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Novel tumor suppressor SPRYD4 inhibits tumor progression in hepatocellular carcinoma by inducing apoptotic cell death

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Abstract

Background

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated deaths worldwide. Although recent studies have proposed different biomarkers for HCC progression and therapy resistance, a better understanding of the molecular mechanisms underlying HCC progression and recurrence, as well as the identification of molecular markers with a higher diagnostic accuracy, are necessary for the development of more effective clinical management strategies. Here, we aimed to identify novel players in HCC progression.

Methods

SPRYD4 mRNA and protein expression analyses were carried out on a normal liver-derived cell line (HL-7702) and four HCC-derived cell lines (HepG2, SMMC7721, Huh-7, BEL-7402) using qRT-PCR and Western blotting, respectively. Cell proliferation Cell Counting Kit-8 (CCK-8) assays, protein expression analyses for apoptosis markers using Western blotting, and Caspase-Glo 3/7 apoptosis assays were carried out on the four HCC-derived cell lines. Expression comparison, functional annotation, gene set enrichment, correlation and survival analyses were carried out on patient data retrieved from the NCBI Gene module, the NCBI GEO database and the TCGA database.

Results

Through a meta-analysis we found that the expression of SPRYD4 was downregulated in primary HCC tissues compared to non-tumor tissues. We also found that the expression of SPRYD4 was downregulated in HCC-derived cells compared to normal liver-derived cells. Subsequently, we found that the expression of SPRYD4 was inversely correlated with a gene signature associated with HCC cell proliferation. Exogenous SPRYD4 expression was found to inhibit HCC cell proliferation by inducing apoptotic cell death. We also found that SPRYD4 expression was associated with a good prognosis and that its expression became downregulated when HCCs progressed towards more aggressive stages and higher grades. Finally, we found that SPRYD4 expression may serve as a biomarker for a good overall and relapse-free survival in HCC patients.

Conclusions

Our data indicate that a decreased SPRYD4 expression may serve as an independent predictor for a poor prognosis in patients with HCC and that increased SPRYD4 expression may reduce HCC growth and progression through the induction of apoptotic cell death, thereby providing a potential therapeutic target.

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Acknowledgements

This work was supported in part by the Science and Technology Innovation Team Project of Liupanshui Normal University (Grant # LPSSYKJTD201602), the key disciplines of Guizhou province of China (Grant # Qian Xuewei He word ZDXK (2014)24), the Liupanshui Key Laboratory for Research and Utilization of Characteristic Fruit Tree Resources (Grant # 52020-2017-02-03) and the Research Foundation for Advanced Talents of Liupanshui Normal University (Grant # LPSSYKYJJ201601).

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Authors and Affiliations

  1. School of Biological Sciences and Technology, Liupanshui Normal University, Liupanshui, 553004, China

    Kashif Rafiq Zahid & Shiming Han

  2. Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China

    Kashif Rafiq Zahid & Fuling Zhou

  3. Department of Multidisciplinary Studies, National University of Medical Sciences (NUMS), Abid Majeed Road, Rawalpindi, Pakistan

    Umar Raza

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Zahid, K.R., Han, S., Zhou, F. et al. Novel tumor suppressor SPRYD4 inhibits tumor progression in hepatocellular carcinoma by inducing apoptotic cell death. Cell Oncol. 42, 55–66 (2019). https://doi.org/10.1007/s13402-018-0407-3

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