Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma

Centre for the Study of Liver Disease and Departments of Surgery, The University of Hong Kong, Queen Mary Hospital, L9-55, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China.
British Journal of Cancer (Impact Factor: 4.84). 11/2006; 95(8):1050-5. DOI: 10.1038/sj.bjc.6603399
Source: PubMed


Tumour recurrence and metastases of hepatocellular carcinoma (HCC) after hepatectomy are the major obstacles of long-term survival. The present study investigated the clinicopathological significance of a possible metastasis regulator Six1 in HCC patients who were undergone hepatectomy. Seventy-two pairs of RNA and 103 pairs of protein from tumour and adjacent nontumour liver tissues of HCC patients were examined. About 85 and 60% of HCC tumour tissues were found to overexpress Six1 mRNA and protein, respectively, compared with nontumour liver tissues. No Six1 protein was detected in HCC nontumour liver tissues and normal liver tissues. Increased Six1 protein expression in HCC patients was significantly correlated with pathologic tumour-node-metastasis (pTNM) stage (P=0.002), venous infiltration (P=0.004) and poor overall survival (P=0.0423). We concluded that Six1 is frequently overexpressed in HCC patients and elevated Six1 protein in HCC patients may be an indication of advanced stage and poor overall survival after hepatectomy.

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Available from: Kwan Man, May 23, 2014
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    • "Th is homeodomain transcription factor has been implicated in tumor progression and embryogenesis[17,18]. Six1 stimulates proliferation and survival of progenitor cells during normal development[19,20]which loss of its function leads to a reduction in size or the absence of various organs, because of a decrease in cell proliferation and increase in apoptosis[16,18,21]. Recent studies showed that Six1 overexpression is associated with a poor prognosis in numerous cancers including ovarian cancer, hepatocellular carcinoma, and cervical cancers[8,22]. Th e overexpression of Six1 protein likely contributes epithelial carcinogenesis by increasing of proliferation and decreasing apoptosis[23], or genomic instability[24]. "
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    ABSTRACT: The resistance of cancer cells to chemotherapeutic agents represents the main problem in cancer treatment. Despite intensive research, mechanisms of resistance have not yet been fully elucidated. Six1 signaling has an important role in the expansion of progenitor cell populations during early embryogenesis. Six1 gene overexpression has been strongly associated with aggressiveness, invasiveness, and poor prognosis of different cancers. In this study, we investigated the role of Six1 signaling in resistance of MCF-7 breast cancer cells to taxanes. We first established in vitro paclitaxel-resistant MCF-7 breast cancer cells. Morphological modifications in paclitaxel-resistant cells were examined via light microscopic images and fluorescence-activated cell sorting analysis. Applying quantitative real-time polymerase chain reaction, we measured Six1, B-cell lymphoma/leukemia(BCL-2), BAX, and P53 mRNA expression levels in both non-resistant and resistant cells. Resistant cells were developed from the parent MCF-7 cells by applying increasing concentrations of paclitaxel up to 64 nM. The inhibitory concentration 50% value in resistant cells increased from 3.5 ± 0.03 to 511 ± 10.22 nM (p = 0.015). In paclitaxel-resistant cells, there was a significant increase in Six1 and BCL-2 mRNA levels (p = 0.0007) with a marked decrease in pro-apoptotic Bax mRNA expression level (p = 0.03); however, there was no significant change in P53 expression (p = 0.025). Our results suggest that identifying cancer patients with high Six1 expression and then inhibition of Six1 signaling can improve the efficiency of chemotherapeutic agents in the induction of apoptosis.
    Full-text · Article · Dec 2015 · Bosnian journal of basic medical sciences / Udruzenje basicnih mediciniskih znanosti = Association of Basic Medical Sciences
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    • "Behbakht et al. suggested that SIX1 might contribute to ovarian epithelial carcinogenesis by simultaneously increasing proliferation and decreasing TRAIL-mediated apoptosis (Behbakht et al., 2007). Ng et al. reported that increased SIX1 protein expression in tumors of hepatocellular carcinoma patients was significantly correlated with pTNM stage, venous infiltration and poor overall survival (Ng et al., 2006). These data indicated that SIX1 potentially contributed to the tumorigenicity of many cancers. "
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    ABSTRACT: Sine oculis homeobox homolog 1 (SIX1) protein is a member of the homeobox transcription factor family. Overexpression of SIX1 contributes to cancer progression and is associated with adverse outcomes in various cancer types including breast, ovarian, uterine cervical and liver. To investigate the clinicopathological significance of SIX1 protein expression in gastric adenocarcinomas (GAC), localization of the SIX1 protein was determined in MKN-1, a gastric cancer cell line, using immunofluorescence (IF) staining, SIX1 mRNA level was detected in fresh tissues of GAC and normal gastric mucosa using quantitative real-time polymerase chain reaction (qRT-PCR), and SIX1 protein expression was assessed in 163 GAC, 35 gastric dysplasia and 26 normal gastric mucosa using immunohistochemical (IHC) staining. Correlations between SIX1 protein expression and pathological parameters of GAC were analyzed using Chi-square tests, differences in survival curves were analyzed using log-rank tests, and multivariate survival analysis was performed using the Cox proportional hazards regression model. SIX1 protein showed a mainly cytoplasmic staining pattern in GAC using IF and IHC staining. The positive SIX1 protein expression rate was 80.4% in GAC, which was significantly higher than in either gastric dysplasia (45.7%) or normal gastric mucosa (26.9%) (P< 0.01). qRT-PCR data also confirmed increased levels of SIX1 mRNA expression in GAC compared with the normal gastric mucosa in fresh tissues. In addition, the strongly positive SIX1 protein expression rate was significantly correlated with clinical stage, lymph node metastasis and serosal invasion of GAC (P< 0.01 or P< 0.05), while there was no association with gender, age, tumor size, Lauren classification or histological types of GAC. Notably, strongly positive signals were frequently observed in tumor blood vessels and/or lymphatic vessels. GAC patients with high expression of the SIX1 had shorter overall and disease-free survival rates than those with low SIX1 protein expression (P< 0.005 and P< 0.05, respectively). Furthermore, using multivariate analysis, SIX1 protein expression was found to be an independent risk factor for survival in patients with GAC along with clinical stage and serosal invasion (P< 0.001). In conclusion, SIX1 protein expression status may be an independent biomarker for prognostic evaluation of GAC.
    Full-text · Article · Aug 2014 · Experimental and Molecular Pathology
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    • "In regard to prognosis, Ng et al. reported that increased SIX1 expression in human hepatocellular carcinoma patients was significantly correlated with the pTNM stage, venous infiltration and poor overall survival (Ng et al., 2006). Our previous study also indicated that SIX1 overexpression was significantly related with the late stage and metastasis of PDAC (Jin et al., 2013). "
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    ABSTRACT: Sineoculis homeobox homolog 1 (SIX1) is one of the transcription factors that act as master regulators of development and is frequently dysregulated in cancer. This study explores the roles of SIX1 in tumor progression and as a prognostic determinant of breast cancer. Breast cancer specimens from 262 patients were selected for analysis of SIX1 protein by immunohistochemistry (IHC). The localization of SIX1 protein was detected in MDA-MB468 breast cancer cells using immunofluorescence (IF) staining. The survival rates were calculated by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazard models. SIX1 protein mainly showed cytoplasmic/perinuclear staining pattern in breast cancer using IHC in paraffin embedded breast cancer tissues and IF in MDA-MB468 cancer cells. The strongly positive rate of SIX1 protein was 61.8% (162/262) in breast cancer and 23.1% (12/52) in ductal carcinoma in situ (DCIS), which was significantly higher than adjacent normal breast tissues (6.7%, 3/45). SIX1 overexpression was positively correlated with clinical stage, lymph node metastasis, Her2 expression status, and disease-free survival (DFS) and 5-year overall survival (OS) rates of patients with breast cancer. Moreover, patients with late stage breast cancer and high SIX1 expression had poorer survival rates than those with low SIX1 expression. Further analysis using a Cox proportional hazard regression model revealed that high SIX1 expression emerged as a significant independent hazard factor for the DFS and OS rates of patients with breast cancers along with Her2 status and clinical stage. SIX1 may potentially be used as an independent biomarker for prognostic evaluation of breast cancer.
    Full-text · Article · Jul 2014 · Experimental and Molecular Pathology
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