Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma
Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma
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DOI：
10.1007/s00280-017-3477-4
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发表时间：
2018-01-01
影响因子：
3
通讯作者：
Shirabe, Ken
中科院分区：
文献类型：
--
作者：
Altan, Bolag;Kaira, Kyoichi;Shirabe, Ken
目的L型氨基酸转运体1(LAT1)与肿瘤细胞增殖、血管生成和多种人类肿瘤的生存有关。虽然LAT1的表达被认为是预测胰腺导管腺癌(PDAC)术后预后的重要指标，但LAT1作为一种化疗耐药因子在PDAC中的临床意义尚不清楚。用抗LAT1抗体对切除的肿瘤标本进行免疫组织化学染色。结果LAT1高表达的比例为64.1%(71/110)。LAT1蛋白的高表达与肿瘤分化程度、肿瘤深度(T因子)、淋巴结转移、静脉侵犯、复发及临床疗效显著相关。经多因素分析，LAT1被确认为预测术后较差生存的独立预后因素。我们分析了TCGA数据集，得到了相似的结果，即SLC7A5高表达组的存活率低于低表达组。LAT1可成功预测术后辅助化疗(n=88)和复发后全身化疗(n=56)患者的预后。所有LAT1高表达的患者均为无反应者，而在LAT1低表达的患者中约有30%为有反应者(p=0.0002)。通过对TCGA在线数据库的分析，发现LAT1与低氧诱导基因PTGES、PYGL和KPNA2密切相关。结论LAT1作为一种独立的预后标志物，是一种潜在的分子靶向基因，可降低PDAC患者的化疗耐药和肿瘤生长，为我们的体外研究提供了支持。
Purpose L-type amino acid transporter 1 (LAT1) is linked to tumor cell proliferation, angiogenesis, and survival in various human cancers. Although the expression of LAT1 was identified as a significant prognostic predictor after surgery in patients with pancreatic ductal adenocarcinoma (PDAC), little is known about the clinical significance of LAT1 as a chemotherapeutic resistance factor in PDAC.Methods A total of 110 patients with surgically resected PDAC were retrospectively reviewed as the training set. Immunohistochemical staining of resected tumor specimens was assessed using anti-LAT1 antibodies. In vitro analysis of chemotherapy resistance and LAT1 function using PDAC cell lines was also performed.Results The rate of high expression of LAT1 was 64.1% (71/110). The high expression of LAT1 protein was significantly associated with tumor differentiation, tumor depth (T factor), lymph node metastasis, venous invasion, recurrence, and clinical response. By multivariate analysis, LAT1 was validated as an independent prognostic factor for predicting worse survival after surgery. We analyzed the TCGA data set and obtained similar results that the survival rates of SLC7A5 high expression group were poorer than that of low expression group. LAT1 could successfully predict the outcome of patients who received adjuvant chemotherapy after surgery (n = 88) and systemic chemotherapy after recurrence (n = 56). All patients with high LAT1 expression were non-responders, whereas approximately 30% of the patients with low LAT1 expression responders (p = 0.0002). By analyzing the TCGA online database, it was found that LAT1 closely correlated with hypoxia-induced genes, such as PTGES, PYGL, and KPNA2.Conclusion LAT1 as an independent prognostic marker is a potential molecular targeting gene to reduce chemoresistance and tumor growth in patients with PDAC, supported by our in vitro study.