1] Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [2] Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [3] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Oncogenesis. 2013 Aug 5;2(8):e59. doi: 10.1038/oncsis.2013.17.
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 p53(R175H) 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.
纤调蛋白（POSTN）是一种细胞基质蛋白，据报道其在支持肿瘤细胞扩散中具有重要作用。然而，POSTN 在肿瘤微环境中的功能的分子机制还知之甚少。在本研究中，我们观察到诱导型 POSTN 敲低可减少体内食管鳞状细胞癌（ESCC）肿瘤的生长，并证明 POSTN 与构象错义 p53 突变协同作用增强侵袭。通路分析显示，表达 POSTN 和 p53（R175H）突变的侵袭性食管细胞显示信号转导和转录激活因子 1（STAT1）靶基因的激活，提示诱导 STAT1 和 STAT1 相关基因可能促进有利于食管上皮细胞侵入细胞外基质的许可微环境。转化的食管上皮细胞中 STAT1 的基因敲低突出了 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，但在 ESCC 肿瘤中诱导型 POSTN 敲低可减弱其激活。总体而言，这些结果突出了 POSTN 在介导 ESCC 发展过程中肿瘤侵袭的新型分子机制，并为针对肿瘤微环境的治疗策略提供了依据。
