Experimental drug treatments for hepatocellular carcinoma: clinical trial failures 2015 to 2021

Brown, Zachary J.; Hewitt, D. Brock; Pawlik, Timothy M.

doi:10.1080/13543784.2022.2079491

Cited by 3 publications

(1 citation statement)

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“…Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and ranks as the sixth most common malignancy in the world ( 1 ). Early stages of HCC lack noticeable symptoms, resulting in ~80% of diagnoses occurring at an advanced stage when curative liver resection is not feasible ( 2 ). Consequently, there is an urgent need to develop novel and effective therapeutic targets for the prevention and treatment of HCC.…”

Section: Introductionmentioning

confidence: 99%

HIF‑1α and RACGAP1 promote the progression of hepatocellular carcinoma in a mutually regulatory way

Wu,

Xu,

et al. 2023

Mol Med Rep

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Hypoxia, a condition characterized by low oxygen levels, serves an important role in the progression of hepatocellular carcinoma (HCC). However, the precise molecular mechanisms underlying hypoxia-induced HCC progression are yet to be fully elucidated. The present study assessed the involvement of two key factors, hypoxia-inducible factor-1α (HIF-1α) and Rac GTPase activating protein 1 (RACGAP1), in HCC development under hypoxic conditions. HIF-1α and RACGAP1 genes were overexpressed and knocked down in Hep3B and Huh7 cells using lentiviral transduction and the levels of HIF-1α and RACGAP1 in the cells were assessed using quantitative PCR, western blotting and immunofluorescence. Co-immunoprecipitation experiments were performed to evaluate the interaction between HIF-1α and RACGAP1. Subsequently, the proliferation, apoptosis, migration and invasion of Hep3B and Huh7 cells were assessed using the Cell Counting Kit-8 assay, flow cytometry, Transwell assay and migration experiments. The expression levels of HIF-1α and RACGAP1 in normal and HCC tumor samples were analyzed utilizing the Gene Expression Profiling Interactive Analysis database. Furthermore, correlations between HIF-1α/RACGAP1 gene expression levels and patient survival outcomes were evaluated using the Kaplan-Meier plotter. Knockdown of HIF-1α resulted in a significant decrease in RACGAP1 expression, whilst overexpression of HIF-1α resulted in a significant increase in RACGAP1 expression. Moreover, overexpression and knockdown of RACGAP1 had the same effect on HIF-1α expression. Additionally, it was demonstrated that HIF-1α and RACGAP1 interacted directly within a complex. Overexpression of HIF-1α or RACGAP1 significantly increased proliferation, invasion and migration, and significantly decreased the proportion of apoptotic Hep3B and Huh7 cells. Conversely, knockdown of HIF-1α or RACGAP1 significantly decreased proliferation, invasion and migration, and significantly increased the proportion of apoptotic Hep3B and Huh7 cells. In addition, the combined knockdown or overexpression of HIF-1α and RACGAP1 had a more pronounced effect on HCC cell migration compared with knockdown of HIF-1α alone. Furthermore, there was a significant positive correlation between the expression levels of HIF-1α and RACGAP1 in HCC tissues and patients with HCC and upregulation of both HIF-1α and RACGAP1 demonstrated a lower overall survival probability. In conclusion, HIF-1α and RACGAP1 may synergistically contribute to the development of HCC, highlighting their potential as valuable targets for HCC therapy.

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Section: Introductionmentioning

confidence: 99%