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Characterization of bridging integrator 1 (BIN1) as a potential tumor suppressor and prognostic marker in hepatocellular carcinoma.

ABSTRACT: It has been shown that bridging integrator 1 (BIN1) can interact with c-myelocytomatosis (c-Myc) oncoprotein in cancer. However, the role of BIN1 in hepatocellular carcinoma (HCC) is not clear. In the present study, we investigated the expression and prognostic role of BIN1 in primary HCC and evaluated the function of BIN1 in hepatocarcinogenesis. Using real-time polymerase chain reaction and Western blot analysis, we found significantly decreased expression of BIN1 in primary HCC tumor tissues (n = 42) compared with adjacent normal tissues and in HCC cell lines. Immunohistochemistry analysis also found decreased BIN1 expression in HCC tumor tissues (n = 117). In clinicopathological analysis, loss of BIN1 expression correlated significantly (P < 0.05) with differentiation scores and tumor size. Importantly, decreased expression of BIN1 in tumors was found to be closely associated with a poor prognosis, and we conclude that BIN1 was an independent prognostic factor in a multivariate analysis. In mechanistic studies, restoring BIN1 expression in BIN1-null HCC cells significantly inhibited cell proliferation and colony formation and induced apoptosis of HCC cells. Furthermore, we found that BIN1 overexpression could significantly suppress the motility and invasion of HCC cells in vitro. Our results indicate that BIN1 may function as a potential tumor suppressor and serve as a novel prognostic marker in HCC patients. The BIN1 molecule might play an important role in tumor growth, cell motility and invasion. Modulation of BIN1 expression may lead to clinical applications of this critical molecule in the control of hepatocellular carcinoma as well as in early and effective diagnosis of this aggressive tumor.

SUBMITTER: Pan K

PROVIDER: S-EPMC3356425 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Characterization of bridging integrator 1 (BIN1) as a potential tumor suppressor and prognostic marker in hepatocellular carcinoma.

Pan Ke K Liang Xiao-ting XT Zhang Hua-kun HK Zhao Jing-jing JJ Wang Dan-dan DD Li Jian-jun JJ Lian Qizhou Q Chang Alfred E AE Li Qiao Q Xia Jian-chuan JC

Molecular medicine (Cambridge, Mass.) 20120509

It has been shown that bridging integrator 1 (BIN1) can interact with c-myelocytomatosis (c-Myc) oncoprotein in cancer. However, the role of BIN1 in hepatocellular carcinoma (HCC) is not clear. In the present study, we investigated the expression and prognostic role of BIN1 in primary HCC and evaluated the function of BIN1 in hepatocarcinogenesis. Using real-time polymerase chain reaction and Western blot analysis, we found significantly decreased expression of BIN1 in primary HCC tumor tissues ...[more]

PMID: 22281836

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Project description:BACKGROUND:Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015). METHODS:First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway. RESULTS:Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/?-catenin signalling pathway. CONCLUSION:The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.

Project description:Sorting nexin-1 (SNX1) is an important functional protein in cell endocytosis, efflux, protein sorting, cell signal transduction, etc; however, the expression, the role and clinical relevance of SNX1 have not been investigated in gastric cancer (GC). In this study, we first performed a bioinformatics investigation using the data obtained from The Cancer Genome Atlas (TCGA) database. The result showed that SNX1 mRNA levels were significantly lower in GC tissues than in paracancerous tissues. In a study of 150 cases of GC, including 60 cases with paired paracancerous and cancer tissues and 90 cases with detailed follow-up information, SNX1 expression was analyzed by immunohistochemistry. Our study on paired paracancerous and cancer tissues showed that SNX1 protein expression remarkably decreased in GC tissues (50/60, 83.33%). A study on 90 patients with detailed follow-up information showed that tumors with higher SNX1 protein level were correlated with better clinicopathologic stages (p = 0.0285), nodal status (p = 0.0286), smaller tumor sizes (p = 0.0294) and a better survival rate in patients with GC (p = 0.0245). Univariate analysis of the 90 patients with GC showed that low-level SNX1 was significantly correlated with decreased overall survival of GC patients (p = 0.008), and associated with a relatively higher cumulative hazard of death. Exogenous expression of SNX1 inhibited the growth, migration, invasion and promoted the apoptosis and enhanced the sensitivity of GC cells to the chemotherapeutic drug 5-Fluorouracil (5-Fu) in vitro, while knockdown of SNX1 by short hairpin RNA (shRNA) significantly promoted the growth, migration, invasion and reduced the apoptosis and the sensitivity of GC cells to 5-Fu. SNX1 also showed to influence the levels of epithelial-mesenchymal transition markers including Vimentin, Snail, and E-cadherin in GC cells in vitro. Taken together, we propose here that SNX1 serves as a tumor suppressor and prognostic marker that reduces tumor cell malignancy for GC.

Dataset Information

Characterization of bridging integrator 1 (BIN1) as a potential tumor suppressor and prognostic marker in hepatocellular carcinoma.

Publications

Characterization of bridging integrator 1 (BIN1) as a potential tumor suppressor and prognostic marker in hepatocellular carcinoma.

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