Differential expression of S100A2 and S100A4 in lung adenocarcinomas: Clinicopathological significance, relationship to p53 and identification of their target genes
Differential expression of S100A2 and S100A4 in lung adenocarcinomas: Clinicopathological significance, relationship to p53 and identification of their target genes
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DOI：
10.1111/j.1349-7006.2005.00121.x
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发表时间：
2005-12-01
期刊：
影响因子：
5.7
通讯作者：
Fukayama, M
中科院分区：
文献类型：
--
作者：
Matsubara, D;Niki, T;Fukayama, M
以前的研究表明，一些S100蛋白与某些类型的癌症的进展有关。然而，目前还没有关于S100家族基因在肺腺癌中表达的全面数据。寡核苷酸阵列、定量逆转录聚合酶链式反应和Western印迹分析表明，S100A2和S100A4分别是S100家族中最显著下调和上调的成员。94例原发性肺腺癌中，S100A2阳性表达(33/94，35.1%)与淋巴道侵犯显著相关(P=0.0233)，S100A4阳性表达(19/94，20.2%)与血管侵犯显著相关(P=0.0454)。有趣的是，S100A4与P53的表达呈显著负相关(P=0.0008)。生存分析显示，S100A4阳性与患者预后不良相关(P=0.042)。当分析整个患者组时，S100A2阳性与患者的生存无关，但在P53阴性肿瘤患者中，S100A2阳性是一个有利的预后指标(P=0.0448)。最后，我们利用寡核苷酸阵列分析鉴定了与肿瘤进展相关的潜在靶基因S100A2和S100A4：S100A2诱导RUNX3和REPRIMO；S100A4诱导Ezrin、RUNX1和WISP1；S100A2抑制EGFR、NFKB2和RELA2；S100A4抑制ANXA10和IL1RN。因此，本研究证实了S100A2和S100A4参与了肺腺癌的发生发展，S100A4与P53的表达呈负相关，并提供了S100A2和S100A4调控的靶点列表。
Previous studies suggest that some S100 proteins are involved in the progression of certain types of cancer. However, no comprehensive data is currently available on the expression of S100 family genes in lung adenocarcinomas. Oligonucleotide array, quantitative reverse transcription-polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively. Immunohistochemical analyses of 94 primary lung adenocarcinomas showed that positive S100A2 expression (33/94, 35.1%) was significantly associated with lymphatic invasion (P = 0.0233) and positive S100A4 expression (19/94, 20.2%) with vascular invasion (P=0.0454). Interestingly, a strong inverse relationship was found between S100A4 and p53 expression (P = 0.0008). Survival analyses showed that S100A4 positivity was associated with poor patient prognosis (P = 0.042). S100A2 positivity was not associated with patient survival when the whole patient group was analyzed; however, S100A2 positivity was a favorable prognostic indicator in patients with p53-negative tumors (P = 0.0448). Finally, we used oligonucleotide array analyses and identified potential S100A2 and S100A4 target genes involved in cancer progression: S100A2 induced RUNX3 and REPRIMO; S100A4 induced EZRIN, RUNX1 and WISP1; S100A2 repressed EGFR, NFKB2 and RELA2; and S100A4 repressed ANXA10 and IL1RN. Thus, the present study demonstrates involvement of S100A2 and S100A4 in the progression of lung adenocarcinomas and an inverse association between S100A4 and p53 expression, and provides a list of targets regulated by S100A2 and S100A4.