Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma
Abstract
The programmed cell death 4 (PDCD4) gene was originally identified as a tumor-related gene in humans and acts as a tumor-suppressor in mouse epidermal carcinoma cells. However, its function and regulatory mechanisms of expression in human cancer remain to be elucidated. We therefore investigated the expression of PDCD4 in human hepatocellular carcinoma (HCC) and the role of PDCD4 in human HCC cells. Downregulation of PDCD4 protein was observed in all HCC tissues tested compared with corresponding noncancerous liver, as revealed by Western blotting or immunohistochemical staining. Human HCC cell line, Huh7, transfected with PDCD4 cDNA showed nuclear fragmentation and DNA laddering characteristic of apoptotic cells associated with mitochondrial changes and caspase activation. Transforming growth factor-beta1 (TGF-beta1) treatment of Huh7 cells resulted in increased PDCD4 expression and occurrence of apoptosis, also concomitant with mitochondrial events and caspase activation. Transfection of Smad7, a known antagonist to TGF-beta1 signaling, protected cells from TGF-beta1-mediated apoptosis and suppressed TGF-beta1-induced PDCD4 expression. Moreover, antisense PDCD4 transfectants were resistant to apoptosis induced by TGF-beta1. In conclusion, these data suggest that PDCD4 is a proapoptotic molecule involved in TGF-beta1-induced apoptosis in human HCC cells, and a possible tumor suppressor in hepatocarcinogenesis.
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PDCD4 protein expression is often down-regulated in tumors but is maintained at high levels in a large number of tumors.
“The expression of PDCD4-protein is often down-regulated in the tumors [17,18,19,20] but is maintained in high levels in a large number of tumors.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [18]
PDCD4 overexpression activates BAX followed by release of cytochrome C from mitochondria and activation of caspases 8, 9, and 3, resulting in induction of apoptosis in hepatoma cells.
“PDCD4 over expression activates the pro-apoptotic member of Bcl2 protein family BAX followed by the release of cytochrome C from mitochondria and activation of caspases 8, 9, and 3, resulting in the induction of apoptosis in hepatoma cells, although the mechanism of BAX activation has not been elucidated [18].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [18]
PDCD4 expression is upregulated and PDCD4 protein is accumulated in cell nuclei as cells undergo apoptosis.
“Regarding apoptosis induction, PDCD4 expression is upregulated and PDCD4-protein is accumulated in the cell nuclei as cells undergo apoptosis [18].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [18]
TGF-β1 treatment of Huh7 hepatoma cells increased PDCD4 expression by up-regulating PDCD4 mRNA through the TGF-β1-activated Smad signaling pathway and induced apoptosis.
“TGF-β1 treatment of Huh7 hepatoma cells increased PDCD4 expression up-regulating PDCD4 mRNA expression through the TGF-β1-activated Smad signaling pathway and induced apoptosis [18].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [18]
Expression of PDCD4 increases in cultured Huh7 hepatoma cells exposed to TGF-β1 and ectopic PDCD4 overexpression induces such cells to undergo apoptosis.
“It was demonstrated that the expression of PDCD4 increases in cultured Huh7 hepatoma cells exposed to TGF-β1 and that ectopic PDCD4 overexpression induces such cells to undergo apoptosis [18].”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [18]
TGF-β1 may induce apoptosis via PDCD4 overexpression in Huh7 hepatoma cells.
“The results indicate that TGF-β1 may induce apoptosis via PDCD4 overexpression in the Huh 7 hepatoma cells.”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [18]
PDCD4 loss is diagnostic for human cancer staging and prognostic for survival in colon, lung, liver, breast, glioma and esophageal cancers.
“its loss is diagnostic for human cancer staging and prognostic for survival in colon, lung, liver, breast, glioma and esophageal cancers (6–11).”
From Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65 (2014) · cites this paper as [11]
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References 41 · Cited by 247
- Authors
- Zhang, H., Ozaki, I., Mizuta, T., Hamajima, H., Yasutake, T., Eguchi, Y., Ideguchi, H., Yamamoto, K., & Matsuhashi, S.
- Affiliations
- Saga University (JP)
- Corresponding author
- Ozaki, I
- Venue
- Oncogene
- Published
- 2006-05-08
- Volume
- 25
- Issue
- 45
- Pages
- 6101-6112
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2067617459
- Cited by
- 247
- References
- 41
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 13 · 2019: 13 · 2018: 11 · 2017: 11 · 2016: 21 · 2015: 18 · 2014: 19 · 2013: 19 · 2012: 11
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ludwig Institute for Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- PDCD4, hepatocellular carcinoma, TGF-β1, apoptosis, tumor suppressor, Smad7, caspase activation, mitochondrial apoptosis, TGF-β1 signaling, antisense transfection, Huh7 cells
- MeSH terms
- Aged, Female, Carcinoma, Hepatocellular, Humans, Immunohistochemistry, Liver Neoplasms, Male, Middle Aged, Down-Regulation, Transforming Growth Factor beta, RNA-Binding Proteins, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Apoptosis Regulatory Proteins, Transforming Growth Factor beta1
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