SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma.
SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma.
复制标题
SMAD4 和 KCNQ3 的改变与食管腺癌的淋巴结转移相关。
DOI：
10.1016/j.bbadis.2023.166867
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Foley K
中科院分区：
文献类型：
--
作者：
Foley K
食管腺癌（OAC）的转移是生存的重要预测因素。放射学分期用于对患者的转移进行分期，并指导治疗选择，但受到方法准确性的限制。分期的改进将改善临床决策和患者结局。对原发性肿瘤和癌前组织的测序研究揭示了OAC的突变景观，越来越便宜和广泛的测序方法提供了改善分期评估的潜力。在这项工作中，我们提出了一个分析发现的淋巴结转移的放射学和病理学采样，确定新的角色的基因SMAD 4和KCNQ 3的转移。通过转录组学分析，我们发现这两个基因都与经典Wnt通路活性相关，但KCNQ3与非经典Wnt信号传导相关的平面细胞极性变化唯一相关。我们继续验证我们在细胞系和异种移植系统中对KCNQ3的观察，表明KCNQ3的过表达减少了伤口闭合和观察到的转移灶数量。我们的研究结果表明，这两个基因作为转移风险的新的生物标志物，并提供新的潜在的药物靶向途径。
Metastasis in oesophageal adenocarcinoma (OAC) is an important predictor of survival. Radiological staging is used to stage metastases in patients, and guide treatment selection, but is limited by the accuracy of the approach. Improvements in staging will lead to improved clinical decision making and patient outcomes. Sequencing studies on primary tumours and pre-cancerous tissue have revealed the mutational landscape of OAC, and increasingly cheap and widespread sequencing approaches offer the potential to improve staging assessment. In this work we present an analysis of lymph node metastases found by radiological and pathological sampling, identifying new roles of the genes SMAD4 and KCNQ3 in metastasis. Through transcriptomic analysis we find that both genes are associated with canonical Wnt pathway activity, but KCNQ3 is uniquely associated with changes in planar cell polaritiy associated with non-canonical Wnt signalling. We go on to validate our observations in KCNQ3 in cell line and xenograph systems, showing that overexpression of KCNQ3 reduces wound closure and the number of metastases observed. Our results suggest both genes as novel biomarkers of metastatic risk and offer new potential routes to drug targeting.