RAF‐targeted therapy for hepatocellular carcinoma in the regenerating liver

Shi, Jihua; Liu, Shuzheng; Wierød, Lene; Scholz, Hanne; Anmarkrud, Jarl Andreas; Huitfeldt, Henrik S.; Zhang, Shuijun; Line, Pål–Dag

doi:10.1002/jso.23224

Cited by 13 publications

(6 citation statements)

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“…Hepatoma cells (4 10 5 cells per well) were grown in 6‐well plates overnight and then treated with various concentrations of Trastuzumab (low concentrations of 0 and 10 g/mL, and high concentrations of 30 and 100 g/mL) for 48 hours. Trypan blue staining confirmed >90% cell viability, and cell numbers were determined by MTT …”

Section: Methodsmentioning

confidence: 99%

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

et al. 2019

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Background The ERBB2 oncogene hypothesis is challenged in hepatocellular carcinoma (HCC) with the conflicting evidences of human epidermal growth factor receptor 2 (HER2) overexpression. HER2 could be a new target as a treatment option for HCC as well as tumor recurrence after surgery. HER2 in HCC biology needs further explorations. Methods Clinical and mRNA data of HCC patients were obtained from TCGA HCC cohort, GSE89377 and GSE115018. Western Blotting and immunohistochemistry were employed to test expression of HER2, E‐cadherin, and Vimentin. In HepG2, JM1, HER2‐transfected McA cells, and TGF‐β cocultured JM1 cells, HCC biology, including cell survival, proliferation, and epithelial‐to‐mesenchymal transition (EMT) phenotypes were evaluated. Results ERBB2 mRNA amplification was found in HCC datasets, and its expression was downregulated in high grade HCC with a worse overall survival. HER2 overexpression was identified in H4IIE, HepG2, JM1 cells, and 82% (14/17) HCC samples, and tumor stage was correlated with expression of HER2, E‐cadherin, and Vimentin (P < 0.05). Trastuzumab with the high concentrations suppressed proliferation of HER2‐positive hepatoma cells (P < 0.05); in the coculture model to induce EMT of JM1 cells, HER2 expression increased with downregulated E‐cadherin and upregulated Vimentin. Trastuzumab intravenous injection inhibited in vivo tumor size and metastases (P < 0.05). Signal analysis revealed that HER2 functioned through upregulation of β‐catenin and inhibition of SMAD3. Conclusion HER2 expression pattern is linked with tumor stage and overall survival; the transforming function of HER2 is found more relevant through β‐catenin and SMAD3. HER2‐targeted treatment is recommended to suppress the HER2‐mediated tumor growth during postoperative liver regeneration.

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Section: Methodsmentioning

confidence: 99%

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

et al. 2019

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“…The viability of co‐cultured BRL cells was determined using 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) at 24 and 48 h after stimulation with 10 nmol/l epidermal growth factor (EGF; E‐1257; Sigma‐Aldrich) 25 .…”

Section: Methodsmentioning

confidence: 99%

Simulated model of RAPID concept: highlighting innate inflammation and liver regeneration

et al. 2020

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Background: The resection and partial liver segment II/III transplantation with delayed total hepatectomy (RAPID) concept is a novel transplantation technique for removal of non-resectable liver tumours. The aim of this study was to establish a simulated RAPID model to explore the mechanism involved in the liver regeneration. Methods: A RAPID model was created in rats involving cold ischaemia and reperfusion of the selected future liver remnant (FLR), portal vein ligation, followed by resection of the deportalized lobes in a second step. Histology, liver regeneration and inflammatory markers in RAPID-treated rats were compared with those in controls that underwent 70 per cent hepatectomy with the same FLR size. The effects of interleukin (IL) 6 and macrophage polarization on hepatocyte viability were evaluated in an in vitro co-culture system of macrophages and BRL hepatocytes. Results: The survival rate in RAPID and control hepatectomy groups was 100 per cent. The regeneration rate was higher in the RAPID-treated rats, with higher levels of IL-6 and M1 macrophage polarization (P < 0⋅050). BRL hepatocytes co-cultured with M1 macrophages showed a higher proliferation rate through activation of the IL-6/signal transducer and activator of transcription 3/extracellular signal-regulated kinase pathway. This enhancement of proliferation was inhibited by tocilizumab or gadolinium trichloride (P < 0⋅050). Conclusion: The surgical model provides a simulation of RAPID that can be used to study the liver regeneration profile.

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“…Moreover, after TACE treatment, overexpression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) may lead to high recurrence of HCC (11). As a multi-kinase inhibitor, sorafenib targets and inhibits multiple the signal transduction pathways of HCC development and restrains tumor cell proliferation and angiogenesis (12). In addition, it works to inhibit VEGF and PDGF receptors (13).…”

Section: Introductionmentioning

confidence: 99%

Efficacy evaluation of the combination therapy of sorafenib and transarterial chemoembolization for unresectable HCC: a systematic review and meta-analysis of comparative studies

Li¹,

Li²,

Geng³

et al. 2020

Ann Transl Med

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Background: Sorafenib and transarterial chemoembolization (TACE) are the standard treatments recommended by guidelines for unresectable hepatocellular carcinoma (HCC). Although previous studies have shown the combination therapy of sorafenib and TACE to be safe, there is no consensus regarding its efficacy. This systematic review and meta-analysis, which was based on the findings of comparative clinical trials, was conducted to provide up-to-date and comprehensive information about the efficacy of combination therapy versus TACE monotherapy in unresectable HCC.Methods: Multiple databases were systematically reviewed to screen studies through particular inclusion criteria. Hazard ratio (HR) with 95% confidence intervals (95% CIs) was collected and analyzed by Revman 5.3 in a fixed or random effects meta-analysis model. Adverse events (AEs) were also evaluated.Results: This review ultimately included 14 comparative studies focused on combination therapy versus TACE monotherapy. Of these: 5 studies conducted TACE plus sorafenib versus TACE with placebo; 9 studies provided overall survival (OS) in combination groups which ranged from 10.3 to 29.7 months; and 10 studies provided time to progression (TTP) in combination groups which ranged from 2.6 to 10.8 months.The disease control rate (DCR) in combination groups ranged from 9.7% to 89.2% in 7 of the studies. After performing a random effects meta-analysis model, our study showed that OS (HR =0.65, 95% CI: 0.54-0.79, P<0.0001) and TTP (HR =0.72, 95% CI: 0.59-0.88, P=0.001) have been significantly improved in the combination therapy group when compared with the TACE monotherapy group. AEs mainly included handfoot skin reaction (HFSR), fatigue and diarrhea and the majority of these were in grade 1 or grade 2.Conclusions: Combination therapy has significant advantages over TACE monotherapy in terms of improving TTP and OS.

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RAF‐targeted therapy for hepatocellular carcinoma in the regenerating liver

Abstract: The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment.

Cited by 13 publications

References 46 publications

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence

Simulated model of RAPID concept: highlighting innate inflammation and liver regeneration

Efficacy evaluation of the combination therapy of sorafenib and transarterial chemoembolization for unresectable HCC: a systematic review and meta-analysis of comparative studies

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