Growth differentiation factor 7 alleviates the proliferation and metastasis of hepatocellular carcinoma

Abstract

Background and aims: Inflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma (HCC). However, the tumor-protective functions of growth differentiation factors (GDFs) in HCC are yet to be clarified. In this study, we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo experiments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC.

Methods: The gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues. A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression. Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC.

Results: The mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in paratumors (P < 0.001). Kaplan-Meier analysis showed that decreased GDF7 expression in HCC was associated with worse overall survival (5-year 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, the presence of microvascular invasion, and elevated alpha-fetoprotein (AFP) levels were independent risk factors for tumor recurrence and poor survival. Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model. GDF7 knockdown promoted migration and invasion via epithelial-mesenchymal transition. Meanwhile, a negative correlation between JunB proto-oncogene (JUNB) and GDF7 was observed in HCC tissues. Modulating JUNB levels altered GDF7 protein expression.

Conclusions: GDF7 is a potential biomarker for predicting superior outcomes in patients with HCC. GDF7 amplification is a potential therapeutic option for HCC.

Keywords

Hepatocellular carcinoma (HCC) / Growth differentiation factor 7 (GDF7) / JunB proto-oncogene (JUNB) / Epithelial-mesenchymal transition (EMT) / Proliferation / Metastasis

Authors’ contributions

Jianyong Zhuo, Huigang Li, and Peiru Zhang contributed equally to this work. Jianyong Zhuo: Writing e original draft, Methodol-ogy, Conceptualization. Huigang Li: Visualization, Validation, Software, Methodology. Peiru Zhang: Software, Methodology. Chiyu He: Visualization, Methodology. Wei Shen: Visualization, Software. Xinyu Yang: Software, Formal analysis. Zuyuan Lin: Visualization, Methodology. Runzhou Zhuang: Resources. Xuyong Wei: Formal analysis, Data curation. Shusen Zheng: Resources, Data curation. Xiao Xu: Writing e review & editing, Supervision, Funding acquisition. Di Lu: Writing e review & editing, Project administration, Conceptualization.

Data availability statement

All the datasets are available from the corresponding authors on reasonable request.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgements

This work was granted by the National Key Research and Devel-opment Program of China (No. 2021YFA1100500), the Major Research Plan of the National Natural Science Foundation of China (No. 92159202), the Key Research & Development Plan of Zhejiang Prov-ince (No. 2021C03118), the National Natural Science Foundation of China (No. 82303387 and No. 82300742), the Natural Science Foun-dation of Zhejiang Province (No. LQ23H160048 and No. LQ22H160052), and the Health Science & Technology Plan of Zhejiang Province (No. 2022RC060). It was also supported by the Construction Fund of Medical Key Disciplines of Hangzhou (No. OO20200093).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2024.09.006.

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