Defect of SLC38A3 promotes epithelial-mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma.
Defect of SLC38A3 promotes epithelial-mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma.
复制标题
SLC38A3的缺陷促进上皮间质转化并预测食管鳞状细胞癌的不良预后
DOI：
10.21147/j.issn.1000-9604.2020.05.01
复制
发表时间：
2020-10-31
期刊：
影响因子：
--
通讯作者：
Zhan Q
中科院分区：
文献类型：
--
作者：
Liu R;Hong R;Wang Y;Gong Y;Yeerken D;Yang D;Li J;Fan J;Chen J;Zhang W;Zhan Q
溶质载体家族38 （slc38）转运蛋白在氨基酸转运和信号转导中起重要作用。然而，它们在肿瘤中的遗传改变和生物学作用在很大程度上仍不清楚。本研究旨在阐明SLC38s转运体的遗传特征及其在食管鳞状细胞癌（ESCC）中的意义。对SLC38A3的体细胞突变和拷贝数改变（CNAs）进行分析。采用免疫组化（IHC）法和Western blot法检测蛋白表达水平。采用MTS法、菌落形成法、transwell法和创面愈合法探讨ESCC细胞的恶性表型。用免疫荧光法验证两种指示蛋白的共定位，用免疫沉淀法确认蛋白的相互作用。我们的研究结果表明，SLC38s家族在ESCC中被显著破坏，存在高频率的CNAs和很少的体细胞突变。SLC38A3是其中最常见的丢失基因，与生存率低和淋巴结转移有关。SLC38A3在肿瘤组织中的表达低于正常组织，且与较差的临床预后显著相关。进一步的实验发现，SLC38A3缺失可以促进ESCC细胞株的EMT， SLC38A3与SETDB1的相互作用可能导致Snail转录减少。药物基因组学分析显示，15种抑制剂与SLC38A3表达显著相关。我们的研究提供了SLC38A3可以作为EMT途径的抑制因子，并作为ESCC中不同药物敏感性的预后因素和预测因子。
Solute carrier family 38 (SLC38s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still largely unclear. This study aimed to elucidate the genetic signatures of SLC38s transporters and their implications in esophageal squamous cell carcinoma (ESCC). Analyses on somatic mutation and copy number alterations (CNAs) of SLC38A3 were performed as described. Immunohistochemistry (IHC) assay and Western blot assay were used to detect the protein expression level. MTS assay, colony formation assay, transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells. Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins. Our findings revealed that SLC38s family was significantly disrupted in ESCC, with high frequent CNAs and few somatic mutations. SLC38A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis. The expression of SLC38A3 was lower in tumor tissues compared to that in normal tissues, which was also significantly associated with worse clinical outcome. Further experiments revealed that depletion of SLC38A3 could promote EMT in ESCC cell lines, and the interaction of SLC38A3 and SETDB1 might lead to the reduced transcription of Snail. Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38A3 expression. Our investigations have provided insights that SLC38A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.