丝氨酸蛋白酶抑制剂A家族成员1是胃癌预后不良的生物标志物。
Serpin peptidase inhibitor clade A member 1 is a biomarker of poor prognosis in gastric cancer.
作者信息
Kwon C H, Park H J, Lee J R, Kim H K, Jeon T Y, Jo H-J, Kim D H, Kim G H, Park D Y
机构信息
Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Korea.
Department of Surgery, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Korea.
出版信息
Br J Cancer. 2014 Nov 11;111(10):1993-2002. doi: 10.1038/bjc.2014.490. Epub 2014 Sep 11.
BACKGROUND
In a previous study, we reported that serpin peptidase inhibitor clade A member 1 (serpinA1) is upregulated in Snail-overexpressing gastric cancer. Although serpinA1 has been studied in several types of cancer, little is known about its roles and mechanisms of action. In this study, we examined the role of serpinA1 in the migration and invasion of gastric cancers and determined its underlying mechanism.
METHODS
Expression levels were assessed by western blot analyses and real-time PCR. Snail binding to serpinA1 promoter was analysed by chromatin immunoprecipitation (ChIP) assays. The roles of serpinA1 were studied using cell invasion and migration assays. In addition, the clinicopathologic and prognostic significance of serpinA1 expression were validated in 400 gastric cancer patients using immunohistochemical analysis.
RESULTS
Overexpression of Snail resulted in upregulation of serpinA1 in gastric cancer cell lines, AGS and MKN45, whereas knockdown of Snail inhibited serpinA1 expression. Chromatin immunoprecipitation analysis showed that overexpression of Snail increased Snail recruitment to the serpinA1 promoter. Overexpression of serpinA1 increased the migration and invasion of gastric cancer cells, whereas knockdown of serpinA1 decreased invasion and migration. Moreover, serpinA1 increased mRNA levels and release of metalloproteinase-8 in gastric cancer cells. Serpin peptidase inhibitor clade A member 1 was observed in the cytoplasm of tumour cells and the stroma by immunohistochemistry. Enhanced serpinA1 expression was significantly associated with increased tumour size, advanced T stage, perineural invasion, lymphovascular invasion, lymph node metastases, and shorter overall survival.
CONCLUSIONS
Serpin peptidase inhibitor clade A member 1 induces the invasion and migration of gastric cancer cells and its expression is associated with the progression of gastric cancer. These results may provide a potential target to prevent invasion and metastasis in gastric cancer.
背景
在之前的一项研究中，我们报道丝氨酸蛋白酶抑制剂A家族成员1（serpinA1）在过表达Snail的胃癌中上调。尽管已在几种类型的癌症中对serpinA1进行了研究，但其作用和作用机制仍知之甚少。在本研究中，我们研究了serpinA1在胃癌迁移和侵袭中的作用，并确定了其潜在机制。
方法
通过蛋白质免疫印迹分析和实时PCR评估表达水平。通过染色质免疫沉淀（ChIP）分析来检测Snail与serpinA1启动子的结合。使用细胞侵袭和迁移试验研究serpinA1的作用。此外，通过免疫组织化学分析在400例胃癌患者中验证了serpinA1表达的临床病理及预后意义。
结果
在胃癌细胞系AGS和MKN45中，Snail的过表达导致serpinA1上调，而Snail的敲低则抑制serpinA1表达。染色质免疫沉淀分析表明，Snail的过表达增加了Snail与serpinA1启动子的结合。serpinA1的过表达增加了胃癌细胞的迁移和侵袭，而serpinA1的敲低则降低了侵袭和迁移能力。此外，serpinA1增加了胃癌细胞中金属蛋白酶-8的mRNA水平和释放。通过免疫组织化学在肿瘤细胞的细胞质和基质中观察到丝氨酸蛋白酶抑制剂A家族成员1。serpinA1表达增强与肿瘤大小增加、T分期进展、神经周围浸润、淋巴管浸润、淋巴结转移及总生存期缩短显著相关。
结论
丝氨酸蛋白酶抑制剂A家族成员1诱导胃癌细胞的侵袭和迁移，其表达与胃癌进展相关。这些结果可能为预防胃癌侵袭和转移提供一个潜在靶点。
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