Department of Urology, Chongming Branch, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
J Cell Physiol. 2021 Jan;236(1):427-439. doi: 10.1002/jcp.29871. Epub 2020 Jun 24.
Increasing evidence suggests that long noncoding RNAs (lncRNAs) are pivotal regulators in oncogenesis. However, the role of numerous lncRNAs has never been unmasked in clear cell renal cell carcinoma (ccRCC). Presently, we investigated the function of long intergenic nonprotein coding RNA 1426 (LINC01426) in ccRCC, as The Cancer Genome Atlas data indicated that LINC01426 was highly expressed in ccRCC tissues and its overexpression was correlated with disappointing prognosis. First, we verified that LINC01426 was indeed upregulated in ccRCC cell lines and its depletion restrained ccRCC cell proliferation and migration. Besides, we proved that LINC01426 facilitated ccRCC tumorigenesis via forkhead box M1 (FOXM1). Moreover, it was revealed that miR-423-5p was downregulated and directly targeted FOXM1 in ccRCC, and that LINC01426 positively regulated FOXM1 via its inhibition on miR-423-5p. Notably, we also uncovered that miR-423-5p was transcriptionally silenced by CTBP1 and HDAC2. Of importance, LINC01426 was certified to distribute both in the cytoplasm and the nucleus of ccRCC cells, and it increased CTBP1 expression through recruiting insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) in cytoplasm whereas interacted with CTBP1 protein to improve the transcriptional repression on miR-423-5p in nucleus. Jointly, our observations unveiled that LINC01426 aggravates ccRCC progression via IGF2BP1/CTBP1/HDAC2/miR-423-5p/FOXM1 axis, highlighting LINC01426 as a novel promising target for ccRCC treatment.
越来越多的证据表明，长非编码 RNA（lncRNA）是肿瘤发生的关键调节因子。然而，大量 lncRNA 在透明细胞肾细胞癌（ccRCC）中的作用尚未被揭示。目前，我们研究了长非编码 RNA1426（LINC01426）在 ccRCC 中的功能，因为癌症基因组图谱数据表明 LINC01426 在 ccRCC 组织中高度表达，其过表达与预后不良相关。首先，我们验证了 LINC01426 在 ccRCC 细胞系中确实上调，其耗竭抑制 ccRCC 细胞增殖和迁移。此外，我们证明 LINC01426 通过叉头框 M1（FOXM1）促进 ccRCC 肿瘤发生。此外，研究表明 miR-423-5p 在 ccRCC 中下调并直接靶向 FOXM1，LINC01426 通过抑制 miR-423-5p 正向调节 FOXM1。值得注意的是，我们还发现 miR-423-5p 被 CTBP1 和 HDAC2 转录沉默。重要的是，LINC01426 被证明在 ccRCC 细胞的细胞质和细胞核中都有分布，它通过在细胞质中招募胰岛素样生长因子 2 mRNA 结合蛋白 1（IGF2BP1）来增加 CTBP1 的表达，而在核内与 CTBP1 蛋白相互作用，提高对 miR-423-5p 的转录抑制。总之，我们的观察结果揭示了 LINC01426 通过 IGF2BP1/CTBP1/HDAC2/miR-423-5p/FOXM1 轴加重 ccRCC 进展，凸显了 LINC01426 作为 ccRCC 治疗的一个新的有希望的靶点。
