Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers 1 . It occurs through mutations mainly of APC and less often of CTNNB1 (encoding β-catenin) 1-3 or AXIN2 (encoding axin-2, also known as conductin) 4 . These mutations allow ligandindependent WNT signaling that culminates in abnormal accumulation of free β-catenin in the nucleus 1-3 . We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzledrelated proteins (SFRPs) in colorectal cancer 5 . SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development 6-10 . Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.

Swift elimination of undesirable cells is an important feature in tumour suppression and immunity. The tumour suppressor p53 and interferon-a and -b (IFN-a/b) are essential for the induction of apoptosis in cancerous cells and in antiviral immune responses, respectively, but little is known about their interrelationship. Here we show that transcription of the p53 gene is induced by IFN-a/b, accompanied by an increase in p53 protein level. IFN-a/b signalling itself does not activate p53; rather, it contributes to boosting p53 responses to stress signals. We show examples in which p53 gene induction by IFN-a/b contributes to tumour suppression. Furthermore, we show that p53 is activated in virally infected cells to evoke an apoptotic response and that p53 is critical for antiviral defence of the host. Our study reveals a hitherto unrecognized link between p53 and IFN-a/b in tumour suppression and antiviral immunity, which may have therapeutic implications.The tumour suppressor p53, activated in response to DNA damage, induces cell cycle arrest or apoptosis through transcriptional activation of its target genes, hence having a central role in tumour suppression [1][2][3][4][5] . So far, it is not known whether p53 contributes to the immune responses that lead to the eradication of pathogens such as viruses. On the other hand, IFN-a/b, both of which are essential cytokines for antiviral immunity, are sometimes referred to as 'negative growth factors' , and manifest anti-oncogenic activities [6][7][8][9][10] . In fact, IFN-a/b are used for the treatment of some forms of human cancer but the molecular basis for the treatment is poorly understood [11][12][13] . Until know, little if anything has been known about the link between the p53 and IFN-a/b system. Induction of p53 protein by IFN-a/bWhen wild-type mouse embryonic fibroblasts (MEFs) were stimulated with IFN-b, a notable increase in the level of p53 was observed (Fig. 1a). A similar observation was made in cells stimulated with IFN-a (data not shown) but not with IFN-g ( Supplementary Fig. 1). The increase in p53 level with IFN-b treatment was dose-dependent, with about fourfold induction achieved at a high concentration of IFN-b (Fig. 1b). The p53 induction by IFN-b was also observed in two human hepatic cancer cell lines, HepG2 and HLE, p53 function being abrogated in the latter cells by a mutation in the DNA-binding domain 14 (Fig. 1c). We performed a pulse-chase experiment to examine whether the observed p53 protein induction is secondary to suppression of the p53 degradation pathway by IFN-b, typically the MDM2-mediated pathway [15][16][17] . However, no difference was observed in the half-life of p53 (40-45 min) between the IFN-treated and untreated MEFs (Fig. 1d), suggesting that p53 protein synthesis is induced by IFN-b stimulation. Induction of the p53 gene by IFN-a/bInformation is limited about the induction of the p53 gene 18 , and the above results prompted us to examine whether IFN-a/b induces p53 gene transcription. Inspection of mouse and human p53...

The 'magic bullet' concept of specifically targeting cancer cells at the same time as sparing normal tissues is now proven, as several monoclonal antibodies and targeted small-molecule compounds have been approved for cancer treatment. Both antibodies and small-molecule compounds are therefore promising tools for target-protein-based cancer therapy. We discuss and compare the distinctive properties of these two therapeutic strategies so as to provide a better view for the development of new drugs and the future direction of cancer therapy.

Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that, in cancer, expression of some miRNAs cells is silenced in association with CpG island hypermethylation. To identify epigenetically silenced miRNAs in colorectal cancer (CRC), we screened for miRNAs induced in CRC cells by 5-aza-2 ¶-deoxycytidine (DAC) treatment or DNA methyltransferase knockout. We found that miRNA-34b (miR-34b) and miR-34c, two components of the p53 network, are epigenetically silenced in CRC; that this down-regulation of miR-34b/c is associated with hypermethylation of the neighboring CpG island; and that DAC treatment rapidly restores miR-34b/c expression. Methylation of the miR34b/c CpG island was frequently observed in CRC cell lines (nine of nine, 100%) and in primary CRC tumors (101 of 111, 90%), but not in normal colonic mucosa. Transfection of precursor miR-34b or miR-34c into CRC cells induced dramatic changes in the gene expression profile, and there was significant overlap between the genes down-regulated by miR-34b/c and those down-regulated by DAC. We also found that the miR-34b/c CpG island is a bidirectional promoter which drives expression of both miR-34b/c and B-cell translocation gene 4 (BTG4); that methylation of the CpG island is also associated with transcriptional silencing of BTG4; and that ectopic expression of BTG4 suppresses colony formation by CRC cells. Our results suggest that miR-34b/c and BTG4 are novel tumor suppressors in CRC and that the miR-34b/c CpG island, which bidirectionally regulates miR34b/c and BTG4, is a frequent target of epigenetic silencing in

Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.