Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors, alone or in combination with SOR, using in vitro and in vivo models of HCC. Methods The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was then tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. Results TAE226 emerged as the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of the nuclear interactome of FAK. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation causing an increase of histone H3 lysine 27 acetylation, counteracting its trimethylation by decreasing the nuclear amount of HDAC1/2. Conclusions Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduce HCC growth in vitro and in vivo. Our data also highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising therapeutic approaches for HCC.

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Overexpressed focal adhesion kinase predicts a higher incidence of extrahepatic metastasis and worse survival in hepatocellular carcinoma

Human Pathology ◽

10.1016/j.humpath.2009.03.006 ◽

2009 ◽

Vol 40 (10) ◽

pp. 1384-1390 ◽

Cited By ~ 21

Author(s):

Yee-Jee Jan ◽

Bor-Sheng Ko ◽

Chiun Hsu ◽

Tzu-Ching Chang ◽

Shyh-Chang Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Extrahepatic Metastasis

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Onodera’s prognostic nutritional index is a strong prognostic indicator for patients with hepatocellular carcinoma after initial hepatectomy, especially patients with preserved liver function

BMC Surgery ◽

10.1186/s12893-020-00917-2 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Akihiro Tanemura ◽

Shugo Mizuno ◽

Aoi Hayasaki ◽

Kazuyuki Gyoten ◽

Takehiro Fujii ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factors ◽

Prognostic Factor ◽

Liver Function ◽

Prognostic Nutritional Index ◽

Independent Prognostic Factor ◽

Related Factors ◽

Impaired Liver Function ◽

Nutritional Index ◽

Initial Hepatectomy

Abstract Background Several inflammation-based scores are used to assess the surgical outcomes of hepatocellular carcinoma (HCC). The aim of the present study was to elucidate the prognostic value of the prognostic nutritional index (PNI) in HCC patients who underwent hepatectomy with special attention to preoperative liver functional reserve. Methods Preoperative demographic and tumor-related factors were analyzed in 189 patients with HCC undergoing initial hepatectomy from August 2005 to May 2016 to identify significant prognostic factors. Results Multivariate analysis for overall survival (OS) revealed that female sex (p = 0.005), tumor size (p < 0.001) and PNI (p = 0.001) were independent prognostic factors. Compared to the High PNI group (PNI ≥ 37, n = 172), the Low PNI group (PNI < 37, n = 17) had impaired liver function and significantly poorer OS (13% vs. 67% in 5-year OS, p = 0.001) and recurrence-free survival (RFS) (8 vs. 25 months in median PFS time, p = 0.002). In the subgroup of patients with a preserved liver function of LHL15 ≥ 0.9, PNI was also independent prognostic factor, and OS (21% vs. 70% in 5-year OS, p = 0.008) and RFS (8 vs. 28 months in median PFS time, p = 0.018) were significantly poorer in the Low PNI group than the High PNI group. Conclusions PNI was an independent prognostic factor for HCC patients who underwent hepatectomy. Patients with PNI lower than 37 were at high risk for early recurrence and poor patient survival, especially in the patients with preserved liver function of LHL ≥ 0.9.

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The preoperative alkaline phosphatase-to-platelet ratio index is an independent prognostic factor for hepatocellular carcinoma after hepatic resection

Medicine ◽

10.1097/md.0000000000005734 ◽

2016 ◽

Vol 95 (51) ◽

pp. e5734 ◽

Cited By ~ 4

Author(s):

Ya-Qun Yu ◽

Jun Li ◽

Yan Liao ◽

Qian Chen ◽

Wei-Jia Liao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Alkaline Phosphatase ◽

Prognostic Factor ◽

Hepatic Resection ◽

Independent Prognostic Factor

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Bile duct invasion can be an independent prognostic factor in early stage hepatocellular carcinoma

Korean Journal of Hepato-Biliary-Pancreatic Surgery ◽

10.14701/kjhbps.2015.19.4.167 ◽

2015 ◽

Vol 19 (4) ◽

pp. 167 ◽

Cited By ~ 4

Author(s):

Ye-Rang Jang ◽

Kwang-Woong Lee ◽

Hyeyoung Kim ◽

Jeong-Moo Lee ◽

Nam-Joon Yi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Bile Duct ◽

Prognostic Factor ◽

Early Stage ◽

Independent Prognostic Factor ◽

Bile Duct Invasion

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TXNRD1 Is an Unfavorable Prognostic Factor for Patients with Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2017/4698167 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Binsheng Fu ◽

Wei Meng ◽

Xiancheng Zeng ◽

Hui Zhao ◽

Wei Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factor ◽

Clinical Stage ◽

Thioredoxin Reductase ◽

Immunohistochemical Analysis ◽

Independent Prognostic Factor ◽

Clinical Samples ◽

Kaplan Meier ◽

Thioredoxin Reductase 1 ◽

N Classification

Thioredoxin reductase 1 (TXNRD1) which is a selenocysteine-containing protein is overexpressed in many malignancies. Its role in the hepatocellular carcinoma (HCC) prognosis has not been investigated. In this study, we investigated whether TXNRD1 functions as an independent prognostic factor for HCC patients. We found TXNRD1 was overexpressed in HCC tissues and cells, immunohistochemical analysis suggested TXNRD1 was elevated in 57 of 120 (47.5%) clinical samples, and its level was increased with the increasing clinical stage. In addition, TXNRD1 expression was positively correlated with clinical stage (p=3.5e-5), N classification (p=4.4e-4), and M classification (p=0.037) of HCC patients. Kaplan-Meier analysis revealed that patients with high TXNRD1 expression had significantly shorter survival time than patients with low TXNRD1 expression. Multivariate analysis found TXNRD1 was an independent prognostic factor for HCC patients. In conclusion, our data suggested that TXNRD1 was a biomarker for the prognosis of patients with HCC.

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LRP1B mutation: a novel independent prognostic factor and a predictive tumor mutation burden in hepatocellular carcinoma

Journal of Cancer ◽

10.7150/jca.53124 ◽

2021 ◽

Vol 12 (13) ◽

pp. 4039-4048

Author(s):

Fahui Liu ◽

Wanyun Hou ◽

Jiadong Liang ◽

Lilan Zhu ◽

Chunying Luo

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Factor ◽

Independent Prognostic Factor ◽

Tumor Mutation Burden ◽

Mutation Burden

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Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.636614 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shanshan Lu ◽

Shenglan Cai ◽

Xiaozhen Peng ◽

Ruochan Cheng ◽

Yiya Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Functional Analysis ◽

Prognostic Factor ◽

Epithelial To Mesenchymal Transition ◽

Immune Cell ◽

Prognostic Significance ◽

Independent Prognostic Factor ◽

Mesenchymal Transition ◽

Immune Infiltration ◽

Geo Database

The Na+/K+-ATPase (NKA), has been proposed as a signal transducer involving various pathobiological processes, including tumorigenesis. However, the clinical relevance of NKA in hepatocellular carcinoma (HCC) has not been well studied. This study revealed the upregulation of mRNA of ATP1A1, ATP1B1, and ATP1B3 in HCC using TCGA, ICGC, and GEO database. Subsequently, ATP1B3 was demonstrated as an independent prognostic factor of overall survival (OS) of HCC. To investigate the potential mechanisms of ATP1B3 in HCC, we analyzed the co-expression network using LinkedOmics and found that ATP1B3 co-expressed genes were associated with immune-related biological processes. Furthermore, we found that ATP1B3 was correlated immune cell infiltration and immune-related cytokines expression in HCC. The protein level of ATP1B3 was also validated as a prognostic significance and was correlated with immune infiltration in HCC using two proteomics datasets. Finally, functional analysis revealed that ATP1B3 was increased in HCC cells and tissues, silenced ATP1B3 repressed HCC cell proliferation, migration, and promoted HCC cell apoptosis and epithelial to mesenchymal transition (EMT). In conclusion, these findings proved that ATP1B3 could be an oncogene and it was demonstrated as an independent prognostic factor and correlated with immune infiltration in HCC, revealing new insights into the prognostic role and potential immune regulation of ATP1B3 in HCC progression and provide a novel possible therapeutic strategy for HCC.

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