HAMP Downregulation Contributes to Aggressive Hepatocellular Carcinoma via Mechanism Mediated by Cyclin4-Dependent Kinase-1/STAT3 Pathway

Shen, Ying; Li, Xin; Su, Yongfu; Badshah, Shaikh Atik; Zhang, Bin; Xue, Yanru; Shang, Peng

doi:10.3390/diagnostics9020048

Cited by 26 publications

(20 citation statements)

References 38 publications

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“…Their results suggested that by lowering liver HAMP levels, HCC cells could secure abundant iron from sources such as enterocytes and macrophages. Shen et al [ 12 ] reported that low HAMP expression is linked with higher rates of metastasis and poor disease-free status in HCC, and that the role of HAMP in cellular proliferation and metastasis is related to cell cycle checkpoints. The group proposed that HAMP serves as a tumor suppressor gene.…”

Section: Introductionmentioning

confidence: 99%

In silico analysis suggests disruption of interactions between HAMP from hepatocytes and SLC40A1 from macrophages in hepatocellular carcinoma

2021

BMC Med Genomics

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Background Identification of factors associated with proliferation in the hepatocellular carcinoma (HCC) microenvironment aids in understanding the mechanisms of disease progression and provides druggable targets. Gene expression profiles of individual cells in HCC and para-carcinoma tissues can be effectively obtained using the single-cell RNA sequencing (scRNA-Seq) technique. Here, we aimed to identify proliferative hepatocytes from HCC and para-carcinoma tissues, detect differentially expressed genes between the two types of proliferative hepatocytes, and investigate their potential roles in aberrant proliferation. Results Two respective gene signatures for proliferative cells and hepatocytes were established and used to identify proliferative hepatocytes from HCC and para-carcinoma tissues based on scRNA-Seq data. Gene expression profiles between the two types of proliferative hepatocytes were compared. Overall, 40 genes were upregulated in proliferative hepatocytes from para-carcinoma tissue, whereas no upregulated genes were detected in those from HCC tissue. Twelve of the genes, including HAMP, were specifically expressed in the liver tissue. Based on previous reports, we found that HAMP modulates cell proliferation through interaction with its receptor SLC40A1. Comprehensive analysis of cells in HCC and para-carcinoma tissues revealed that: (1) HAMP is specifically expressed in hepatocytes and significantly downregulated in malignant hepatocytes; (2) a subset of macrophages expressing SLC40A1 and genes reacting to various infections is present in para-carcinoma but not in HCC tissue. We independently validated the findings with scRNA-Seq and large-scale tissue bulk RNA-Seq/microarray analyses. Conclusion HAMP was significantly downregulated in malignant hepatocytes. In addition, a subset of macrophages expressing SLC40A1 and genes reacting to various infections was absent in HCC tissue. These findings support the involvement of HAMP-SLC40A1 signaling in aberrant hepatocyte proliferation in the HCC microenvironment. The collective data from our in silico analysis provide novel insights into the mechanisms underlying HCC progression and require further validation with wet laboratory experiments.

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Section: Introductionmentioning

confidence: 99%

In silico analysis suggests disruption of interactions between HAMP from hepatocytes and SLC40A1 from macrophages in hepatocellular carcinoma

2021

BMC Med Genomics

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“…However, we did not measure it on this occasion because hepcidin expression as a standalone or the effect of iron on hepcidin in HepG2 cells has been previously examined by various groups 20 , 21 , 43 – 51 . In addition, we already know that hepcidin expression is diminished in hepatocellular carcinoma, unlike other cancers, and its reduction contributes to the aggressiveness of the disease 52 , 53 . We also know the significance of hepcidin-ferroportin axis in metastasis where hepcidin is thought to play a contributory role in promoting cancer cell homing and fostering metastasis 54 .…”

Section: Discussionmentioning

confidence: 99%

Iron elevates mesenchymal and metastatic biomarkers in HepG2 cells

Mehta

Sharp

2020

Sci Rep

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Liver iron excess is observed in several chronic liver diseases and is associated with the development of hepatocellular carcinoma (HCC). However, apart from oxidative stress, other cellular mechanisms by which excess iron may mediate/increase HCC predisposition/progression are not known. HCC pathology involves epithelial to mesenchymal transition (EMT), the basis of cancer phenotype acquisition. Here, the effect of excess iron (holo-transferrin 0–2 g/L for 24 and 48 h) on EMT biomarkers in the liver-derived HepG2 cells was investigated. Holo-transferrin substantially increased intracellular iron. Unexpectedly, mRNA and protein expression of the epithelial marker E-cadherin either remained unaltered or increased. The mRNA and protein levels of metastasis marker N-cadherin and mesenchymal marker vimentin increased significantly. While the mRNA expression of EMT transcription factors SNAI1 and SNAI2 increased and decreased, respectively after 24 h, both factors increased after 48 h. The mRNA expression of TGF-β (EMT-inducer) showed no significant alterations. In conclusion, data showed direct link between iron and EMT. Iron elevated mesenchymal and metastatic biomarkers in HepG2 cells without concomitant decrement in the epithelial marker E-cadherin and altered the expression of the key EMT-mediating transcription factors. Such studies can help identify molecular targets to devise iron-related adjunctive therapies to ameliorate HCC pathophysiology.

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“…In human HCC cell lines, iron enhances proliferation and iron deprivation leads to cell cycle arrest and increased apoptosis [110] . It has been reported that increased iron concentration in HCC cells was associated with enhanced migration, invasion, high metastasis rate and recurrence [111] .…”

Section: Mechanisms Of Iron Toxicity In Hh Leading To Hccmentioning

confidence: 99%

Association between hereditary hemochromatosis and hepatocellular carcinoma: a comprehensive review

Jayachandran¹,

Shrestha²,

Bridle³

et al. 2020

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Hepatocellular carcinoma (HCC) is a significant global health problem with high morbidity and mortality. Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates. Even though significant advances have been made in HCC treatment, fewer than 20% of patients with HCC are suitable for potentially curative treatment. Hereditary hemochromatosis (HH) is an important genetic risk factor for HCC. HH is an autosomal recessive disorder of iron metabolism, characterised by elevated iron deposition in most organs including the liver, leading to progressive organ dysfunction. HCC is a complication of HH, nearly always occurring in patients with cirrhosis and contributes to increased mortality rates. Identifying the susceptibility of development of HCC in HH patients has gained much traction. This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research. In this review, we focus particularly on HFE gene-related HH. Herein, we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development. We also focus on the therapeutic tools in the management of HCC associated with HH.

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HAMP Downregulation Contributes to Aggressive Hepatocellular Carcinoma via Mechanism Mediated by Cyclin4-Dependent Kinase-1/STAT3 Pathway

Cited by 26 publications

References 38 publications

In silico analysis suggests disruption of interactions between HAMP from hepatocytes and SLC40A1 from macrophages in hepatocellular carcinoma

In silico analysis suggests disruption of interactions between HAMP from hepatocytes and SLC40A1 from macrophages in hepatocellular carcinoma

Iron elevates mesenchymal and metastatic biomarkers in HepG2 cells

Association between hereditary hemochromatosis and hepatocellular carcinoma: a comprehensive review

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