Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China.
Cancer Sci. 2022 Dec;113(12):4165-4180. doi: 10.1111/cas.15585. Epub 2022 Sep 29.
Early recurrence (within 2 years after resection) is the primary cause of poor outcomes among hepatocellular carcinoma (HCC) patients, and liver cancer stem cells are the main contributors to postsurgical HCC recurrence. Nucleolar and spindle-associated protein 1 (NUSAP1) has been reported to be involved in tumor progression. We investigated the function and clinical value of NUSAP1 in early recurrence of HCC. Data from public datasets and our cohort were used to assess the association between NUSAP1 expression and early HCC recurrence. Gain- and loss-of-function experiments were carried out in vivo and in vitro. The predictive effect of NUSAP1 on early HCC recurrence was further evaluated by a validation cohort. We found that elevated NUSAP1 expression in HCC specimens was correlated with poor outcome, especially in cases with postoperative early recurrence. Functional studies indicated that NUSAP1 significantly promotes HCC progression. A postsurgical recurrence murine model further revealed that upregulated NUSAP1 dramatically increased the likelihood of HCC early recurrence. RNA sequencing data revealed that the gene sets of cancer stemness and the signal transducer and activator of transcription 3 (STAT3) pathway were enriched by NUSAP1 overexpression. Mechanistically, NUSAP1 enhanced cancer stemness through stimulating STAT3 nuclear translocation and activation through receptor of activated protein C kinase 1 (RACK1). In a validation cohort with 112 HCC patients, NUSAP1 effectively predicted HCC early recurrence. Our results indicated that NUSAP1 promotes early recurrence of HCC by sustaining cancer stemness and could serve as a valuable predictive indicator for postsurgical intervention in HCC patients.
早期复发（切除后 2 年内）是肝癌（HCC）患者预后不良的主要原因，肝癌干细胞是术后 HCC 复发的主要原因。核仁纺锤体相关蛋白 1（NUSAP1）已被报道参与肿瘤进展。我们研究了 NUSAP1 在 HCC 早期复发中的作用和临床价值。使用公共数据集和我们的队列数据来评估 NUSAP1 表达与 HCC 早期复发之间的关联。在体内和体外进行了增益和功能丧失实验。通过验证队列进一步评估了 NUSAP1 对 HCC 早期复发的预测作用。我们发现 HCC 标本中 NUSAP1 的表达升高与不良预后相关，尤其是在术后早期复发的情况下。功能研究表明，NUSAP1 可显著促进 HCC 进展。术后复发的小鼠模型进一步表明，上调的 NUSAP1 大大增加了 HCC 早期复发的可能性。RNA 测序数据显示，NUSAP1 过表达富集了癌症干性和信号转导及转录激活因子 3（STAT3）通路的基因集。在包含 112 例 HCC 患者的验证队列中，NUSAP1 可有效预测 HCC 早期复发。我们的结果表明，NUSAP1 通过维持癌症干性促进 HCC 的早期复发，可以作为 HCC 患者术后干预的有价值的预测指标。
