Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment.
Periostin cooperates with mutant p53 to mediate invasion through the induction of STAT1 signaling in the esophageal tumor microenvironment.
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DOI：
10.1038/oncsis.2013.17
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发表时间：
2013-08-05
期刊：
影响因子：
6.2
通讯作者：
Rustgi, A. K.
中科院分区：
文献类型：
--
作者：
Wong, G. S.;Lee, J-S;Park, Y-Y;Klein-Szanto, A. J.;Waldron, T. J.;Cukierman, E.;Herlyn, M.;Gimotty, P.;Nakagawa, H.;Rustgi, A. K.
骨膜蛋白（Periostin，POS2）是一种基质细胞蛋白，在支持肿瘤细胞播散中起重要作用。然而，肿瘤微环境中的POSTs功能的分子机制知之甚少。在这项研究中，我们观察到，诱导敲低POR4降低食管鳞状细胞癌（ESCC）肿瘤的生长在体内，并证明POR4与构象错义p53突变，以增强侵袭。通路分析显示，表达POR4和p53 R175 H突变的侵袭性食管细胞显示信号转导子和转录激活子1（STAT1）靶基因的激活，这表明STAT1和STAT1相关基因的诱导可以培养一个允许的微环境，促进食管上皮细胞侵入细胞外基质。在转化的食管上皮细胞中STAT1的基因敲低强调了STAT1在促进侵袭中的重要性。此外，我们发现STAT1在ESCC异种移植肿瘤中被激活，但这种激活在ESCC肿瘤中被诱导性敲低的POR4减弱。总的来说，这些结果突出了新的分子机制，支持在ESCC的发展过程中，PORYSTINE介导肿瘤侵袭的能力，并有针对肿瘤微环境的治疗策略的影响。
Periostin (POSTN), a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, the molecular mechanisms underlying POSTN function within the tumor microenvironment are poorly understood. In this study, we observe that the inducible knockdown of POSTN decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that POSTN cooperates with a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing POSTN and p53R175H mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix. Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in promoting invasion. Furthermore, we find that STAT1 is activated in ESCC xenograft tumors, but this activation is attenuated with inducible knockdown of POSTN in ESCC tumors. Overall, these results highlight the novel molecular mechanisms supporting the capacity of POSTN in mediating tumor invasion during ESCC development and have implications of therapeutic strategies targeting the tumor microenvironment.
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影响因子：
3.7
作者：
Khodarev NN;Roach P;Pitroda SP;Golden DW;Bhayani M;Shao MY;Darga TE;Beveridge MG;Sood RF;Sutton HG;Beckett MA;Mauceri HJ;Posner MC;Weichselbaum RR
通讯作者：
Weichselbaum RR
DOI：
10.1083/jcb.201009059
发表时间：
2011-01-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Muller PA;Vousden KH;Norman JC
通讯作者：
Norman JC
影响因子：
3.9
作者：
Petitjean, Audrey;Mathe, Ewy;Olivier, Magali
通讯作者：
Olivier, Magali
影响因子：
50.3
作者：
Bao, SD;Ouyang, G;Wang, XF
通讯作者：
Wang, XF
影响因子：
8.4
作者：
Bykov, VJN;Selivanova, G;Wiman, KG
通讯作者：
Wiman, KG