S100P is a molecular determinant of E-cadherin function in gastric cancer
S100P is a molecular determinant of E-cadherin function in gastric cancer
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DOI：
10.1186/s12964-019-0465-9
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发表时间：
2019-11-25
影响因子：
8.4
通讯作者：
Seruca, Raquel
中科院分区：
文献类型：
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作者：
Carneiro, Patricia;Moreira, Ana Margarida;Seruca, Raquel
背景 E-钙粘蛋白在散发性和遗传性胃癌的病因学中发挥着关键作用。在这项研究中，我们的目的是确定影响与癌症相关的 E-钙粘蛋白表达和功能的分子相互作用因子。方法 使用数据挖掘方法来预测胃特异性候选基因，发现 S100P 是关键候选基因。通过体外功能测定评估了 S100P 的作用，并在胃癌组织微阵列 (TMA) 中研究了其表达。结果发现 S100P 有助于依赖 E-钙粘蛋白功能背景的癌症途径。特别是，我们证明 S100P 在野生型 E-钙粘蛋白环境中充当 E-钙粘蛋白正调节因子，其抑制导致 E-钙粘蛋白表达和功能降低。相比之下，S100P 可能是功能性 E-钙粘蛋白丧失的胃癌细胞的促生存因子，有助于致癌分子程序。此外，胃癌TMA的表达分析显示，S100P表达对患有Ecad(-)肿瘤的患者产生负面影响，尽管其本身与总生存期没有显着相关。结论 我们认为 S100P 在胃癌中具有双重作用，在 E-钙粘蛋白缺失的情况下充当致癌因子，在功能性 E-钙粘蛋白环境中充当肿瘤抑制因子。 S100P 在不同 E-钙粘蛋白背景下的拮抗作用的发现将有助于对可能受益于 S100P 靶向治疗的胃癌患者进行分层。
Background E-cadherin has been awarded a key role in the aetiology of both sporadic and hereditary forms of gastric cancer. In this study, we aimed to identify molecular interactors that influence the expression and function of E-cadherin associated to cancer. Methods A data mining approach was used to predict stomach-specific candidate genes, uncovering S100P as a key candidate. The role of S100P was evaluated through in vitro functional assays and its expression was studied in a gastric cancer tissue microarray (TMA). Results S100P was found to contribute to a cancer pathway dependent on the context of E-cadherin function. In particular, we demonstrated that S100P acts as an E-cadherin positive regulator in a wild-type E-cadherin context, and its inhibition results in decreased E-cadherin expression and function. In contrast, S100P is likely to be a pro-survival factor in gastric cancer cells with loss of functional E-cadherin, contributing to an oncogenic molecular program. Moreover, expression analysis in a gastric cancer TMA revealed that S100P expression impacts negatively among patients bearing Ecad(-) tumours, despite not being significantly associated with overall survival on its own. Conclusions We propose that S100P has a dual role in gastric cancer, acting as an oncogenic factor in the context of E-cadherin loss and as a tumour suppressor in a functional E-cadherin setting. The discovery of antagonist effects of S100P in different E-cadherin contexts will aid in the stratification of gastric cancer patients who may benefit from S100P-targeted therapies.