SMAD4-Dependent Regulation of Hepatocellular Carcinoma Growth and Progression

Hernanda, Pratika Yuhyi (2014) SMAD4-Dependent Regulation of Hepatocellular Carcinoma Growth and Progression. Elsevier BV (Netherlands). (Unpublished)

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13. Smad4-dependent regulation of hepatocellular carcinoma growth and progression.pdf

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SMAD4 is recognized as a central mediator of Transforming Growth Factor Beta (TGF-b) and Bone Morphogenetic Protein (BMP) signaling pathways which are involved in regulating tumor progression. In general, SMAD4 is considered a tumor suppressor. Here we investigated the role of SMAD4 in hepatocellular carcinoma (HCC). We performed immunohistochemical stainings in paraffin embedded-tissue microarray patient HCC (n=42). Three HCC cell lines were used for functional assay in vitro and in immune-deficient mice. The results were SMAD4 protein level was significantly higher in human HCC tissue compared with adjacent liver tissue (n=42, P<0.05). High SMAD4 levels were significantly associated with higher recurrence rate (p=0.05), shorter time to recurrence (p<0.05) and more tumor lesion (p<0.01). Interestingly, high SMAD4 levels were associated with low p-SMAD 1/5/8 (a downstream target of BMP signaling) expression, both in patients and HCC cell lines. Knockdown of SMAD4 in HCC cell lines showed a significant decrease of migratory and colony formation capacity, whereas ectopic overexpression of SMAD4 resulted in increased migration activity demonstrated by the ring-barrier migration assay. However, knockdown of SMAD4 conferred resistance to the anti-growth effects of BMP4, TGF-b and Activin in HCC cell lines. Interim analysis (at day 12) of xenograft experiment showed that Smad4 knockdown appears to delay tumor initiation of HCC cells in nude mice. Conclusion: Basal SMAD4 expression is required for the anti-tumor function of BMP signaling in HCC. Elevated Smad4 expression correlates with poor outcome in HCC patients and more aggressive phenotype and function of HCC cells.

Item Type: Other
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine > Medicine Study Program
Depositing User: Sulimin BP3
Date Deposited: 25 Mar 2021 04:37
Last Modified: 25 Mar 2021 04:37

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