Long noncoding RNA LINC00518 induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop in melanoma.
Long noncoding RNA LINC00518 induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop in melanoma.
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长非编码 RNA LINC00518 通过黑色素瘤中的 miR-33a-3p/HIF-1α 负反馈环调节糖酵解来诱导放射抗性
DOI：
10.1038/s41419-021-03523-z
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发表时间：
2021-03-04
影响因子：
9
通讯作者：
Cao K
中科院分区：
文献类型：
--
作者：
Liu Y;He D;Xiao M;Zhu Y;Zhou J;Cao K
长链非编码RNA LINC 00518在各种类型的癌症中高度表达，并参与癌症进展。尽管LINC 00518促进皮肤恶性黑色素瘤（CMM）的转移，但其对CMM放射敏感性影响的机制仍不清楚。在这项研究中，LINC 00518表达在CMM样本中显著上调，LINC 00518水平与CMM患者的不良预后相关。CMM细胞中LINC 00518的敲低显著抑制细胞侵袭、迁移、增殖和克隆形成。LINC 00518介导的侵袭、迁移、增殖和克隆形成在体外受到microRNA miR-33 a-3 p的负调控，其通过抑制缺氧诱导因子1α（HIF-1α）/乳酸脱氢酶A糖酵解轴增加对放射治疗的敏感性。此外，HIF-1α识别miR-33 a-3 p启动子区域，募集组蛋白去乙酰化酶2，降低miR-33 a-3 p的表达，形成LINC 00518/miR-33 a-3 p/HIF-1α负反馈环。此外，与最初激活的糖酵解和辐射抗性在CMM细胞中的信号转导受损Santacruzamate A，组蛋白脱乙酰酶抑制剂，和2-脱氧-D-葡萄糖，糖酵解抑制剂。最后，在体内皮下植入的肿瘤模型中，LINC 00518表达的敲低使CMM癌细胞对放射疗法敏感。LINC 00518是CMM中的一个癌基因，通过miR-33 a-3 p/HIF-1α负反馈环调控糖酵解而诱导辐射抗性。我们的研究，可能提供一个潜在的策略，以改善放射治疗的疗效在CMM。
The long noncoding RNA, LINC00518, is highly expressed in various types of cancers and is involved in cancer progression. Although LINC00518 promotes the metastasis of cutaneous malignant melanoma (CMM), the mechanism underlaying its effects on CMM radiosensitivity remains unclear. In this study, LINC00518 expression was significantly upregulated in CMM samples, and LINC00518 levels were associated with poor prognosis of patients with CMM. Knockdown of LINC00518 in CMM cells significantly inhibited cell invasion, migration, proliferation, and clonogenicity. LINC00518-mediated invasion, migration, proliferation, and clonogenicity were negatively regulated by the microRNA, miR-33a-3p, in vitro, which increased sensitivity to radiotherapy via inhibition of the hypoxia-inducible factor 1α (HIF-1α)/lactate dehydrogenase A glycolysis axis. Additionally, HIF-1α recognized the miR-33a-3p promoter region and recruited histone deacetylase 2, which decreased the expression of miR-33a-3p and formed an LINC00518/miR-33a-3p/HIF-1α negative feedback loop. Furthermore, signaling with initially activated glycolysis and radioresistance in CMM cells was impaired by Santacruzamate A, a histone deacetylase inhibitor, and 2-deoxy-D-glucose, a glycolytic inhibitor. Lastly, knockdown of LINC00518 expression sensitized CMM cancer cells to radiotherapy in an in vivo subcutaneously implanted tumor model. In conclusion, LINC00518 was confirmed to be an oncogene in CMM, which induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop. Our study, may provide a potential strategy to improve the treatment outcome of radiotherapy in CMM.
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