Chen Jun-Feng, Ye Sha-Zhou, Wang Ke-Jie, Meng Xiang-Yu, Yang Bin-Bin, Wu Ke Rong, Ma Qi
Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, Ningbo Clinical Research Center for Urological Disease, Comprehensive Urogenital Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
Department of Urology, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
Sci Rep. 2025 Jan 2;15(1):359. doi: 10.1038/s41598-024-83154-4.
Long noncoding RNAs (lncRNAs) have been recognized as essential regulators in various human malignancies. Hundreds of lncRNAs were known to be abnormally expressed in renal cell carcinoma (RCC) through a lncRNA expression microarray, among which lncRNA OSTM1 antisense RNA 1(OSTM1-AS1) was revealed as one of the most abundant lncRNAs. However, the function of OSTM1-AS1 in RCC remains unknown. Here, we examined OSTM1-AS1 functional roles and mechanism in RCC development. OSTM1-AS1 expression was significantly highly expressed among RCC tissue specimens and cell lines. Functionally, OSTM1-AS1 knockdown significantly suppressed cell proliferation, migration along with metastasis of RCC cells. Mechanistically, miR-491-5p was targeted via OSTM1-AS1, and down-regulation of miR-491-5p reversed OSTM1-AS1 knockdown impact on RCC migration and invasion. MMP-9 was targeted via miR-491-5p, and MMP-9 overexpression reversed miR-491-5p or OSTM1-AS1 knockdown impact on cell migration and invasion. MMP-9 abundance was decreased by OSTM1-AS1 silence, that was reduced by miR-491-5p deficiency. Importantly, our investigation revealed that OSTM1-AS1 has the ability to interact with miR-491-5p, thereby increasing the MMP-9 expression. The in vivo trial demonstrated that OSTM1-AS1 suppression resulted in tumor growth inhibition among nude mice. In summary, our findings indicate, for the first time, at least to the best of our knowledge, that OSTM1-AS1 serves as an oncogene among RCC by promoting proliferation, invasion, and metastasis through its targeting of the miR-491-5p/MMP9 axis. Therefore, this axis could represent a promising alternative therapeutic target for RCC treatment.
长链非编码RNA（lncRNAs）已被公认为多种人类恶性肿瘤中的重要调节因子。通过lncRNA表达微阵列已知数百种lncRNAs在肾细胞癌（RCC）中异常表达，其中lncRNA OSTM1反义RNA 1（OSTM1-AS1）被发现是最丰富的lncRNAs之一。然而，OSTM1-AS1在RCC中的功能仍不清楚。在此，我们研究了OSTM1-AS1在RCC发生发展中的功能作用及机制。OSTM1-AS1在RCC组织标本和细胞系中显著高表达。在功能上，敲低OSTM1-AS1可显著抑制RCC细胞的增殖、迁移和转移。机制上，miR-491-5p是OSTM1-AS1的靶标，miR-491-5p的下调可逆转OSTM1-AS1敲低对RCC迁移和侵袭的影响。MMP-9是miR-491-5p的靶标，MMP-9的过表达可逆转miR-491-5p或OSTM1-AS1敲低对细胞迁移和侵袭的影响。OSTM1-AS1沉默可降低MMP-9的丰度，而miR-491-5p缺乏可进一步降低MMP-9的丰度。重要的是，我们的研究表明OSTM1-AS1能够与miR-491-5p相互作用，从而增加MMP-9的表达。体内试验表明，抑制OSTM1-AS1可导致裸鼠肿瘤生长受到抑制。总之，我们的研究结果首次表明，至少就我们所知，OSTM1-AS1通过靶向miR-491-5p/MMP9轴促进增殖、侵袭和转移，在RCC中作为癌基因发挥作用。因此，该轴可能是RCC治疗中一个有前景的替代治疗靶点。
