LncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma.
LncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma.
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LncRNA HOTAIR 通过抑制肾细胞癌中的 miR-217 来调节 HIF-1alpha/AXL 信号传导。
DOI：
10.1038/cddis.2017.181
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发表时间：
2017-05-11
影响因子：
9
通讯作者：
Chen XM
中科院分区：
文献类型：
--
作者：
Hong Q;Li O;Zheng W;Xiao WZ;Zhang L;Wu D;Cai GY;He JC;Chen XM
长非编码RNA HOTAIR被认为是多种癌症中的癌基因。以往的研究表明，HOTAIR参与了肾癌细胞的增殖和肿瘤的发生，而microRNA(MiR)-217在肾癌(RCC)中起着肿瘤抑制的作用。然而，肾细胞癌中HOTAIR的潜在分子机制，特别是与miR-217相关的分子机制尚未被研究。在这项研究中，我们首先证明了HOTAIR的表达上调，这与肿瘤的进展有关，而miR-217在肾癌组织和细胞中下调。重要的是，肾癌组织中HOTAIR的表达与miR-217的表达呈负相关。HOTAIR的获得和功能丧失表明HOTAIR作为miR217的CENA促进HIF-1α的表达，进而上调Ax1水平，促进肾细胞癌的增殖、迁移和内皮细胞转化过程，并抑制细胞凋亡。此外，在体内，HOTAIR基因敲除可抑制肿瘤生长，降低增殖抗原Ki-67、HIF-1α和Ax1的表达，上调miR-217的表达。最后，在AXL抑制剂BGB324的作用下，我们证实HOTAIR在体外和体内都通过AXL信号通路促进了RCC的活性。综上所述，HOTAIR通过miR217/HIF-1α/AXL信号通路促进肾细胞癌的发生，为肾细胞癌的诊断和治疗提供了新的靶点。
Long non-coding RNA HOTAIR was regarded as an oncogene in multiple cancers. Previous studies have shown that HOTAIR is involved in the proliferation and tumorigenesis of renal carcinoma cells, while microRNA (miR)-217 functions as a tumor suppressor in renal cell carcinoma (Rcc). However, the underlying molecular mechanism of HOTAIR in Rcc, especially in association with miR-217, has not been studied. In this study, we first demonstrated that HOTAIR expression was upregulated, which was correlated with tumor progression, and miR-217 downregulated in Rcc tissues and cells. Importantly, HOTAIR expression was negatively correlated with miR-217 expression in Rcc tissues. Gain- and loss-of-function of HOTAIR revealed that HOTAIR functioned as a ceRNA for miR-217 to facilitate HIF-1α expression and then upregulated AXL level promoting Rcc proliferation, migration, and EMT process, and inhibiting apoptosis. Furthermore, HOTAIR knockdown suppressed tumor growth and reduced the expression of proliferation antigen ki-67, HIF-1α, and AXL, but upregulated the expression of miR-217 in vivo. Finally, with AXL inhibitor BGB324, we confirmed that HOTAIR promoted Rcc activity through AXL signaling both in vitro and in vivo. In conclusion, these results suggest that HOTAIR promotes Rcc tumorigenesis via miR-217/HIF-1α/AXL signaling, which may provide a new target for the diagnosis and therapy of Rcc disease.
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