Plasma microRNA profiles: identification of miR-1229-3p as a novel chemoresistant and prognostic biomarker in gastric cancer
Plasma microRNA profiles: identification of miR-1229-3p as a novel chemoresistant and prognostic biomarker in gastric cancer
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DOI：
10.1038/s41598-020-59939-8
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发表时间：
2020-02-21
影响因子：
4.6
通讯作者：
Otsuji, Eigo
中科院分区：
文献类型：
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作者：
Nishibeppu, Keiji;Komatsu, Shuhei;Otsuji, Eigo
本研究旨在探索血浆中新的microRNAs用于预测胃癌患者辅助化疗的化疗耐药情况。我们使用基于TORAY 3D基因microRNA阵列的方法来比较根治性胃切除术后复发和无复发的GC患者的术前血浆microRNA水平。所有患者均采用口服氟嘧啶类药物S-1辅助化疗。从2566个候选基因中筛选出6个候选microRNAs(miR-1229-3p、1249-5p、762、711、1268a和1260b)，它们在术后复发患者的血浆中高表达。在一项大规模的定量逆转录聚合酶链式反应的验证分析中，我们关注了高水平的miR-1229-3p，它是无复发生存率的一个独立的预后不良因素(P=0.009，HR=3.71)。在体内外，miR-1229-3p过表达可诱导胃癌细胞对5-氟尿嘧啶(5-FU)耐药，胸苷合成酶(TS)和二氢嘧啶脱氢酶(DPD)表达上调，SLC22A7表达下调。小鼠腹腔注射miR-1229-3p对5-FU产生明显的化疗耐药，并伴有血浆和肿瘤组织中高水平的miR-1229-3p。提示血浆miR-1229-3p可作为预测胃癌患者对S-1耐药和选择其他或联合强化化疗方案的有价值的生物标志物。
This study aimed to explore novel microRNAs in plasma for predicting chemoresistance in adjuvant chemotherapy for patients with gastric cancer (GC). We used the Toray 3D-Gene microRNA array-based approach to compare preoperative plasma microRNA levels between GC patients with and without recurrences after curative gastrectomy. All patients underwent adjuvant chemotherapy with S-1, an oral fluoropyrimidine. Of 2566 candidates, six candidate microRNAs (miR-1229-3p, 1249-5p, 762, 711, 1268a and 1260b), which were highly expressed in the preoperative plasma of patients with subsequent recurrences, were selected. In a large-scale validation analysis by quantitative RT-PCR, we focused on high plasma levels of miR-1229-3p, which was an independent poor prognostic factor for recurrence free survival (P = 0.009, HR = 3.71). Overexpression of miR-1229-3p in GC cells induced significant chemoresistance to 5-fluorouracil (5-FU), up-regulation of thymidylate synthase (TS) and dihydroprimidine dehydrogenase (DPD) and down-regulation of SLC22A7 both in vitro and in vivo. Intraperitoneal injection of miR-1229-3p in mice induced significant chemoresistance to 5-FU, accompanied by high levels of miR-1229-3p in plasma and tumor tissue. These findings suggest that plasma miR-1229-3p might be a clinically useful biomarker for predicting chemoresistance to S-1 and selecting other or combined intensive chemotherapy regimens in GC patients.