Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma

Ng, Kevin Tak‐Pan; Man, K; Ck, Sun; Lee, Terence; Rt, Poon; Lo, CM; Fan, ST

doi:10.1038/sj.bjc.6603399

Cited by 87 publications

(88 citation statements)

References 24 publications

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“…Similarly high Six1 expression in tumors occurs in more than 60% of women with metastatic ovarian cancer and is strongly associated with worse survival in these patients (Behbakht et al, 2007). Six1 is additionally associated with worsened survival in hepatocellular carcinoma (Ng et al, 2006). Thus Six1 expression may represent a mechanism of TRAIL resistance that is very common in advanced metastatic cancers.…”

Section: Resistance Related To Six1 Expressionmentioning

confidence: 99%

TRAIL receptor-targeted therapeutics: Resistance mechanisms and strategies to avoid them

Thorburn

Behbakht

Ford

2008

Drug Resistance Updates

145

134

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Tumor Necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) receptors are attractive therapeutic targets in cancer because agents that activate these receptors directly induce tumor cell apoptosis and have low toxicity to normal tissues. Consequently, several different drugs that target these receptors (recombinant TRAIL and various agonistic antibodies that activate one of the two TRAIL receptors) have been developed and are being tested in human clinical trials. However, in vitro and in vivo data suggest that resistance to these agents may limit their clinical effectiveness. In this review, we discuss recent findings about some of the ways these resistance mechanisms arise, potential biomarkers to identify TRAIL resistance in patients (Six1, GALNT14, XIAP, certain microRNAs) and potential ways to circumvent resistance and resensitize tumors.

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Section: Resistance Related To Six1 Expressionmentioning

confidence: 99%

TRAIL receptor-targeted therapeutics: Resistance mechanisms and strategies to avoid them

Thorburn

Behbakht

Ford

2008

Drug Resistance Updates

145

134

View full text Add to dashboard Cite

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“…The Six1 homeoprotein is a member of the Six family of homeodomain transcription factors and has been found to be upregulated in multiple cancers, including breast cancer (12,20,24), rhabdomyosarcomas (18,25,26), hepatocellular carcinomas (19), ovarian cancer (13) and Wilms' tumors (17). In addition, Six1 plays a role in cellular migration and invasion during embryogenesis (22,(27)(28)(29)(30) and in breast cancer (31,32).…”

Section: Six1 Expression N -----------------------------------------mentioning

confidence: 99%

“…The correct expression of this gene is crucial for the development of multiple organs, including the brain, eye, ear, craniofacial structures and kidney sensory structures (9)(10)(11). In addition to the involvement of Six1 in the early development of organs, the gene is often misexpressed in diverse tumors, including breast cancer (12), ovarian cancer (13,14), cervical cancer (15,16), Wilms' tumors (17), rhabdomyosarcomas (18) and hepatocellular carcinoma (19). Additionally, the misexpression of Six1 in cancer may induce developmental programs out of context, contributing to tumor onset and progression (20,21).…”

Section: Introductionmentioning

confidence: 99%

Six1 expression is associated with a poor prognosis in patients with glioma

Zhang

2017

Oncology Letters

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Abstract. Glioma is the most common human brain cancer and has poor prognosis. Messenger RNA profiling identified that sineoculis homeobox homolog 1 (Six1) is dysregulated in glioma tumor progenitor cells from glial progenitor cells isolated from normal white matter. However, the expression and role of Six1 in glioma remains unclear. The purpose of the present study was to investigate the expression level of Six1 in glioma tissues and the association between Six1 expression and clinicopathological characteristics and prognosis of gliomas. The Six1 protein was detected by immunohistochemistry in 163 glioma tissues of distinct malignancy grades, and Kaplan-Meier survival analysis was performed to assess the prognosis of the patients. The Six1 protein was stained in 49.1% (80 out of 163) of the glioma tissues, including 34.2% of low-grade [World Health Organization (WHO) I/II] gliomas and 80.8% of high-grade (WHO III/IV) gliomas. Normal brain tissues rarely expressed the Six1 protein. In addition, Six1 expression was significantly associated with WHO grade (P<0.001). According to the log-rank test and Cox regression model, Six1 may be suggested as an independent prognostic factor, in addition to the WHO grade. Overall, Six1 protein expression varies between different grades of glioma and is associated with the WHO grade. Upregulation of Six1 is more frequent in high-grade glioma and is an independent prognostic factor of poor clinical outcome.

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“…The new TNM staging and Edmonson staging of these patients was based on the clinical and pathological diagnosis (Ng et al, 2006). The study protocol was approved by the Institutional Review Board of the University of Hong Kong.…”

Section: Patientsmentioning

confidence: 99%

The significance of proline-rich tyrosine kinase2 (Pyk2) on hepatocellular carcinoma progression and recurrence

Sun

et al. 2007

Br J Cancer

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Understanding the precise molecular mechanisms that trigger liver cancer cell migration and invasion could develop novel therapeutic strategies targeting cancer cell invasion to increase the sensitivity to current treatment modalities. In the current study, 49 patients with hepatocellular carcinoma (HCC) were included prospectively. Liver tumour and adjacent non-tumour tissues were detected for the expression of Proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK), ezrin and fibronectin at protein and/or gene levels. Correlation between the expressions of Pyk2/FAK with the clinical pathological data was analysed. Protein expression of Pyk2 was also examined in a nude mice orthotopic liver tumour model with higher metastatic potential. There were 59% (29 out of 49) and 57% (28 out of 49) of HCC patients with higher levels of Pyk2 and FAK protein/gene expression, respectively. We observed a positive correlation between the protein and gene expression levels of Pyk2 and FAK (P ¼ 0.000, r ¼ 0.875). Overexpression of Pyk2 and FAK was significantly correlated with shorter disease-free survival. Patients with higher levels of Pyk2/FAK had larger tumour size and advanced Edmonson grading. In the animal studies, Pyk2 overexpression was found in infiltrative tumour cells and lung metastatic nodules. In conclusion, overexpression of Pyk2 and FAK was found in nearly 60% of HCC patients and was significantly correlated with poor prognosis. The significance of Pyk2 in HCC invasiveness was confirmed by animal studies. Understanding the precise molecular networks that trigger liver cancer cell migration and invasion could develop novel therapeutic strategies targeting cancer cell invasion to increase the sensitivity to current treatment modalities. Focal adhesion kinase (FAK) is an important mediator of cell proliferation, cell survival and migration. Recently, clinical evidences demonstrated that FAK was involved in liver tumour progression and had prognostic significance for hepatocellular carcinoma (HCC) patients (Fujii et al, 2004;Itoh et al, 2004). In addition to clinical relevance, animal experiments also demonstrated that FAK might play important roles in the regulation of metastatic adhesion of cancer cells with liver sinusoids and formation of organ-specific distant metastases. An in vitro study confirmed that FAK integrated growth-factor and integrin signals to promote cell migration (Sieg et al, 2000). An in vivo animal model also demonstrated that FAK is important for lung metastasis in a breast cancer model (van Nimwegen et al, 2005).Proline-rich tyrosine kinase 2 (Pyk2), also known as cell adhesion kinaseb (CAKb), is a tyrosine kinase that is structurally related to focal adhesion kinase (FAK) (Sasaki et al, 1995). Pyk2 has been demonstrated to be able to promote migration and invasion of glioma cells (Lipinski et al, 2005) as well as mediate angiogenesis of pulmonary vascular endothelial cells (Tang et al, 2002). Moreover, Pyk2 also mediated vascular endothelial cadherin-based cell -cell adhesion an...

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Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma

Cited by 87 publications

References 24 publications

TRAIL receptor-targeted therapeutics: Resistance mechanisms and strategies to avoid them

TRAIL receptor-targeted therapeutics: Resistance mechanisms and strategies to avoid them

Six1 expression is associated with a poor prognosis in patients with glioma

The significance of proline-rich tyrosine kinase2 (Pyk2) on hepatocellular carcinoma progression and recurrence

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