis CG
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