The cell cycle is strictly regulated by numerous mechanisms to ensure cell division. The transcriptional regulation of cell-cyclerelated genes is poorly understood, with the exception of the E2F family that governs the cell cycle. Here, we show that a transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-associated genes and is highly expressed in multiple solid tumors. RNA-interference (RNAi)-mediated knockdown of ZNF143 showed that expression of 152 genes was downregulated in human prostate cancer PC3 cells. Among these ZNF143 targets, 41 genes (27%) were associated with cell cycle and DNA replication including cell division cycle 6 homolog (CDC6), polo-like kinase 1 (PLK1) and minichromosome maintenance complex component (MCM) DNA replication proteins. Furthermore, RNAi of ZNF143 induced apoptosis following G2 ⁄ M cell cycle arrest. Cell growth of 10 lung cancer cell lines was significantly correlated with cellular expression of ZNF143. Our data suggest that ZNF143 might be a master regulator of the cell cycle. Our findings also indicate that ZNF143 is a member of the growing list of non-oncogenes that are promising cancer drug targets. (Cancer Sci 2010; 101: 2538-2545 T ranscriptional regulation of gene expression requires the orchestrated recruitment of transcription factors by sequence-specific DNA binding regulators. Staf was initially identified as the transcriptional activator of the RNA polymerase III-dependent Xenopus tRNA gene.(1) It has recently been shown that its human ortholog zinc finger protein 143 (ZNF143; formerly known as hStaf) is also involved in RNA-polymerase-IIdependent gene transcription.(2,3) The DNA binding domain of ZNF143 is located in the central part of the protein and consists of seven zinc finger domains.(1,4) The ZNF143 DNA binding site is thought to be at least 18 bp long because the protein has seven zinc fingers; by analogy, the well-known zinc finger transcription factor Sp family and members of the KLF family contain three zinc fingers and recognize DNA sequences approximately 6 bp long.(5) Recently, it has been shown by a bioinformatics approach that ZNF143 binding sites are widely distributed in the CpG island-type promoters of the human genome.(6) Functional classification of ZNF143 target genes has revealed that many of the identified genes are important for cell growth: 27% of the genes are categorized as cell cycle ⁄ DNA replication ⁄ DNA repair proteins.We have previously reported that expression of ZNF143 is induced by DNA-damaging agents and is enhanced in cisplatinresistant cell lines.(7) ZNF143 binds preferentially to cisplatinmodified DNA. We also found that ZNF143 binding sites are frequently found in the promoter region of DNA repair genes. Here, we investigated the ZNF143 target genes by RNA interference (RNAi). One hundred and fifty-two genes were downregulated by ZNF143-specific small interfering RNA (siRNA) transfection. Among them, 41 genes are categorized as concerned with cell cycle and DNA replication. ZNF143 wa...

MicroRNAs (miRs) function as key regulators of gene expression and their deregulation is associated with the carcinogenesis of various cancers. In the present study, we investigated the biological role and mechanism of miR-361-5p in colorectal carcinoma (CRC) and gastric cancer (GC). We showed that microRNA-361-5p (miR-361-5p) was down-regulated in CRC and GC in comparison to the controls. Meanwhile, the expression levels of miR-361-5p negatively correlated with lung metastasis and prognosis in clinical CRC patients. Overexpression of miR-361-5p markedly suppressed proliferation, migration and invasion of cancer cells. Additionally, this phenotype could be partially rescued by the ectopic expression of staphylococcal nuclease domain containing-1 (SND1). SND1 was identified as a target of miR-361-5p using bioinformatics analysis and in vitro luciferase reporter assays. In turn, SND1 bound to pre-miR-361-5p and suppressed the expression of miR-361-5p, thus exerting a feedback loop. Most interestingly, in vivo studies showed that restoration of miR-361-5p significantly inhibited tumor growth and especially the lung metastasis in nude mice. Therefore, it could be concluded that miR-361-5p functions as a tumor-suppressive miRNA through directly binding to SND1, highlighting its potential as a novel agent for the treatment of patients with CRC and GC.

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more “normal” 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.

Our results indicate that YB-1 plays a role in the process of GC metastasis, and that the immunohistochemical detection of this protein potentially delivers valuable insight regarding the prediction of liver metastasis and shorter DFS in patients undergoing curative resection for advanced GC.