Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

Tümen, Deniz; Heumann, Philipp; Gülow, Karsten; Demirci, Cagla-Nur; Cosma, Lidia-Sabina; Müller, Martina; Kandulski, Arne

doi:10.3390/biomedicines10123202

Cited by 54 publications

(43 citation statements)

References 297 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of clinical relevance, hepatitis B virus (HBV) has additional properties to induce liver carcinogenesis, including the action of a viral oncoprotein and the integration of the virus in the human genome [43]. Mutations of p53 are observed in 20-50% of HCC [44,45]. Based on genomic, transcriptomic, and epigenetic data, a classification of HCC correlating with clinical characteristics, risk factors and histopathology was suggested [44].…”

Section: Discussionmentioning

confidence: 99%

The p53 Family of Transcription Factors Represses the Alpha- fetoprotein Gene Expression in Hepatocellular Carcinoma

Wölfel,

Ostheim,

Staub

et al. 2023

JGLD

View full text Add to dashboard Cite

Background: p53 deletion and mutation as well as upregulation of alpha-fetoprotein (AFP) are hallmarks of hepatocarcinogenesis. p63 and p73 belong to the family of p53-related transcription factors expressing a variety of isoforms. The expression of dominant negative (ΔN) p73 is related to the reduced survival of patients with hepatocellular carcinoma (HCC). In this study, we characterized the interaction between p53 family-dependent signaling pathways and the regulation of AFP at the gene and protein levels as essential determinants of therapeutic response and prognosis in HCC. Methods: Putative p53-, p63- and p73-binding sites within the AFP gene were identified in silico. Hep3B cells were transfected with plasmids encoding for p53, p63 and p73 to analyze the interplay of the p53 family with AFP. AFP transcription was determined by RT-qPCR. Protein levels of AFP, p53, p63 and p73 were analyzed by Western blot. Results: Underlining the importance of the crosstalk between the p53 family-dependent pathways and AFP regulation we identified eight novel putative binding sites for the members of the p53 family within the introns 1, 2, 3, 4, 7, 8, 11, and 12 of the AFP gene. Accordingly, full-length isoforms of p53, p63 and p73 efficiently downregulated AFP both on mRNA and protein level. Thus, the p53 family members were identified to be major regulators of AFP repression. Of note, p63 was characterized as a novel and p73 as the most efficient repressor of AFP. Conclusion: p53 mutation and upregulation of AFP are essential oncogenic events in the development of HCC. Here we show that AFP gene regulation occurs via a combined action of the p53 family members p53, p63 and p73. All three tumor suppressors reduce AFP gene and protein expression. Thus, our findings reveal a novel interaction of p53 family-dependent signaling pathways and AFP regulation at the gene and protein levels in HCC.

show abstract

Section: Discussionmentioning

confidence: 99%

The p53 Family of Transcription Factors Represses the Alpha- fetoprotein Gene Expression in Hepatocellular Carcinoma

Wölfel,

Ostheim,

Staub

et al. 2023

JGLD

View full text Add to dashboard Cite

show abstract

“…Detailed pathophysiological factors implicated in HCC pathogenesis, including gene mutation and epigenetic changes, have been recently reviewed [ 85 ].…”

Section: Pathogenesis Of Hccmentioning

confidence: 99%

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

2023

View full text Add to dashboard Cite

The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.

show abstract

“…Clinical staging systems currently provide a valuable and practical method for forecasting the prognosis of HCC patients and categorizing them according to observable physical signs and symptoms 13,14,15 .…”

Section: Introductionmentioning

confidence: 99%

HN1-mediated Activation of Lipogenesis Through AKT-SREBP Signaling Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis

Kim,

Jin,

Meng

et al. 2024

Preprint

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with more than 800,000 deaths each year, and its five-year survival rate is less than 12%. The role of the HN1 gene in HCC has remained elusive, despite its upregulation in various cancer types. In our investigation, we identified HN1’s heightened expression in HCC tissues, which, upon overexpression, fosters cell proliferation, migration, and invasion, unveiling its role as an oncogene in HCC. In addition, silencing HN1 diminished the viability and metastasis of HCC cells, whereas HN1 overexpression stimulated their growth and invasion. Gene expression profiling revealed HN1 silencing downregulated 379 genes and upregulated 130 genes, and suppressive proteins associated with the lipogenic signaling pathway networks. Notably, suppressing HN1 markedly decreased the expression levels of SREBP1 and SREBP2, whereas elevating HN1 had the converse effect. This dual modulation of HN1 affected lipid formation, hindering it upon HN1 silencing and promoting it upon HN1 overexpression. Moreover, HN1 triggers the Akt pathway, fostering tumorigenesis via SREBP1-mediated lipogenesis and silencing HN1 effectively curbed HCC tumor growth in mouse xenograft models by deactivating SREBP-1, emphasizing the potential of HN1 as a therapeutic target, impacting both external and internal factors, it holds promise as an effective therapeutic strategy for HCC.

show abstract

Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

Cited by 54 publications

References 297 publications

The p53 Family of Transcription Factors Represses the Alpha- fetoprotein Gene Expression in Hepatocellular Carcinoma

The p53 Family of Transcription Factors Represses the Alpha- fetoprotein Gene Expression in Hepatocellular Carcinoma

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

HN1-mediated Activation of Lipogenesis Through AKT-SREBP Signaling Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis

Contact Info

Product

Resources

About