Effect of urokinase-type plasminogen activator combined with clinical stage and Barcelona Clinic Liver Cancer stage on the prognosis of patients with hepatocellular carcinoma

Jiebin Wu; Min Sun; Zhizhen Li; Yang Shen; Yingjun Wu; Hesong Zhang; Zhichao Xu; Qingxiang Gao

doi:10.21037/jgo-23-311

Effect of urokinase-type plasminogen activator combined with clinical stage and Barcelona Clinic Liver Cancer stage on the prognosis of patients with hepatocellular carcinoma

J Gastrointest Oncol. 2023 Jun 30;14(3):1434-1450. doi: 10.21037/jgo-23-311.

Authors

Jiebin Wu¹, Min Sun¹, Zhizhen Li², Yang Shen², Yingjun Wu², Hesong Zhang¹, Zhichao Xu¹, Qingxiang Gao²

Affiliations

¹ Department of Hepatobiliary Surgery, The Second People's Hospital of Wuhu, Wuhu, China.
² Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.

Abstract

Background: The aim of this investigation is to evaluate the association and potential mechanism between plasminogen activator urokinase (PLAU) and the prognosis of patients with liver hepatocellular carcinoma (LIHC).

Methods: We verified PLAU expression and its correlation with LIHC patients' prognosis in The Cancer Genome Atlas (TCGA) database. The interaction network for protein-gene was established in the GeneMania database and the STRING database, and the association between PLAU and immune cells was assessed in Tumor Immune Estimation Resource (TIMER) and TCGA databases. The potential physiological mechanism was elucidated by the Gene Set Enrichment Analysis (GSEA) enrichment assessment. Finally, the individual clinical data of 100 LIHC patients were retrospectively evaluated to further analyze the clinical value of PLAU.

Results: The PLAU expression in LIHC tissues was greater than in paracancerous tissues, and LIHC patients with low PLAU expression had better disease-specific survival (DSS), overall survival (OS), and progression free interval (PFI) than those with high PLAU expression. In the TIMER database, the PLAU expression was positively associated with six kinds of infiltrating immune cells: CD4⁺ T, neutrophils, CD8⁺ T, macrophages, B, and dendritic cells, while GSEA enrichment analysis indicated PLAU may impact the biological activities of LIHC by taking part in MAPK and JAK_STAT signaling pathways, angiogenesis, and P53. There were statistically significant differences in T-stage and Edmondson grading between the two groups of patients with high and low expression of PLAU (P<0.05). The tumor progression rates were 88% (44/50) and 92% (46/50) respectively in the low and high PLAU groups, with early recurrence rates of 60% (30/50) and 72% (36/50), and median PFS of 29.5 and 23 months, respectively. The COX regression analysis showed PLAU expression and CS and Barcelona Clinic Liver Cancer (BCLC) stages were independent prognostic factors affecting tumor progression in LIHC patients.

Conclusions: The decreased expression of PLAU can prolong the DSS, OS, and PFI in LIHC patients, and can be utilized as a novel predictive index. PLAU combined with CS staging and BCLC staging has good clinical value in the early screening and prognosis of LIHC. These results reveal an efficient approach for developing anticancer strategies against LIHC.

Keywords: Plasminogen activator urokinase (PLAU); immune infiltration; liver hepatocellular carcinoma (LIHC); prognosis.