Inflammatory and Senescent Phenotype of Pancreatic Stellate Cells Induced by Sqstm1 Downregulation Facilitates Pancreatic Cancer Progression
Inflammatory and Senescent Phenotype of Pancreatic Stellate Cells Induced by Sqstm1 Downregulation Facilitates Pancreatic Cancer Progression
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Sqstm1 下调诱导的胰腺星状细胞炎症和衰老表型促进胰腺癌进展
DOI：
10.7150/ijbs.27825
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发表时间：
2019-04
影响因子：
9.2
通讯作者：
Chen Wei
中科院分区：
文献类型：
--
作者：
Shao Chuxiao;Tu Chaoyong;Cheng Xiangdong;Xu Zhiyuan;Wang Xiaoguang;Shen Jian;Chai Kequn;Chen Wei
胰腺导管腺癌（PDAC）具有独特的微环境，成纤维细胞广泛浸润，成纤维细胞主要来源于固有的胰腺星状细胞（PaSC）。由于活化的PaSC构成胰腺癌进展的主要贡献者，因此其活化的机制一直在深入研究。先前的研究表明，Sequestosome-1（sqstm 1）可以调节肿瘤成纤维细胞的功能状态。在这里，我们进一步描述了sqstm 1在PaSC中的作用。PDAC患者样本的分析揭示了在mRNA和蛋白质水平上活化的PaSC中sqstm 1表达的降低。在PaSC中通过shRNA下调sqstm 1导致炎症和衰老表型，IL 8、CXCL 1和CXCL 2表达增加。进一步的分析表明，细胞内活性氧水平的增加导致了sqstm 1下调的PaSC的衰老。这是通过受损的NRF 2活性介导的，因为减少sqstm 1导致KEAP 1的积累。同时，我们发现自噬增强引起的sqstm 1降解与衰老表型的转化无关。最后，数据显示sqstm 1下调的PaSCs促进胰腺肿瘤细胞生长、侵袭和巨噬细胞表型转化。总的来说，目前的研究表明，sqstm 1控制PaSC衰老表型的转化，这反过来又是促肿瘤发生的。
Pancreatic ductal adenocarcinoma (PDAC) has unique microenvironment with extensive infiltration of fibroblasts, which are mainly derived from the resident pancreatic stellate cells (PaSCs). As activated PaSCs constitute a major contributor to pancreatic cancer progression, the mechanisms underlying their activation have been being intensively studied. Previous studies showed that Sequestosome-1 (sqstm1) can modulate the functional status of fibroblasts in cancer. Here, we further delineated the role of sqstm1 in PaSCs. The analysis of PDAC patient samples revealed reduction of sqstm1 expression in activated PaSCs in both mRNA and protein level. Downregulated sqstm1 via shRNA in PaSCs led to an inflammatory and senescent phenotype with increased IL8, CXCL1, and CXCL2 expression. Further analysis demonstrated that increased intracellular reactive oxygen species level contributed to the senescence in sqstm1-downregulated PaSCs. This was mediated via impaired NRF2 activity since reduced sqstm1 resulted in accumulation of KEAP1. Meanwhile, we found that sqstm1 degradation caused by enhanced autophagy was not associated with transformation of senescent phenotype. At last, the data revealed that sqstm1-downregulated PaSCs promoted pancreatic tumor cell growth, invasion, and macrophage phenotype transformation. Collectively, the current study indicated that sqstm1 controlled transformation of senescent phenotype of PaSCs, which in turn is pro-tumorigenic.
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DOI：
10.1016/j.bbamcr.2017.02.005
发表时间：
2017-05-01
影响因子：
5.1
作者：
Geismann, Claudia;Grohmann, Frauke;Arlt, Alexander
通讯作者：
Arlt, Alexander
影响因子：
64.8
作者：
Sousa CM;Biancur DE;Wang X;Halbrook CJ;Sherman MH;Zhang L;Kremer D;Hwang RF;Witkiewicz AK;Ying H;Asara JM;Evans RM;Cantley LC;Lyssiotis CA;Kimmelman AC
通讯作者：
Kimmelman AC
影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
影响因子：
64.5
作者：
Moscat, Jorge;Karin, Michael;Diaz-Meco, Maria T.
通讯作者：
Diaz-Meco, Maria T.
影响因子：
29.4
作者：
Froeling, Fieke E. M.;Feig, Christine;Kocher, Hemant M.
通讯作者：
Kocher, Hemant M.