Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation

Shih Ming Yang; Tsung Hui Hu; Jian Ching Wu; Li Na Yi; Hsiao Mei Kuo; Mei Lang Kung; Tian Huei Chu; Shih Tsung Huang; Chao Cheng Huang; Ying Hsien Kao; Yu Wei Lin; Ming Hong Tai

doi:10.1016/j.labinv.2025.104127

Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation

Shih Ming Yang, Tsung Hui Hu, Jian Ching Wu, Li Na Yi, Hsiao Mei Kuo, Mei Lang Kung, Tian Huei Chu, Shih Tsung Huang, Chao Cheng Huang, Ying Hsien Kao, Yu Wei Lin^*, Ming Hong Tai

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Journal Article › peer-review

Abstract

Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. In this study, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent nontumor tissue, were analyzed for expression of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The Cancer Genome Atlas cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in patients with HCC. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated alpha-fetoprotein, and poor survival and recurrent outcomes in the liver cancer cohort. HDGF knockout mice exhibited decreased liver C-tail--phosphorylated PTEN (p-PTEN) levels and increased PTEN expression. Furthermore, an in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, whereas knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of phosphatidylinositol 3,4,5-trisphosphate. Blockade of HDGF and casein kinase 2 signaling using anti-HDGF and a casein kinase 2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for patients with HCC.

Original language	English
Article number	104127
Pages (from-to)	104127
Journal	Laboratory Investigation
Volume	105
Issue number	6
Early online date	11 03 2025
DOIs	https://doi.org/10.1016/j.labinv.2025.104127
State	Published - 06 2025

Bibliographical note

Keywords

casein kinase II
hepatoma-derived growth factor
liver cancer
phosphatase and tensin homolog
posttranslational modification

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.labinv.2025.104127

Cite this

Yang, S. M., Hu, T. H., Wu, J. C., Yi, L. N., Kuo, H. M., Kung, M. L., Chu, T. H., Huang, S. T., Huang, C. C., Kao, Y. H., Lin, Y. W., & Tai, M. H. (2025). Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation. Laboratory Investigation, 105(6), 104127. Article 104127. https://doi.org/10.1016/j.labinv.2025.104127

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title = "Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation",

abstract = "Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. In this study, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent nontumor tissue, were analyzed for expression of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The Cancer Genome Atlas cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in patients with HCC. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated alpha-fetoprotein, and poor survival and recurrent outcomes in the liver cancer cohort. HDGF knockout mice exhibited decreased liver C-tail--phosphorylated PTEN (p-PTEN) levels and increased PTEN expression. Furthermore, an in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, whereas knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of phosphatidylinositol 3,4,5-trisphosphate. Blockade of HDGF and casein kinase 2 signaling using anti-HDGF and a casein kinase 2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for patients with HCC.",

keywords = "casein kinase II, hepatoma-derived growth factor, liver cancer, phosphatase and tensin homolog, posttranslational modification",

author = "Yang, \{Shih Ming\} and Hu, \{Tsung Hui\} and Wu, \{Jian Ching\} and Yi, \{Li Na\} and Kuo, \{Hsiao Mei\} and Kung, \{Mei Lang\} and Chu, \{Tian Huei\} and Huang, \{Shih Tsung\} and Huang, \{Chao Cheng\} and Kao, \{Ying Hsien\} and Lin, \{Yu Wei\} and Tai, \{Ming Hong\}",

note = "Copyright {\textcopyright} 2025. Published by Elsevier Inc.",

year = "2025",

month = jun,

doi = "10.1016/j.labinv.2025.104127",

language = "英语",

volume = "105",

pages = "104127",

journal = "Laboratory Investigation",

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TY - JOUR

T1 - Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation

AU - Yang, Shih Ming

AU - Hu, Tsung Hui

AU - Wu, Jian Ching

AU - Yi, Li Na

AU - Kuo, Hsiao Mei

AU - Kung, Mei Lang

AU - Chu, Tian Huei

AU - Huang, Shih Tsung

AU - Huang, Chao Cheng

AU - Kao, Ying Hsien

AU - Lin, Yu Wei

AU - Tai, Ming Hong

PY - 2025/6

Y1 - 2025/6

N2 - Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. In this study, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent nontumor tissue, were analyzed for expression of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The Cancer Genome Atlas cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in patients with HCC. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated alpha-fetoprotein, and poor survival and recurrent outcomes in the liver cancer cohort. HDGF knockout mice exhibited decreased liver C-tail--phosphorylated PTEN (p-PTEN) levels and increased PTEN expression. Furthermore, an in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, whereas knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of phosphatidylinositol 3,4,5-trisphosphate. Blockade of HDGF and casein kinase 2 signaling using anti-HDGF and a casein kinase 2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for patients with HCC.

AB - Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. In this study, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent nontumor tissue, were analyzed for expression of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The Cancer Genome Atlas cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in patients with HCC. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated alpha-fetoprotein, and poor survival and recurrent outcomes in the liver cancer cohort. HDGF knockout mice exhibited decreased liver C-tail--phosphorylated PTEN (p-PTEN) levels and increased PTEN expression. Furthermore, an in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, whereas knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of phosphatidylinositol 3,4,5-trisphosphate. Blockade of HDGF and casein kinase 2 signaling using anti-HDGF and a casein kinase 2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for patients with HCC.

KW - casein kinase II

KW - hepatoma-derived growth factor

KW - liver cancer

KW - phosphatase and tensin homolog

KW - posttranslational modification

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U2 - 10.1016/j.labinv.2025.104127

DO - 10.1016/j.labinv.2025.104127

M3 - 文章

C2 - 40081662

AN - SCOPUS:105002872416

SN - 0023-6837

VL - 105

SP - 104127

JO - Laboratory Investigation

JF - Laboratory Investigation

IS - 6

M1 - 104127

ER -

Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation

Abstract

Bibliographical note

Keywords

UN SDGs

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