Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway.
Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway.
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miR-939表达减少通过SLC34A2和Raf/MEK/ERK通路失调导致胃癌化疗耐药和转移
DOI：
10.1186/s12943-017-0586-y
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发表时间：
2017-01-23
期刊：
影响因子：
37.3
通讯作者：
Ye S
中科院分区：
文献类型：
--
作者：
Zhang JX;Xu Y;Gao Y;Chen C;Zheng ZS;Yun M;Weng HW;Xie D;Ye S
研究背景化疗耐药和转移是胃癌患者死亡的主要原因，但其分子机制尚不清楚。miRNAs的失调与包括GC在内的多种疾病相关。最近，微阵列分析显示miR-939在人胃癌中表达异常，但miR-939在胃癌中的作用尚未得到深入研究。MethodsIn本研究，我们首先检测了miR-939在两个独立队列的临床胃癌样本中的表达模式：一个队列包含112例接受手术后接受辅助化疗的I-III期胃癌患者;另一组为110例接受姑息化疗的IV期胃癌患者。一系列的在体内和体外试验，然后进行调查的功能，miR-939在GC.ResultsWe检测到，miR-939的表达减少与化疗耐药和增加肿瘤复发的风险在GC患者。进一步的功能研究表明，miR-939的过表达抑制了GC细胞的生长，并通过损害细胞生长和诱导凋亡在体外和体内增强了5-氟尿嘧啶诱导的化疗敏感性。此外，miR-939在体外可抑制胃癌细胞的迁移和侵袭，在体内可减少肺癌转移的发生。我们进一步确定溶质载体家族34成员2（SLC 34 A2）是miR-939的新靶点。从机制上讲，我们阐明了miR-939主要通过抑制GC中激活的SLC 34 A2/Raf/MEK/ERK通路发挥其作用。多因素分析显示miR-939、SLC 34 A2及其联合是胃癌患者预后不良和肿瘤复发的独立指标。结论miR-939是胃癌的抑癌miRNA，miR-939/SLC 34 A2轴为胃癌的治疗提供了新的思路。
BackgroundThe development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated.MethodsIn the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC.ResultsWe detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients.ConclusionOur data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment.