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Graphical abstract Abstract Advanced hepatocellular carcinoma (HCC) is a highly aggressive malignancy that is a serious threat to the public health system of China. Urokinase-plasminogen activator (uPA) can promote the invasive growth and metastasis of HCC cells by activating matrix metalloproteinases (MMPs), leading to the breakage of the extra-cellular matrix. uPA is a promising target for advanced HCC treatment. In this stuy the expression of uPA was examined by quantitative polymerase chain reaction in hepatic cell lines. Protein interaction between uPA and SPINK13 was identified by immunoprecipitation. In vitro biochemical assay was used to examine the inhibitory effect of the SPINK13 on the direct cleaving of the recombinant pro-MMP9 by uPA. The antitumor effect of SPINK13 was examined by transwell assay or the nude mice tumor model.The expression of uPA was much higher in highly aggressive HCC cell lines than in lowly aggressive HCC cell lines or non-tumor hepatic cell lines. SPINK13 interacted with uPA in HCC cells and directly inhibited the cleaving of MMP9 by uPA. Treatment of the recombinant SPINK13 protein inhibited the invasion of HCC cells in several experiments, such as transwell experiments or the intrahepatic growth model. The results of the study indicated that SPINK13 could function as a promising therapeutic approach for patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Aim: To propose an appropriate staging system for hepatocellular carcinoma (HCC) classification., Methods: Here, 288 in-patients with HCC were studied and divided into three groups: those with expansive growth, invasive growth (including satellite nodules, nodule fusions and direct tumor invasion of adjacent organs), or disseminative growth (including vascular involvement, regional lymph node metastasis and distant metastasis). A survival analysis was performed using a Kaplan-Meier analysis, and prognostic factors for overall survival were determined by the Cox proportional hazards regression model., Results: The overall survival (OS) of patients with invasive tumor growth was shorter than that of patients with expansive tumor growth (27.796 ± 3.730 and 57.398 ± 4.873 mo, respectively, P < 0.001). No significant difference in survival was observed between patients with vascular involvement and patients with regional lymph node metastasis (21.667 ± 4.773 and 14.619 ± 2.456 mo, respectively, P = 0.801). The OS of patients with distant metastasis (6.417 ± 1.395 mo) was shorter than that of the other groups (P < 0.001). No significant difference in survival was observed between patients with expansive tumor growth and vascular and/or regional lymph node involvement and patients with invasive tumor growth and no vascular and/or lymph node involvement (25.762 ± 7.024, 21.200 ± 7.794 and 39.533 ± 5.840 mo, respectively; P = 0.871, 0.307 and 0.563, respectively)., Conclusion: These data led to the proposal of a new staging system: the Expansive-Invasive-Disseminative growth staging classification.