BACKGROUND Long non-coding RNAs (lncRNAs) possess significant regulatory functions in multiple biological and pathological processes, especially in cancer. Dysregulated lncRNAs in hepatocellular carcinoma (HCC) and their therapeutic applications remain unclear. METHODS Differentially expressed lncRNA profile in HCC was constructed using TCGA data. LINC00958 expression level was examined in HCC cell lines and tissues. Univariate and multivariate analyses were performed to demonstrate the prognostic value of LINC00958. Loss-of-function and gain-of-function experiments were used to assess the effects of LINC00958 on cell proliferation, motility, and lipogenesis. Patient-derived xenograft model was established for in vivo experiments. RNA immunoprecipitation, dual luciferase reporter, biotin-labeled miRNA pull-down, fluorescence in situ hybridization, and RNA sequencing assays were performed to elucidate the underlying molecular mechanisms. We developed a PLGA-based nanoplatform encapsulating LINC00958 siRNA and evaluated its superiority for systemic administration. RESULTS We identified a lipogenesis-related lncRNA, LINC00958, whose expression was upregulated in HCC cell lines and tissues. High LINC00958 level independently predicted poor overall survival. Functional assays showed that LINC00958 aggravated HCC malignant phenotypes in vitro and in vivo. Mechanistically, LINC00958 sponged miR-3619-5p to upregulate hepatoma-derived growth factor (HDGF) expression, thereby facilitating HCC lipogenesis and progression. METTL3-mediated N6-methyladenosine modification led to LINC00958 upregulation through stabilizing its RNA transcript. A PLGA-based nanoplatform loaded with si-LINC00958 was developed for HCC systemic administration. This novel drug delivery system was controlled release, tumor targeting, safe, and presented satisfactory antitumor efficacy. CONCLUSIONS Our results delineate the clinical significance of LINC00958 in HCC and the regulatory mechanisms involved in HCC lipogenesis and progression, providing a novel prognostic indicator and promising nanotherapeutic target.

中文翻译：

---

M6A 介导的 LINC00958 上调增加脂肪生成并作为肝细胞癌的纳米治疗靶点。

背景长链非编码RNA（lncRNA）在多种生物学和病理过程中具有重要的调节功能，尤其是在癌症中。肝细胞癌（HCC）中失调的lncRNA及其治疗应用仍不清楚。方法使用TCGA数据构建HCC中差异表达的lncRNA谱。在 HCC 细胞系和组织中检查了 LINC00958 表达水平。进行单变量和多变量分析以证明 LINC00958 的预后价值。功能丧失和功能获得实验用于评估 LINC00958 对细胞增殖、运动和脂肪生成的影响。建立患者来源的异种移植模型用于体内实验。RNA 免疫沉淀、双荧光素酶报告基因、生物素标记的 miRNA pull-down、荧光原位杂交、并进行了 RNA 测序分析以阐明潜在的分子机制。我们开发了一种封装 LINC00958 siRNA 的基于 PLGA 的纳米平台，并评估了其在全身给药方面的优越性。结果我们鉴定了一种与脂肪生成相关的 lncRNA LINC00958，其在 HCC 细胞系和组织中的表达上调。高 LINC00958 水平独立预测较差的总生存率。功能分析表明，LINC00958 在体外和体内加重了 HCC 恶性表型。从机制上讲，LINC00958 吸收 miR-3619-5p 以上调肝癌衍生生长因子 (HDGF) 的表达，从而促进 HCC 脂肪生成和进展。METTL3 介导的 N6-甲基腺苷修饰通过稳定其 RNA 转录物导致 LINC00958 上调。一种装载有 si-LINC00958 的基于 PLGA 的纳米平台被开发用于 HCC 全身给药。这种新型给药系统控释、靶向肿瘤、安全，并具有令人满意的抗肿瘤疗效。结论 我们的结果描绘了 LINC00958 在 HCC 中的临床意义以及参与 HCC 脂肪生成和进展的调节机制，提供了一种新的预后指标和有希望的纳米治疗靶点。