Department of Laboratory Medicine, Jinzhou Medical University Graduate Training Base, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, People's Republic of China.
Clin Transl Oncol. 2024 Mar;26(3):698-708. doi: 10.1007/s12094-023-03294-3. Epub 2023 Aug 4.
There is compelling evidence that long-stranded non-coding RNAs (lncRNAs) play an important role in the progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of lncRNA XXYLT1 antisense-2 (XXYLT1-AS2) in HCC progression.
Real-time PCR was used to assess the levels of XXYLT1-AS2 in plasma from HCC and normal patients. Cell proliferation, apoptosis, migration, and invasion were monitored, and tumor xenografts were established to investigate the biological functions of XXYLT1-AS2 by gain-of-function and loss-of-function studies in vitro and in vivo, the expression of autophagy biomarkers and transcriptional factor EB (TFEB) was examined by immunoprecipitation, ubiquitination assays, and western blotting. Autophagy inhibitor, 3-methyladenine (3MA), and proteasome inhibitor, MG132, were used to verify the role of autophagy in HCC progression and the effect of XXYLT1-AS2 on TFEB ubiquitination, respectively.
In this study, we identified that lncRNA XXYLT1-AS2 is highly expressed in HCC plasma and promotes tumor growth in vivo. In functional studies, it was found that silent expression of XXYLT1-AS2 inhibited HCC proliferation, migration, invasion, and activated autophagy of HCC cells, which were attenuated by autophagy inhibitor, 3MA. Mechanistically, XXYLT1-AS2 decreased the protein level of TFEB through promoting its degradation by ubiquitin proteasome pathway.
XXYLT1-AS2 plays an oncogenic role in HCC progression through inhibition of autophagy via promoting the degradation of TFEB, and thus could be a novel target for HCC treatment.
大量证据表明长链非编码 RNA（lncRNA）在肝细胞癌（HCC）的进展中起着重要作用。本研究旨在探讨 lncRNA XXYLT1 反义-2（XXYLT1-AS2）在 HCC 进展中的作用。
实时 PCR 用于评估 HCC 和正常患者血浆中 XXYLT1-AS2 的水平。通过体外和体内的功能获得和功能丧失研究，监测细胞增殖、凋亡、迁移和侵袭，建立肿瘤异种移植体，以研究 XXYLT1-AS2 的生物学功能，通过免疫沉淀、泛素化测定和 Western blot 检测自噬生物标志物和转录因子 EB（TFEB）的表达。使用自噬抑制剂 3-甲基腺嘌呤（3MA）和蛋白酶体抑制剂 MG132 分别验证自噬在 HCC 进展中的作用以及 XXYLT1-AS2 对 TFEB 泛素化的影响。
在这项研究中，我们发现 lncRNA XXYLT1-AS2 在 HCC 血浆中高度表达，并促进体内肿瘤生长。在功能研究中，发现沉默表达 XXYLT1-AS2 抑制 HCC 细胞的增殖、迁移、侵袭，并激活 HCC 细胞的自噬，自噬抑制剂 3MA 可减弱这种作用。机制上，XXYLT1-AS2 通过促进其通过泛素蛋白酶体途径降解来降低 TFEB 的蛋白水平。
XXYLT1-AS2 通过促进 TFEB 的降解抑制自噬，在 HCC 进展中发挥致癌作用，因此可能成为 HCC 治疗的新靶点。
