Small nucleolar RNA (snoRNA) dysfunctions have been associated with cancer development. SNORD126 is an orphan C/D box snoRNA that is encoded within introns 5-6 of its host gene, cyclin B1-interacting protein 1 (CCNB1IP1). The cancer-associated molecular mechanisms triggered by SNORD126 are not fully understood. Here, we demonstrate that SNORD126 is highly expressed in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patient samples. SNORD126 increased Huh-7 and SW480 cell growth and tumorigenicity in nude mice. Knockdown of SNORD126 inhibited HepG2 and LS174T cell growth. We verified that SNORD126 was not processed into small RNAs with miRNA activity. Moreover, SNORD126 did not show a significant expression correlation with CCNB1IP1 in HCC samples or regulate CCNB1IP1 expression. Our gene expression profile analysis indicated that SNORD126-upregulated genes frequently mapped to the PI3K-AKT pathway. SNORD126 overexpression increased the levels of phosphorylated AKT, GSK-3β, and p70S6K and elevated fibroblast growth factor receptor 2 (FGFR2) expression. siRNA-mediated knockdown or AZD4547-mediated inactivation of FGFR2 in SNORD126-overexpressing Huh-7 cells inhibited AKT phosphorylation and suppressed cell growth. These findings indicate an oncogenic role for SNORD126 in cancer and suggest its potential as a therapeutic target.

Uterine intravenous leiomyomatosis (IVL) is a distinct smooth muscle neoplasm with a potential of clinical aggressiveness due to its ability to extend into intrauterine and extrauterine vasculature. In this study, chromosomal alterations analyzed by oligonucleotide array comparative genomic hybridization were performed in 9 cases of IVL. The analysis was informative in all cases with multiple copy number losses and/or gains observed in each tumor. The most frequent recurrent loss of 22q12.3-q13.1 was observed in 6 tumors (66.7%), followed by losses of 22q11.23-q13.31, 1p36.13-p33, 2p25.3-p23.3, and 2q24.2-q32.2 and gains of 6p22.2, 2q37.3 and 10q22.2-q22.3, in decreasing order of frequency. Copy number variants were identified at 14q11.2, 15q11.1-q11.2, and 15q26.2. Genes mapping to the regions of loss include CHEK2, EWS, NF2, PDGFB, and MAP3K7IP1 on chromosome 22q, HEI10 on chromosome 14q, and succinate dehydrogenase subunit B, E2F2, ARID1A KPNA6, EIF3S2 , PTCH2, and PIK3R3 on chromosome 1p. Regional losses on chromosomes 22q and 1p and gains on chromosomes 12q showed overlaps with those previously observed in uterine leiomyosarcomas. In addition, presence of multiple chromosomal aberrations implies a higher level of genetic instability. Follow-up polymerase chain reaction (PCR) sequencing analysis of MED12 gene revealed absence of G> A transition at nucleotides c.130 or c.131 in all 9 cases, a frequent mutation found in uterine leiomyoma and its variants. In conclusion, this is the first report of high-resolution, genome-wide investigation of IVL by oligonucleotide array comparative genomic hybridization. The presence of high frequencies of recurrent regional loss involving several chromosomes is an important finding and likely related to the pathogenesis of the disease.

Cohesin, a multiunit complex of SMC1A, SMC3 and Rad21, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. It has been reported that SMC1A is mutated in some cancer types, leading to genomic instability and abnormal cell growth. In this study, we investigated the role of SMC1A in human glioma. We found that SMC1A was expressed at abnormally high levels in human glioma tissue and in cultured U251 glioma cells. Knocking down SMC1A expression in U251 cells with SMC1A-targeted interfering RNAs inhibited cell growth and induced G2/M cell cycle arrest. Furthermore, expression of the cell cycle associated gene CCNB1IP1 was dramatically increased, whereas expression of Cyclin B1 was decreased in SMC1A-deficienct U251 cells. These results suggest that SMC1A upregulation is involved in the pathogenesis of glioma.

PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance.
METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival.
RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis.
CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.

Protein ubiquitination is critical for many cellular processes, through its ability to regulate protein degradation and various signaling mechanisms. In the ubiquitin (Ub) system, substrate specificity is achieved through the E3 family of Ub ligases. Because alterations of the ubiquitination machinery have been reported in human cancers, the selective interference with Ub ligases might represent a powerful therapeutic tool. Here, we report the first wide survey of misregulation of Ub ligases in cancer. We analysed 82 Ub ligases in nine types of cancer by in situ hybridization on tissue microarrays. We found 27 instances in which an Ub ligase was altered in a given type of tumor, when compared with normal tissues: 21 cases of overexpression and 6 cases of underexpression. We further analysed selected Ub ligases in large cohorts of breast and non-small-cell lung carcinomas. In five, of six, of these extended analyses (HUWE1, CCNB1IP1, SIAH1 and SIAH2 in breast cancer and CCNB1IP1 in lung cancer), we found that the levels of Ub ligases correlated significantly with relevant prognostic factors, and with clinical outcome. Our findings show that the alteration of Ub ligases is a frequent event in cancer and identify candidate targets for molecular therapies.

The neurofibromatosis 2 (NF2) tumor suppressor protein merlin is commonly mutated in human benign brain tumors. The gene altered in NF2 was located on human chromosome 22q12 in 1993 and the encoded protein named merlin and schwannomin. Merlin has homology to ERM family proteins, ezrin, radixin, and moesin, within the protein 4.1 superfamily. In efforts to determine merlin function several groups have discovered 34 merlin interacting proteins, including ezrin, radixin, moesin, CD44, layilin, paxillin, actin, N-WASP, betaII-spectrin, microtubules, TRBP, eIF3c, PIKE, NHERF, MAP, RalGDS, RhoGDI, EG1/magicin, HEI10, HRS, syntenin, caspr/paranodin, DCC, NGB, CRM1/exportin, SCHIP1, MYPT-1-PP1delta, RIbeta, PKA, PAK (three types), calpain and Drosophila expanded. Many of the proteins that interact with the merlin N-terminal domain also bind ezrin, while other merlin interacting proteins do not bind other members of the ERM family. Merlin also interacts with itself. This review describes these proteins, their possible roles in NF2, and the resultant hypothesized merlin functions. Review of all of the merlin interacting proteins and functional consequences of losses of these interactions reveals multiple merlin actions in PI3-kinase, MAP kinase and small GTPase signaling pathways that might be targeted to inhibit the proliferation of NF2 tumors.

Melanomas of sporadic and familial origin develop in a stepwise fashion in approximately 40-80% of all cases; yet, the genetic events governing the progression from nevocytic precursor lesions to early and advanced-stage melanomas remain largely unknown. In the present study, we provide an analysis of genes that were identified in four recently generated primary and metastatic melanoma Serial Analysis of Gene Expression (SAGE) libraries. In addition to SAGE tags corresponding to transcripts with unknown function, or to unidentified transcripts, known genes were identified that hitherto have not been shown to be expressed or have a function in early and advanced-stage melanomas and/or melanoma precursor lesions. Conducting fluorescence imaging analysis with cyanine dye-conjugated antibodies and oligonucleotides, we established the expression pattern of ATM, HEI10, PKD1, KAI11, IL-10R, and hypothetical protein FLJ11151 in nevus and melanoma specimens.

Uterine leiomyoma, a benign smooth-muscle tumor of the myometrium, is the most commonly encountered neoplasm in women of reproductive age. Band q15 of chromosome 12 is often rearranged in benign mesenchymal tumors such as uterine leiomyomas, and the HMGIC gene, encoding a protein of the high-mobility-group (HMG), is present in that region. Using 3' rapid amplification of cDNA ends (3'RACE) experiments, we isolated an ectopic sequence that was fused to HMGIC in a uterine leiomyoma. Cloning of the fusion cDNA identified a gene termed rising dbl quote, left (low)homo sapiens enhancer of invasion 10" (HEI10) as the fusion partner. Radiation hybrid mapping revealed that the normal location of HEI10 is at 14q11. In the fusion transcript the first two exons of the HMGIC gene, which encode DNA-binding domains, were fused to the 3' portion of the HEI10 gene. This rearrangement implicates HMGIC in the tumorigenesis of uterine leiomyoma, and suggests that its fusion HMGIC product may play a role in mesenchymal differentiation.