Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

The DNA‐binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/β‐catenin signalling pathway in human cancer and normal cells as well as in mouse intestinal tissues. Furthermore, β‐catenin binds to TRF2 gene regulatory regions that are functional in a luciferase transactivating assay. Reduced β‐catenin expression in cancer cells triggers a marked increase in telomere dysfunction, which can be reversed by TRF2 overexpression. We conclude that the Wnt/β‐catenin signalling pathway maintains a level of TRF2 critical for telomere protection. This is expected to have an important role during development, adult stem cell function and oncogenesis.     

Wnt and planar cell polarity signaling in cystic renal disease

Cystic kidney diseases can cause end stage renal disease, affecting millions of individuals worldwide. They may arise early or later in life, are characterized by a spectrum of symptoms and can be caused by diverse genetic defects. The primary cilium, a microtubule-based organelle that can serve as a signaling antenna, has been demonstrated to have a significant role in ensuring correct kidney development and function. In the kidney, one of the signaling pathways that requires the cilium for normal development is Wnt signaling. In this review, the roles of primary cilia in relation to canonical and non-canonical Wnt/PCP signaling in cystic renal disease are described. The evidence of the associations between cilia, Wnt signaling and cystic renal disease is discussed and the significance of planar cell polarity-related mechanisms in cystic kidney disease is presented. Although defective Wnt signaling is not the only cause of renal disease, research is increasingly highlighting its importance, encouraging the development of Wnt-associated diagnostic and prognostic tools for cystic renal disease.     

Powerful Drosophila screens that paved the wingless pathway

The Wnt/Wingless (Wg) signaling cascade controls a number of biological processes in animal development and adult life; aberrant Wnt/Wg signaling can cause diseases. In the 1980s genes were discovered that encode core Wnt/Wg pathway components: their mutant phenotypes were similar and an outline of a signaling cascade emerged. Over the years our knowledge of this important signaling system increased and more components were uncovered that are instrumental for Wnt/Wg secretion and transduction. Here we provide an overview of these discoveries, the technologies involved, with a particular focus on the important role Drosophila screens played in this process.     

Wnt5a抑制Wnt3a促黑素细胞黑素生成的作用探究

目的：研究WntSa对Wnt3a处理过的melan—a细胞分泌黑色素的影响。方法：体外培养黑色素细胞（melan-a细胞）,分别进行GFP、Wnt3a、Wnt3a＋WntSa处理,比较细胞的突起,酪氨酸酶的活性以及黑素合成相关基因（TYR、TRP2、MITF）表达情况。结果：Wnt3a促进黑色素细胞突起的生长和TYR、TRP2、MITF的表达,而Wnt5a逆转了Wnt3a对黑色素细胞的作用。结论：Wnt5a抑制Wnt3a促黑素细胞黑素生成的作用,表明在melan．a黑素细胞中Wnt5a可有效抑制wnt经典通路。     

Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β‐catenin signalling and apoptosis regulation in breast cancer cells

Dickkopf‐related protein 3 (DKK3) is an antagonist of Wnt ligand activity. Reduced DKK3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour‐specific methylation of DKK3 in breast cancer. Ectopic expression of DKK3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial‐mesenchymal transition (EMT) and down‐regulating stem cell markers. DKK3 inhibited canonical Wnt/β‐catenin signalling through mediating β‐catenin translocation from nucleus to cytoplasm and membrane, along with reduced active‐β‐catenin, further activating non‐canonical JNK signalling. Thus, our findings demonstrate that DKK3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.     

Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer

Colorectal cancer (CRC) is one of the common malignant tumors worldwide. Both genetic and epigenetic changes are regarded as important factors of colorectal carcinogenesis. Loss of DACH1 expression was found in breast, prostate, and endometrial cancer. To analyze the regulation and function of DACH1 in CRC, 5 colorectal cancer cell lines, 8 cases of normal mucosa, 15 cases of polyps and 100 cases of primary CRC were employed in this study. In CRC cell lines, loss of DACH1 expression was correlated with promoter region hypermethylation, and re-expression of DACH1 was induced by 5-Aza-2'-deoxyazacytidine treatment. We found that DACH1 was frequently methylated in primary CRC and this methylation was associated with reduction in DACH1 expression. These results suggest that DACH1 expression is regulated by promoter region hypermethylation in CRC. DACH1 methylation was associated with late tumor stage, poor differentiation, and lymph node metastasis. Re-expression of DACH1 reduced TCF/LEF luciferase reporter activity and inhibited the expression of Wnt signaling downstream targets (c-Myc and cyclinD1). In xenografts of HCT116 cells in which DACH1 was re-expressed, tumor size was smaller than in controls. In addition, restoration of DACH1 expression induced G2/M phase arrest and sensitized HCT116 cells to docetaxel. DACH1 suppresses CRC growth by inhibiting Wnt signaling both in vitro and in vivo. Silencing of DACH1 expression caused resistance of CRC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human CRC and methylation of DACH1 may serve as detective and prognostic marker in CRC.     

lncRNA SNHG11 promotes lung cancer cell proliferation and migration via activation of Wnt/β-catenin signaling pathway

Lung cancer ranks topmost among the most frequently diagnosed cancers. Despite increasing research, there are still unresolved mysteries in the molecular mechanism of lung cancer. Long noncoding RNA small nucleolar RNA host gene 11 (SNHG11) was found to be upregulated in lung cancer and facilitated lung cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition progression while suppressed cell apoptosis. Moreover, the high expression of SNHG11 was correlated with poor prognosis of lung cancer patients, TNM stage, and tumor size. Further assays demonstrated that SNHG11 functioned in lung cancer cells via Wnt/β-catenin signaling pathway. Subsequently, Wnt/β-catenin pathway was found to be activated through SNHG11/miR-4436a/CTNNB1 ceRNA axis. As inhibiting miR-4436 could only partly rescue the suppression of cell function induced by silencing SNHG11, it was suspected that β-catenin might enter cell nucleus through other pathways. Mechanism investigation proved that SNHG11 would directly bind with β-catenin to activate classic Wnt pathway. Subsequently, in vivo tumorigenesis was also demonstrated to be enhanced by SNHG11. Hence, SNHG11 was found to promote lung cancer progression by activating Wnt/β-catenin pathway in two different patterns, implying that SNHG11 might contribute to lung cancer treatment by acting as a therapeutic target.