Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer.
Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer.
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Lnc RNA HOTAIR 作为竞争性内源 RNA 通过海绵 miR-331-3p 调节胃癌中的 HER2 表达
DOI：
10.1186/1476-4598-13-92
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发表时间：
2014-04-28
期刊：
影响因子：
37.3
通讯作者：
Wang ZX
中科院分区：
文献类型：
--
作者：
Liu XH;Sun M;Nie FQ;Ge YB;Zhang EB;Yin DD;Kong R;Xia R;Lu KH;Li JH;De W;Wang KM;Wang ZX
背景越来越多的证据表明长链非编码RNA HOTAIR在肿瘤的进展和转移中起着关键作用。然而，HOTAIR在胃癌发生中的整体生物学作用和临床意义仍然在很大程度上unknown.MethodsHOTAIR表达测定在78配对癌和非癌组织样本通过实时PCR。采用过表达和RNA干扰的方法研究HOTAIR对胃癌细胞的作用。通过生物信息学分析、荧光素酶检测和RNA结合蛋白免疫沉淀（RIP）等方法，对竞争性内源RNA（ceRNA）的作用机制进行了深入的研究。HOTAIR/HER 2的正相互作用通过免疫组化检测和双变量相关分析进行了鉴定和验证。结果HOTAIR的上调与较大的肿瘤大小、晚期病理分期和广泛转移有关，并且与较短的胃癌患者的总生存期有关。此外，HOTAIR过表达促进胃癌细胞的增殖、迁移和侵袭，而HOTAIR缺失则抑制胃癌细胞的侵袭和存活，并在体外和体内诱导生长停滞。具体而言，HOTAIR可作为ceRNA，有效地成为miR-331- 3 p的接收器，从而调节HER 2的去抑制并施加额外水平的转录后调节。最后，HOTAIR/HER 2的正相关性与进展期胃癌显著相关。结论HOTAIR过表达是胃癌预后不良的生物标志物，可能赋予肿瘤细胞恶性表型。涉及HOTAIR的ceRNA调控网络以及HOTAIR和HER 2之间的正相互作用可能有助于更好地理解胃癌发病机制，并促进针对该疾病的lncRNA指导的诊断和治疗的发展。
BackgroundAccumulating evidence indicates that the long non-coding RNA HOTAIR plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of HOTAIR in gastric carcinogenesis remains largely unknown.MethodsHOTAIR expression was measured in 78 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches in vitro and in vivo. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation (RIP). The positive HOTAIR/HER2 interaction was identified and verified by immunohistochemistry assay and bivariate correlation analysis.ResultsHOTAIR upregulation was associated with larger tumor size, advanced pathological stage and extensive metastasis, and also correlated with shorter overall survival of gastric cancer patients. Furthermore, HOTAIR overexpression promoted the proliferation, migration and invasion of gastric carcinoma cells, while HOTAIR depletion inhibited both cell invasion and cell viability, and induced growth arrest in vitro and in vivo. In particular, HOTAIR may act as a ceRNA, effectively becoming a sink for miR-331-3p, thereby modulating the derepression of HER2 and imposing an additional level of post-transcriptional regulation. Finally, the positive HOTAIR/HER2 correlation was significantly associated with advanced gastric cancers.ConclusionsHOTAIR overexpression represents a biomarker of poor prognosis in gastric cancer, and may confer malignant phenotype to tumor cells. The ceRNA regulatory network involving HOTAIR and the positive interaction between HOTAIR and HER2 may contribute to a better understanding of gastric cancer pathogenesis and facilitate the development of lncRNA-directed diagnostics and therapeutics against this disease.
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