The tumor inhibitory function of growth differentiation factors on hepatocellular carcinoma

Abstract

Abstract Purpose Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies with very poor outcomes. Inflammatory factors play a huge role in the incidence and development of HCC. But, the tumor-protective functions of growth differentiation factor (GDF) on HCC were not yet clarified clearly. Methods The gene expressions of 10 GDF in HCC and paratumors were compared by using the TCGA dataset and tissues from hospital. We enrolled 108 HCC patients who underwent liver transplantation to explore the prognostic role of GDF7 expression. Loss-of-function experiments in vitro and in vivo were executed to investigated the role of GDF7 in HCC cells. Results The mRNA and protein levels of GDF7 were significantly decreased in HCC tumors compared to paratumors (P < 0.001). The Kaplan-Meier analysis showed that decreased GDF7 expression in HCC indicated worse overall survival (OS, 5-year OS rate: 61.8% vs. 27.5%, P < 0.001) and increased recurrence risk (P < 0.001). Multivariate Cox regression analysis demonstrated that low GDF7 expression, presence of microvascular invasion, and elevated AFP level were independent risk factors for post-transplant tumor recurrence and poor survival. In vitro, GDF7 was downregulated by JUNB, and down-regulation of GDF7 increased the tumor proliferation, migration, invasion via the EMT pathway. Moreover, GDF7 knockdown could enhance the tumor growth in HCC xenograft model. Conclusion GDF7 could be a potential biomarker to predict superior outcomes of HCC patients. GDF7 amplification might be a potential cancer-directed therapeutic option.