MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function. DICER1 | expression profile | multiple myeloma | risk stratification | system biology M icroRNAs (miRNAs) belong to a class of noncoding small RNAs with mature sequences that contain ≈22 nucleotides (1). As repressors of gene expression, miRNAs can bind to the 3′ untranslated region (3′UTR) of an mRNA and inhibit its translation or induce its degradation (1).Dysregulation of miRNA is involved in cancer initiation and progression (2, 3), and miRNA expression profiles have prognostic implications (4-6). Inhibiting miRNA has proved effective in vivo (7) and therefore could be a novel therapeutic strategy for cancer (8, 9). To date, few studies have investigated the roles of miRNA in multiple myeloma (MM), a plasma cell dyscrasia that homes to and expands in the bone marrow and produces disease manifestations that include osteolytic bone destruction with hypercalcemia, anemia, immunosuppression, and end-organ damage (10). Several miRNAs have been implicated in survival and growth of myeloma cells and myeloma tumor growth. For instance, miR-21 is a target of Stat3 and thus a critical component in IL-6/Stat3-dependent survival and growth pathways of myeloma cells (11). In addition, IL-6 inhibitor SOCS1 and p53 pathway component p300-CBPassociated factor are targets of multiple miRNAs, including miR-106b-25 cluster, miR-32, miR-181a/b, and miR-19a/b (12); suppression of these miRNAs inhibited myeloma tumor growth in nude mice (12).Applying miRNA expression profiles, Pichiorri et al. (12) identified miRNAs that were differentially expressed in plasma cells of healthy donors, subjects with a benign precursor to MM (monoclonal gammopathy of undetermined significance), and patients with MM. In other miRNA expression profiling studies, Roccaro et al. (13) To further investigate the potential involvement o...
Long non-coding RNAs (lncRNAs) can serve as blood-based biomarkers for cancer detection. To identify novel lncRNA biomarkers for gastric cancer (GC), we conducted, for the first time, genome-wide lncRNA screening analysis in two sets of samples: five paired preoperative and postoperative day 14 plasma samples from GC patients, and tissue samples from tumor and adjacent normal tissues. Candidate tumor-related lncRNAs were then quantitated and evaluated in three independent phases comprising 321 participants. The expression levels of lncRNAs were also measured in GC cell lines and the corresponding culture medium. Biomarker panels, lncRNA-based Index I and carcinoembryonic antigen (CEA)-based Index II, were constructed using logistic regression, and their diagnostic performance compared. Fagan's nomogram was plotted to facilitate clinical application. As a result, we identified five novel plasma lncRNAs (TINCR, CCAT2, AOC4P, BANCR and LINC00857), which, when combined in the lncRNA-based Index I, outperformed the CEA-based Index II (P < 0.001) and could distinguish GC patients from healthy controls with an area under the receiver-operating curve (AUC) of 0.91 (95% confidence interval (CI): 0.88-0.95). The lncRNA-based index decreased significantly by postoperative day 14 (P = 0.016), indicating its ability to monitor tumor dynamics. High values of the lncRNA-based index were correlated with tumor size (P = 0.036), depth of invasion (P = 0.025), lymphatic metastasis (P = 0.012) and more advanced tumor stages (P = 0.003). The lncRNA-based index was also able to discriminate GC patients from precancerous individuals and patients with gastrointestinal stromal tumor with AUC values of 0.82 (95% CI: 0.71-0.92) and 0.80 (95% CI: 0.68-0.91), respectively. Taken together, our findings demonstrate that this panel of five plasma lncRNAs could serve as a set of novel diagnostic biomarkers for GC detection.
Overexpression of CKS1B, a gene mapping within a minimally amplified region between 153 to 154 Mb of chromosome 1q21, is linked to a poor prognosis in multiple myeloma (MM). CKS1B binds to and activates cyclin-dependent kinases and also interacts with SKP2 to promote the ubiquitination and proteasomal degradation of p27 Kip1 . Overexpression of CKS1B or SKP2 contributes to increased p27 Kip1 turnover, cell proliferation, and a poor prognosis in many tumor types. Using 4 MM cell lines harboring MAF-, FGFR3/MMSET-, or CCND1-activating translocations, we show that lentiviral delivery of shRNA directed against CKS1B resulted in ablation of CKS1B mRNA and protein with concomitant stabilization of p27 Kip1 , cell cycle arrest, and apoptosis. Although shRNA-mediated knockdown of SKP2 and forced expression of a nondegradable form of p27 Kip1 (p27 T187A ) led to cell cycle arrest, apoptosis was modest. Of importance, while knockdown of SKP2 or overexpression of p27 T187A induced cell cycle arrest in KMS28PE, an MM cell line with biallelic deletion of CDKN1B/p27 Kip1 , CKS1B ablation induced strong apoptosis. These data suggest that CKS1B influences myeloma cell growth and survival through SKP2-and p27 Kip1 -dependent and -independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking. IntroductionThe molecular lesions causing myeloma initiation and progression are not completely understood. We have previously shown that overexpression of genes mapping to 1q are highly correlated with increased risk of early death in patients diagnosed with multiple myeloma (MM). 1 Gains of the q arm of chromosome 1 are one of the most common genetic abnormalities in MM, 2 and we and others have shown that tandem duplications and jumping segmental duplications of the chromosome 1q band, resulting from decondensation of pericentromeric heterochromatin, are frequently associated with disease progression. [3][4][5] Using a combination of arraybased comparative genomic hybridization (aCGH) and microarray data on cells isolated from newly diagnosed disease, we recently produced a high-resolution map of recurrent gains and losses of DNA in MM. 6 Using unsupervised clustering and nonnegative matrix factorization of the aCGH data, we found that hyperdiploid disease could be segregated into 2 groups, one exhibiting trisomies of the odd-number chromosomes and another also exhibiting gains of chromosomes 1q and 7, deletion of chromosome 13, and the absence of trisomy 11. 6 This method also identified 2 nonhyperdiploid subtypes: one characterized by high-level amplification of 1q21 and 1q22 and deletions of chromosome 1p and chromosome 13, and another characterized by an absence of chromosome 1 abnormalities but harboring deletions of chromosomes 8 and 13. 6 Using interphase fluorescence in situ hybridization (FISH) analysis, we recently showed that while monoclonal gammopathy of undetermined significance (MGUS) l...
Eph receptor tyrosine kinases and their ephrin ligands are involved in various signalling pathways and mediate critical steps of a wide variety of physiological and pathological processes. Increasing experimental evidence demonstrates that both Eph receptor and ephrin ligands are overexpressed in a number of human tumours, and are associated with tumour growth, invasiveness and metastasis. In this regard, the Eph/ephrin system provides the foundation for potentially exciting new targets for anticancer therapies for Eph-expressing tumours. The purpose of this review is to outline current advances in the role of Eph receptors and ephrin ligands in cancer, and to discuss novel therapeutic approaches of anticancer therapies.
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