Strong Smad4 Expression Correlates with Poor Prognosis After Surgery in Patients with Hepatocellular Carcinoma

Hiwatashi, Kiyokazu; Ueno, S.; Shimada, Masahiko; Kubo, Fumitake; Tateno, Taro; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Ishigami, Sumiya; Shinchi, Hiroyuki

doi:10.1245/s10434-009-0614-2

Cited by 24 publications

(20 citation statements)

References 17 publications

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“…Strong expression of Smad4 in HCC patients has been correlated with poor prognosis after surgery (Hiwatashi et al, 2009). Together with our findings, Smad4 levels are affected by HCC, by infection with hepatitis virus, and by the presence of thrombosis.…”

Section: Discussionsupporting

confidence: 85%

“…In HCC, Smad4 mutations that alter the TGF-β pathway have been observed (Yakicier et al, 1999). The over-expressed Smad4 protein observed in HCC (Torbenson et al, 2002;Lu et al, 2008;Yamazaki et al, 2011) has been correlated with poor prognosis (Hiwatashi et al, 2009), and suggested to contribute to HBV-associated liver fibrosis through enhanced TGF-β signaling that pathologically accelerates collagen gene transcription (Inagaki et al, 2001;Lee et al, 2001;Yamazaki et al, 2011). Torbenson and colleagues (2002) found that Smad4 was over-expressed in 10 of 20 HCC patients, while Ji and colleagues found that the expression of Smad4 was lower in HCC tissue than in its adjacent tissue (Ji et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Smad4 Expression in Hepatocellular Carcinoma Differs by Hepatitis Status

Yao¹,

Li²,

Tang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Aims: Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viral infection. Smad4 is known to mediate the TGF-β pathway to suppress tumorigenesis. However, the function of Smad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or without hepatitis virus infection and adjacent normal-appearing liver. Methods: Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. Results: We found that tumor tissues expressed less Smad4 mRNA and protein than the adjacent tissues. Most HCC tumor tissues were negative for Smad4 in IHC staining, while the majority of adjacent tissues were positively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those without virus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to function as a tumor suppressor gene (TSG). Conclusion: Patients with hepatitis viral infection, at higher risk for HCC, exhibited increased Smad4 protein expression suggesting hepatitis virus may modulate Smad4 expression, which is functionally distinct from its putative role as a TSG. Smad4 expression may thus be an applicable marker for diagnosis and/or a target to develop therapeutic agents for HCC.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Smad4 Expression in Hepatocellular Carcinoma Differs by Hepatitis Status

Yao¹,

Li²,

Tang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Thus, it was questionable whether the role of Smad4 as only a tumour suppressor could explain the opposing results of previous studies, especially in breast cancer. A few studies have demonstrated that high Smad4 expression correlates to a high histological grade and advanced tumour stage in different types of cancer [41,42] . Which target molecule Smad4 is involved with can decide its function as an oncogenic or tumour suppressor.…”

Section: Discussionmentioning

confidence: 99%

Expression Pattern of Smad4/GATA3 as a Predictor of Survival in Invasive Ductal Carcinoma of the Breast

Min

Kim²,

Im³

et al. 2017

Pathobiology

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Background: Smad4 and GATA3 proteins are known prognostic markers in various cancers. Smad4 is a mediator linked to both tumour suppression and progression. GATA3 is a regulator of development and morphogenesis of the mammary gland. We assessed and compared the predictive performance of Smad4 and GATA3 for clinical outcomes in patients with breast cancer. Methods: The combined expression pattern based on Smad4+/- and GATA3+/- was evaluated by immunostaining using breast cancer tissue microarray, and the relationships between protein expression and clinicopathological variables were analysed. Results: Smad4 expression was only associated with an ill-defined tumour border, whereas GATA3 was associated with several good prognostic factors. On analysis of combined markers, there was a significant difference in the expression of fascin (an important factor for cancer invasiveness) between the Smad4+/GATA3- and Smad4-/GATA3+ groups. Smad4+/GATA3- was correlated with worse clinicopathological parameters, relapse-free survival (RFS), and overall survival (OS), compared to Smad4-/GATA3+. Conclusion: Combined markers of Smad4/GATA3 showed a superior performance compared to single markers for predicting RFS and OS in patients with breast cancer.

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“…Interestingly, increased expression of smad4 has been observed in hepatocellular carcinoma (HCC)37–39 and correlates with poor prognosis 40. Increased TGF-β receptor II and smad4 immunohistochemical labelling in surgically resected HCCs has been shown to be associated with a worse nuclear grade and increased mitotic activity 37…”

Section: Smad4/dpc4 In Disease and Cancermentioning

confidence: 99%

Smad4/DPC4

McCarthy¹,

Chetty²

2018

J Clin Pathol

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Smad4 or DPC4 belongs to a family of signal transduction proteins that are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor beta (TGF-β) signaling via several pathways. The gene acts as a tumour suppressor gene and inactivation of smad4/DPC4 is best recognised in pancreatic cancer. However, smad4/DPC4 is also mutated in other conditions and cancers such as juvenile polyposis syndrome with and without hereditary haemorrhagic telangiectasia, colorectal and prostate cancers.Immunohistochemistry for smad4/DPC4 protein is most useful in separating benign/reactive conditions from pancreatic cancer in needle/core biopsies. In normal and reactive states, the protein is localised to the cytoplasm and nucleus, while the protein is lost in high-grade pancreatic intraepithelial neoplasia/carcinoma in situ and pancreatic cancer.

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Strong Smad4 Expression Correlates with Poor Prognosis After Surgery in Patients with Hepatocellular Carcinoma

Cited by 24 publications

References 17 publications

Smad4 Expression in Hepatocellular Carcinoma Differs by Hepatitis Status

Smad4 Expression in Hepatocellular Carcinoma Differs by Hepatitis Status

Expression Pattern of Smad4/GATA3 as a Predictor of Survival in Invasive Ductal Carcinoma of the Breast

Smad4/DPC4

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