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SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma

Oncogene volume 34, pages 5055–5068 (2015)Cite this article

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Abstract

Further understanding of the molecular biology and pathogenesis of hepatocellular carcinoma (HCC) is crucial for future therapeutic development. SMAD4, recognized as an important tumor suppressor, is a central mediator of transforming growth factor beta (TGFB) and bone morphogenetic protein (BMP) signaling. This study investigated the role of SMAD4 in HCC. Nuclear localization of SMAD4 was observed in a cohort of 140 HCC patients using tissue microarray. HCC cell lines were used for functional assay in vitro and in immune-deficient mice. Nuclear SMAD4 levels were significantly increased in patient HCC tumors as compared with adjacent tissues. Knockdown of SMAD4 significantly reduced the efficiency of colony formation and migratory capacity of HCC cells in vitro and was incompatible with HCC tumor initiation and growth in mice. Knockdown of SMAD4 partially conferred resistance to the anti-growth effects of BMP ligand in HCC cells. Importantly, simultaneous elevation of SMAD4 and phosphorylated SMAD2/3 is significantly associated with poor patient outcome after surgery. Although high levels of SMAD4 can also mediate an antitumor function by coupling with phosphorylated SMAD1/5/8, this signaling, however, is absent in majority of our HCC patients. In conclusion, this study revealed a highly non-canonical tumor-promoting function of SMAD4 in HCC. The drastic elevation of nuclear SMAD4 in sub-population of HCC tumors highlights its potential as an outcome predictor for patient stratification and a target for personalized therapeutic development.

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Acknowledgements

We thank the support from the Daniel den Hoed Foundation for a Centennial Award fellowship (to Q Pan), the Netherlands Organization for Scientific Research (NWO/ZonMw) for a VENI grant (no. 916-13-032) (to Q Pan), the Dutch Digestive Foundation (MLDS) for a career development grant (no. CDG 1304) (to Q Pan) and the European Association for the Study of the Liver (EASL) for a Sheila Sherlock Fellowship (to Q Pan). Support from the Science and Technology Department Commonwealth Technology Applied Research Project (no. 2012F82G2060018) of Zhejiang Province, China and the National Nature Science Foundation of China (No. 81272687) (to K Chen) is gratefully acknowledged. We thank Dr Ron Smits from Erasmus Medical Center Rotterdam for critical reading of the manuscript and thank Dr Jie Xu from the Animal Care at Hangzhou Normal University, Hangzhou, China for helping with the animal experiments.

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Author notes

  1. P Y Hernanda, K Chen, A M Das and K Sideras: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands

    P Y Hernanda, K Chen, K Sideras, W Wang, J Li, W Cao, S J A Bots, L L Kodach, R A de Man, H L A Janssen, D Sprengers, M J Bruno, H J Metselaar, J Kwekkeboom, M P Peppelenbosch & Q Pan

  2. Laboratory of Medical Genetics, Biomolecular Research Centre, Wijaya Kusuma University, Surabaya, Indonesia

    P Y Hernanda

  3. Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China

    K Chen

  4. Department of Surgery, Laboratory of Experimental Surgical Oncology Section Surgical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands

    A M Das & T L M ten Hagen

  5. Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands

    J N M Ijzermans

  6. Division of Gastroenterology, University Health Network, Toronto, Ontario, Canada,

    H L A Janssen

  7. Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands

    A P Stubbs

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  1. P Y Hernanda
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Correspondence to Q Pan.

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Hernanda, P., Chen, K., Das, A. et al. SMAD4 exerts a tumor-promoting role in hepatocellular carcinoma. Oncogene 34, 5055–5068 (2015). https://doi.org/10.1038/onc.2014.425

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