ERINA Is an Estrogen-Responsive LncRNA That Drives Breast Cancer through the E2F1/RB1 Pathway.
ERINA Is an Estrogen-Responsive LncRNA That Drives Breast Cancer through the E2F1/RB1 Pathway.
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DOI：
10.1158/0008-5472.can-20-1031
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Fang Z;Wang Y;Wang Z;Xu M;Ren S;Yang D;Hong M;Xie W
对治疗药物的耐药性是治疗包括乳腺癌在内的癌症的主要挑战。已知长非编码 RNA (lncRNA) 具有多种生理和病理生理功能，包括在癌症中的功能。在寻找负责癌症耐药性的lncRNA时，我们发现了一种基因间lncRNA ERINA（雌激素诱导型lncRNA）作为一种在多种癌症类型中高表达的新型lncRNA，特别是在雌激素受体（ER）阳性乳腺癌中。 ERINA的表达与ER阳性乳腺癌患者的生存率以及乳腺癌细胞系对CDK抑制剂的敏感性呈负相关。功能表征确定 ERINA 是一种致癌 lncRNA，因为乳腺癌细胞中 ERINA 的敲低可抑制细胞周期进展和体外肿瘤细胞增殖以及体内异种移植肿瘤生长。相反，ERINA 的过度表达促进细胞生长和细胞周期进展。 ERINA 通过与 E2F 转录因子 1 (E2F1) 相互作用来促进细胞周期进程，从而阻止 E2F1 与肿瘤抑制视网膜母细胞瘤蛋白 1 (RB1) 的结合。 ERINA 还充当雌激素和 ER 响应基因，并且内含子 ER 结合位点被鉴定为介导 ERINA 反式激活的增强子。总之，ERINA 是一种雌激素响应性致癌 lncRNA，可作为乳腺癌的新型生物标志物和潜在治疗靶点。
Resistance to therapeutic drugs is a major challenge in the treatment of cancers including breast cancer. Long noncoding RNAs (lncRNA) are known to have diverse physiological and pathophysiological functions, including in cancer. In searching for lncRNA responsible for cancer drug resistance, we identified an intergenic lncRNA ERINA (estrogen inducible lncRNA) as a novel lncRNA highly expressed in multiple cancer types, especially in estrogen receptor (ER)-positive breast cancers. Expression of ERINA was inversely correlated with survival of ER-positive breast cancer patients and sensitivity to CDK inhibitor in breast cancer cell lines. Functional characterization established ERINA as an oncogenic lncRNA, as knockdown of ERINA in breast cancer cells inhibited cell cycle progression and tumor cell proliferation in vitro and xenograft tumor growth in vivo. In contrast, overexpression of ERINA promoted cell growth and cell cycle progression. ERINA promoted cell cycle progression by interacting with the E2F transcription factor 1 (E2F1), which prevents the binding of E2F1 to the tumor suppressor retinoblastoma protein 1 (RB1). ERINA also functioned as an estrogen and ER-responsive gene, and an intronic ER binding site was identified as an enhancer that mediates the transactivation of ERINA. In summary, ERINA is an estrogen-responsive oncogenic lncRNA that may serve as a novel biomarker and potential therapeutic target in breast cancer.