Department of Gastrointestinal Cancer Translational Research Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing Institute for Cancer Research, Beijing, 100142, P. R. China.
Department of Radiation Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, P. R. China.
Cancer Commun (Lond). 2022 Nov;42(11):1141-1161. doi: 10.1002/cac2.12367. Epub 2022 Oct 9.
Gastric cancer (GC) is among the most malignant tumors, yet the pathogenesis is not fully understood, especially the lack of detailed information about the mechanisms underlying long non-coding RNA (lncRNA)-mediated post-translational modifications. Here, the molecular mechanisms and clinical significance of the novel lncRNA syndecan-binding protein 2-antisense RNA 1 (SDCBP2-AS1) in the tumorigenesis and progression of GC were investigated.
The expression levels of SDCBP2-AS1 in 132 pairs of GC and adjacent normal tissues were compared, and the biological functions were assessed in vitro and in vivo. RNA pull-down and immunoprecipitation assays were conducted to clarify the interactions of SDCBP2-AS1 and heterogeneous nuclear ribonucleoprotein (hnRNP) K. RNA-sequencing, immunoprecipitation, immunofluorescence, and luciferase analyses were performed to investigate the functions of SDCBP2-AS1.
SDCBP2-AS1 was significantly downregulated in GC tissues and predictive of poor patient prognosis. Silencing of SDCBP2-AS1 promoted the proliferation and migration of GC cells both in vitro and in vivo. Mechanically, SDCBP2-AS1 physically bound to hnRNP K to repress SUMOylation of hnRNP K and facilitated ubiquitination of hnRNP K and β-catenin, thereby promoting the degradation of β-catenin in the cytoplasm. Silencing of SDCBP2-AS1 caused SUMOylation of hnRNP K and stabilized β-catenin activity, which altered transcription of downstream genes, resulting in tumorigenesis and metastasis of GC. Moreover, the knockdown of hnRNP K partially abrogated the effects of SDCBP2-AS1.
SDCBP2-AS1 interacts with hnRNP K to suppress tumorigenesis and metastasis of GC and regulates post-transcriptional modifications of hnRNP K to destabilize β-catenin. These findings suggest SDCBP2-AS1 as a potential target for the treatment of GC.
胃癌（GC）是最恶性的肿瘤之一，但发病机制尚不完全清楚，特别是缺乏关于长链非编码 RNA（lncRNA）介导的翻译后修饰机制的详细信息。在这里，我们研究了新型 lncRNA 结合蛋白 2 反义 RNA 1（SDCBP2-AS1）在 GC 发生和发展中的分子机制及其临床意义。
比较了 132 对 GC 组织和相邻正常组织中 SDCBP2-AS1 的表达水平，并在体外和体内评估了其生物学功能。通过 RNA 下拉和免疫沉淀实验来阐明 SDCBP2-AS1 和异质核核糖核蛋白（hnRNP）K 的相互作用。进行 RNA 测序、免疫沉淀、免疫荧光和荧光素酶分析来研究 SDCBP2-AS1 的功能。
SDCBP2-AS1 在 GC 组织中显著下调，并预测患者预后不良。沉默 SDCBP2-AS1 可促进 GC 细胞在体外和体内的增殖和迁移。机制上，SDCBP2-AS1 与 hnRNP K 物理结合，抑制 hnRNP K 的 SUMO 化，并促进 hnRNP K 和 β-连环蛋白的泛素化，从而促进细胞质中β-连环蛋白的降解。沉默 SDCBP2-AS1 导致 hnRNP K 的 SUMO 化和 β-连环蛋白活性的稳定，改变下游基因的转录，导致 GC 的发生和转移。此外，hnRNP K 的敲低部分消除了 SDCBP2-AS1 的作用。
SDCBP2-AS1 与 hnRNP K 相互作用，抑制 GC 的发生和转移，并调节 hnRNP K 的转录后修饰，使β-连环蛋白不稳定。这些发现表明 SDCBP2-AS1 可能成为 GC 治疗的潜在靶点。
