NUSAP1, a novel stemness‐related protein, promotes early recurrence of hepatocellular carcinoma

Abstract

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.

Unveiling NUSAP1 as a common gene signature linking chronic HBV infection and HBV-related HCC

“…In breast cancer, NUSAP1 has been associated with poor overall survival and infiltration of various immune cells [ 17 ]. Moreover, in HCC, increased NUSAP1 expression has been linked to a poor prognosis, particularly early recurrence, and has been shown to facilitate early recurrence of HCC [ 18 ].…”

“…In CHB patients, a wider range of immune cells was observed to infiltrate. Our hypothesis is that this may be linked to the reported biological function of NUSAP1 in enhancing tumor stemness [ 18 , 19 ]. NUSAP1 knockout decreased the expression of surface markers of cancer stem cells (CSCs), and NUSAP1 was highly expressed in self-renewing CSCs.…”

The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma

“…A recent study demonstrated that NUSAP1 was significantly associated with worse prognosis and early postoperative recurrence of HCC patients. Mechanistic study showed that NUSAP1 increased the likelihood of HCC early recurrence in murine model by promoting cancer stemness via STAT3/RACK1 pathway 161 . Similarly, Abelson interactor 2 was identified to drive HCC recurrence by activating cancer stemness‐related pathway 162 …”

“…Mechanistic study showed that NUSAP1 increased the likelihood of HCC early recurrence in murine model by promoting cancer stemness via STAT3/RACK1 pathway. 161 Similarly, Abelson interactor 2 was identified to drive HCC recurrence by activating cancer stemness-related pathway. 162…”

Contrast enhanced ultrasound combined with serology predicts hepatocellular carcinoma recurrence: a retrospective observation cohort study

“…Owing to the development of radiological techniques and serological detection capabilities, noninvasive prediction of postoperative recurrence has become possible. Although radiology techniques (artificial intelligence, radiomics) or serologic markers (mortalin, nucleolar, and spindle-associated protein 1) are used to predict recurrence (13)(14)(15)(16), artificial intelligence and radiomics are complex and difficult to master and serologic markers change dynamically. Studies combining the two techniques are extremely rare.…”