The intratumoral distribution of nuclear β‐catenin is a prognostic marker in colon cancer

BACKGROUND:

Most colon cancers harbor mutations of APC or β‐catenin, both of which may lead to nuclear β‐catenin accumulation in the tumor cells and constitutively activated expression of its target genes. In many colon cancers, however, nuclear β‐catenin accumulation is heterogeneous throughout the tumor and often confined to the tumor margin. Herein, the authors investigated whether the intratumoral distribution of nuclear β‐catenin can serve as a prognostic marker for survival and tumor progression of stage IIA colon cancer patients.

METHODS:

In total, 142 patients with primarily resected, moderately differentiated stage IIA colon cancer were included in this study. The patterning of nuclear β‐catenin expression was evaluated on immunohistochemically stained whole tissue sections of the tumors and was correlated with cancer‐specific survival and disease‐free survival using univariate and multivariate statistical analyses.

RESULTS:

Four distinct patterns of nuclear β‐catenin expression were identified, and 2 main categories comprising tumors with or without intratumoral regulation of nuclear β‐catenin were distinguished. Moreover, the results demonstrated that the patterning, and especially the regulation or absence of regulation of nuclear β‐catenin expression, was a strong predictive marker of patient survival and tumor progression.

CONCLUSIONS:

The current results indicated that the distribution of nuclear β‐catenin expression can be used as a good prognostic marker in patients with stage IIA colon cancer. Thus, the evaluation of nuclear β‐catenin may help to identify patients who will have a shorter than average survival and patients with a greater risk of disease progression who may be considered for adjuvant therapeutic modalities and intensified clinical aftercare in the future. Cancer 2009. © 2009 American Cancer Society.     

HBO1 promotes cell proliferation in bladder cancer via activation of Wnt/β‐catenin signaling

Histone acetyltransferase binding to ORC1 (HBO1), a histone acetyltransferase, was recently identified as an oncoprotein; however, its role in bladder cancer remains unknown. In this study, we showed that HBO1 was highly expressed at both the mRNA and the protein levels in bladder cancer. HBO1 expression was associated with the clinical features of human bladder cancer, including tumor size (P = 0.018) and T (P = 0.007) classifications. Patients with higher HBO1 expression had shorter recurrence‐free survival time, whereas patients with lower HBO1 expression had better survival time. Moreover, we found that ectopic overexpression of HBO1 promoted, whereas HBO1 silencing inhibited tumor growth in bladder cancer cells both in vitro and in vivo. We further demonstrated that upregulation of HBO1 activated the Wnt/β‐catenin signaling pathway and led to nuclear localization of β‐catenin and upregulation of downstream targets of of Wnt/β‐catenin signaling. These findings suggest that HBO1 plays a key role in the progression of bladder cancer via the Wnt/β‐catenin pathway, and may serve as a potential therapeutic target for the treatment of bladder cancer.     

HBx mutations promote hepatoma cell migration through the Wnt/β‐catenin signaling pathway

HBx mutations (T1753V, A1762T, G1764A, and T1768A) are frequently observed in hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). Aberrant activation of the Wnt/β‐catenin signaling pathway is involved in the development of HCC. However, activation of the Wnt/β‐catenin signaling pathway by HBx mutants has not been studied in hepatoma cells or HBV‐associated HCC samples. In this study, we examined the effects of HBx mutants on the migration and proliferation of HCC cells and evaluated the activation of Wnt/β‐catenin signaling in HBx‐transfected HCC cells and HBV‐related HCC tissues. We found that HBx mutants (T, A, TA, and Combo) promoted the migration and proliferation of hepatoma cells. The HBx Combo mutant potentiated TOP‐luc activity and increased nuclear translocation of β‐catenin. Moreover, the HBx Combo mutant increased and stabilized β‐catenin levels through inactivation of glycogen synthase kinase‐3β, resulting in upregulation of downstream target genes such as c‐Myc, CTGF, and WISP2. Enhanced activation of Wnt/β‐catenin was found in HCC tissues with HBx TA and Combo mutations. Knockdown of β‐catenin effectively abrogated cell migration and proliferation stimulated by the HBx TA and Combo mutants. Our results indicate that HBx mutants, especially the Combo mutant, allow constitutive activation of the Wnt signaling pathway and may play a pivotal role in HBV‐associated hepatocarcinogenesis.     

CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

Cancer‐associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumor‐promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF‐mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co‐culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF‐573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF‐573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.     

Retinoid X receptor α enhances human cholangiocarcinoma growth through simultaneous activation of Wnt/β‐catenin and nuclear factor‐κB pathways

Retinoid X receptor α (RXRα) plays important roles in the malignancy of several cancers such as human prostate tumor, breast cancer, and thyroid tumor. However, its exact functions and molecular mechanisms in cholangiocarcinoma (CCA), a chemoresistant carcinoma with poor prognosis, remain unclear. In this study we found that RXRα was frequently overexpressed in human CCA tissues and CCA cell lines. Downregulation of RXRα led to decreased expression of mitosis‐promoting factors including cyclin D1and cyclin E, and the proliferating cell nuclear antigen, as well as increased expression of cell cycle inhibitor p21, resulting in inhibition of CCA cell proliferation. Furthermore, RXRα knockdown attenuated the expression of cyclin D1 through suppression of Wnt/β‐catenin signaling. Retinoid X receptor α upregulated proliferating cell nuclear antigen expression through nuclear factor‐κB (NF‐κB) pathways, paralleled with downregulation of p21. Thus, the Wnt/β‐catenin and NF‐κB pathways account for the inhibition of CCA cell growth induced by RXRα downregulation. Retinoid X receptor α plays an important role in proliferation of CCA through simultaneous activation of Wnt/β‐catenin and NF‐κB pathways, indicating that RXRα might serve as a potential molecular target for CCA treatment.     

Tumor inhibition by sodium selenite is associated with activation of c‐Jun NH2‐terminal kinase 1 and suppression of β‐catenin signaling

Epidemiological and clinical studies suggest that an increased intake of dietary selenium significantly reduces overall cancer risk, but the anticancer mechanism of selenium is not clear. In this study, we fed intestinal cancer mouse model. Muc2/p21 double mutant mice with a selenium‐enriched (sodium selenite) diet for 12 or 24 weeks, and found that sodium selenite significantly inhibited intestinal tumor formation in these animals (p < 0.01), which was associated with phosphorylation of JNK1 and suppression of β‐catenin and COX2. In vitro studies showed that sodium selenite promoted cell apoptosis and inhibited cell proliferation in human colon cancer cell lines HCT116 and SW620. These effects were dose‐ and time course‐dependent, and were also linked to an increase of JNK1 phosphorylation and suppression of β‐catenin signaling. Reduced JNK1 expression by small RNA interference abrogated sufficient activation of JNK1 by sodium selenite, leading to reduced inhibition of the β‐catenin signaling, resulting in reduced efficacy of inhibiting cell proliferation. Taken together, our data demonstrate that sodium selenite inhibits intestinal carcinogenesis in vivo and in vitro through activating JNK1 and suppressing β‐catenin signaling, a novel anticancer mechanism of selenium.     

Extracellular 5′‐nucleotidase (CD73) promotes human breast cancer cells growth through AKT/GSK‐3β/β‐catenin/cyclinD1 signaling pathway

To identify the role and to explore the mechanism of extracellular 5′‐nucleotidase (CD73) in human breast cancer growth, CD73 expression was measured firstly in breast cancer tissues and cell lines, and then interfered with or over‐expressed by recombinant lentivirus in cell lines. Impacts of CD73 on breast cancer cell proliferation and cell cycle were investigated with colony formation assay, CCK‐8 and flow cytometry. The relationship between CD73 and AKT/GSK‐3β/β‐catenin pathway was assessed with adenosine, adenosine 2A receptor antagonist (SCH‐58261), adenosine 2A receptor agonist (NECA), CD73 enzyme inhibitor (APCP) and Akt inhibitor (MK‐2206). Moreover, the effect of CD73 on breast cancer growth in vivo was examined with human breast cancer transplanting model of nude mice. The results showed that the expression of CD73 was high in breast cancer tissues and increased with advanced tumor grades and lympho‐node status. CD73 expression was higher in more malignant cells, and CD73 overexpression promoted breast cancer cell proliferation in both in vivo and in vitro. It activated AKT/GSK‐3β/β‐catenin/cyclinD1 signaling pathway through CD73 enzyme activity and other mechanism.