Linking miRNA regulation to BCR-ABL expression: the next dimension

The introduction of tyrosine kinase inhibitors in the treatment of BCR-ABL1-rearranged malignancies has revolutionized therapy, but the prognosis for acute leukemias remains suboptimal. In this issue of Cancer Cell, Bueno et al. (2008) add a new dimension to the regulation of ABL1 expression. The authors demonstrate that ABL1 is a direct target of miR-203, miR-203 is silenced by genetic and epigenetic mechanisms in hematopoietic malignancies expressing either ABL1 or BCR-ABL1, and restoration of miR-203 expression reduces ABL1 and BCR-ABL1 levels and inhibits cell proliferation. These findings may have broad implications for mechanisms underlying malignant transformation in hematopoietic and other malignancies.     

ABNORMAL PROTEIN TYROSINE KINASES ASSOCIATED WITH HUMAN HAEMATOLOGICAL MALIGNANCIES

Protein tyrosine kinases (PTKs) catalyse the phosphorylation of tyrosine residues by transfer of a phosphate group from ATP. They form a family of over 100 enzymes that all participate in signal transduction pathwaysregulating cellular growth, activation and differentiation. PTKs fall into two groups: receptor (or transmembrane) PTKs and non-receptor (or intracellular) PTKs. Receptor PTKs provide transmembrane signals in response to ligand binding, often consequent to ligand-induced di…     

RETRACTED ARTICLE: miR-203 suppression in gastric carcinoma promotes Slug-mediated cancer metastasis

MicroRNAs (miRNAs) play critical roles in tumorigenesis and cancer metastasis. Recently, miR-203 was reported as a tumor suppressor microRNA silenced in different malignancies including hepatocellular carcinoma, prostate cancer, oral cancer, breast cancer, and hematopoietic malignancy, whereas its role in the carcinogenesis of gastric carcinoma (GC) has not been evaluated. Here, we analyzed the levels of miR-203 and Slug in the GC specimen and studied their correlation. We analyzed the binding of miR-203 to the 3′-UTR of Slug messenger RNA (mRNA) and its effects on Slug translation by bioinformatics analysis and by luciferase-reporter assay, respectively. We modified miR-203 levels in GC cells and studied their effects on the cell invasiveness in transwell cell migration assay. We found that in GC, miR-203 levels were significantly decreased and Slug levels were significantly increased. miR-203 and Slug inversely correlated in patients’ specimen. Bioinformatic analysis predicted that miR-203 may target the 3′-UTR of Slug mRNA to inhibit its translation, which was confirmed by luciferase-reporter assay. Overexpression of miR-203 inhibited Slug and cell invasiveness, while depletion of miR-203 increased Slug and cell invasiveness. These data suggest that miR-203 suppression in GC promotes Slug-mediated cancer metastasis.     

微小RNA在淋巴瘤凋亡调控中的研究进展

 【摘要】　微小RNA是一类高度保守的单链非编码RNA,通过对基因转录后水平的调节,在造血系统及肿瘤的发生发展中起到了重要作用。逃逸凋亡是肿瘤发生的一项重要机制,近年研究表明,许多微小RNA的异常表达通过调节靶基因的表达调控多条凋亡通路,促进（如miR-15a／16-1、miR-150）或者抑制（如miR-17～92簇、miR-21）细胞凋亡,从而发挥其功能上的癌基因或抑癌基因的活性。此外,微小RNA在淋巴瘤各亚型中的表达差异可能为淋巴瘤的分型及预后判断提供新的依据,并为淋巴瘤的治疗提供潜在的治疗靶点。     

ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors

The BCR-ABL oncogene is responsible for most cases of chronic myelogenous leukemia and some acute lymphoblastic leukemias. The fusion protein encoded by BCR-ABL possesses an aberrantly regulated tyrosine kinase activity. Imatinib mesylate (Gleevec, STI-571) is an inhibitor of ABL tyrosine kinase activity that has been remarkably effective in slowing disease progression in patients with chronic phase chronic myelogenous leukemia, but the emergence of imatinib resistance underscores the need for additional therapies. Targeting signaling pathways activated by BCR-ABL is a promising approach for drug development. The study of signaling components downstream of BCR-ABL and the related murine oncogene v-Abl has revealed a complex web of signals that promote cell division and survival. Of these, activation of phosphoinositide 3-kinase (PI3K) has emerged as one of the essential signaling mechanisms in ABL leukemogenesis. This review describes molecular mechanisms by which PI3K is activated and the downstream PI3K effectors that propagate the signal to promote myeloid and lymphoid transformation. Of particular recent interest is the mammalian target of rapamycin, a PI3K-regulated kinase that regulates protein synthesis and contributes to leukemogenesis.     

MicroRNA analysis of microdissected normal squamous esophageal epithelium and tumor cells

Previous studies have identified several dysregulated microRNAs in esophageal squamous cell carcinoma (ESCC); however, to date there are no ex vivo analyses comparing expression levels of these regulatory molecules in esophageal squamous cell tumors versus patient-matched normal epithelium. We describe here a technical strategy to evaluate microRNAs in normal esophageal basal cells (NB), normal esophageal differentiated cells (ND), and tumor cells (T). Laser capture microdissection was used to procure target populations from five cases and 18 ESCC-associated microRNAs were measured by RT-qPCR. Five microRNAs (miR-25, miR-106b, miR-21, miR-203, and miR-145) demonstrated consistent differential expression in at least one of the three comparisons: T vs. NB, T vs. ND, or NB vs. ND. The potential regulatory role of the microRNAs in ESCC was further evaluated by correlating their expression with a matched mRNA dataset, which included the same five cases and cell populations. In conclusion, the present work demonstrates the feasibility of studying microRNA levels in precisely dissected cell populations from clinical samples, and sheds light on the molecular mechanisms associated with ESCC.     

MicroRNA-203 suppresses cell proliferation and migration by targeting BIRC5 and LASP1 in human triple-negative breast cancer cells

Background

This study was performed to investigate the effect of microRNA-203 (miR-203) on cell proliferation and migration in triple-negative breast cancer (TNBC).

Methods

Real-time PCR was performed to detect the expression of miR-203 in TNBC cell lines. miR-203 precursor and control microRNA (miRNA) were transfected into triple-negative breast cancer (TNBC) cell lines and the effects of miR-203 up-regulation on the proliferation and migration of cells were investigated. Meanwhile, the mRNA and protein levels of baculoviral IAP repeat-containing protein 5 (BIRC5) and Lim and SH3 domain protein 1 (LASP1) were measured. Luciferase assays were also performed to validate BIRC5 and LASP1 as miR-203 targets.

Results

Both miR-203 and BIRC5 siRNA signicantly inhibited cell proliferation in TNBC cells. Both miR-203 and LASP1 siRNA signicantly inhibited cell migration in TNBC cells, also. Moreover, up-regulated of BIRC5 and LASP1 was able to abrogate the effects induced by transfection with the miR-203 precursor.

Conclusions

These data suggest that miR-203 may function as a tumor suppressor in TNBC cells. Thus, miR-203 could be a potential therapeutic target for this disease.     

AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications

The abnormal BCR-ABL oncoprotein is a constitutively active tyrosine kinase driving aberrant proliferation of transformed hematopoietic cells. BCR-ABL regulates activation of many mitogenic and pro-survival pathways, including the PI 3'K/AKT/mTOR pathway that controls various effectors and regulates initiation of mRNA translation in mammalian cells. Although tyrosine kinase inhibitors (TKIs) that target the ABL kinase domain have remarkable clinical activity and have dramatically changed the natural history of Ph+ leukemias, resistance to these agents also develops via a wide range of mechanisms. Efforts to target the PI3'K/AKT/mTOR signaling pathway using kinase inhibitors have been the focus of extensive ongoing investigations by several research groups. Here we review the effects of activation of the AMPK kinase, which regulates downstream targeting and inhibition of mTOR. The potential for future clinical-translational applications of AMPK activators such as AICAR, metformin and resveratrol for the treatment of chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) are discussed.     

MicroRNA-31 suppresses medulloblastoma cell growth by inhibiting DNA replication through minichromosome maintenance 2

Medulloblastoma is an aggressive childhood brain tumor with poor prognosis. Recent studies indicate that dys-regulation of microRNA expression plays important roles in tumorigenesis. By comparing microRNA levels between mouse medulloblastoma and normal cerebellar tissues, we identified a set of down-regulated microRNAs including miR-31. Here, we show that the genomic region surrounding human miR-31 at 9p21.3 is frequently deleted in many solid tumor cell lines, and reintroducing miR-31 into DAOY cells, a line of human medulloblastoma cells devoid of miR-31, strongly suppresses cell growth, causes cell cycle arrest at the G1/S boundary, and inhibits colony formation in vitro and xenograft tumorigenesis in nude mice. Global gene expression profiling of mouse medulloblastomas and bioinformatics analyses of microRNA targets suggest that minichromosome maintenance complex component 2 (MCM2) is a likely target gene of miR-31 in suppressing cell growth. We demonstrate that miR-31 inhibits MCM2 expression via its 3''-untranslated region, that knockdown of MCM2 in DAOY cells leads to a degree of growth inhibition comparable to that by miR-31 restoration, and that overexpression of miR-31 reduces the chromatin loading of MCM2 at the point of G1/S transition. Taken together, these data indicate that miR-31 suppresses medulloblastoma tumorigenesis by negatively regulating DNA replication via MCM2.     

MicroRNA-19 and neoplasms

The miR-17-92 cluster, consisting of six individual microRNAs, including miR-17, miR-20a,miR-18a, miR-19a, miR-19b and miR-92a-1, is a kind of typical oncogenic polycistron microRNA. MiR-19 (containing miR-19a and miR-19b), as the key oncogenic component in miR-17-92 cluster, is overexpressed in human cancers including lymphomas, leukaemia, lung cancer, breast cancer and multiple myeloma, and has been one of research focus in recent years. It is found that miR-19 promotes tumor growth,invasion and metastasis through negative regulation of target genes such as PTEN, PP2A, Bim,SOCS1, and is correlated strongly with PI3K-AKT-mTOR pathway. MiR-19 plays an important role in tumor genesis and development.     

ING1b-inducible microRNA203 inhibits cell proliferation

Background:

The ING family of type II tumour suppressors serve as both epigenetic ‘readers'' and target histone acetyl transferase (HAT) and histone deacetylase (HDAC) ‘writers'' of the epigenetic histone code. The ING1 protein has also been implicated in regulating microRNA (miRNA) levels. In this study, we identify a link between ING1b and the miRNA epigenetic network.

Methods:

Primary fibroblasts infected with adenoviruses expressing GFP control or GFP plus ING1b were examined for alterations in miRNA profiles using a miRNA PCR array. Additional experiments confirmed specificity and consequences of altered miRNA expression.

Results:

MicroRNAs miR-203, miR-375, miR-449b and miR-200c were increased by ING1b overexpression. Ectopic expression of miR-203 inhibited U2OS and MDA-MB-231 cancer cell growth, and induced G1 cell cycle arrest in U2OS cells as estimated by flow cytometry. Transfection with miR-203 inhibitor reversed the proliferation inhibition induced by ING1b in U2OS cells. CHIP assays showed that ING1b bound to the promoter of miR-203. Western blot analyses showed that CDK6, c-Abl and Src were downregulated by the transfection of miR-203.

Conclusion:

These results indicate that ING1b epigenetically regulates several miRNAs including miR-203. The several-fold increase in miR-203 by ING1b might inhibit cancer cell proliferation through coordinate downregulation of CDK6, c-Abl and Src.     

miR-19与肿瘤

 miR-17~92基因簇编码6种成熟的miRNA,包括miR-17、miR-20a、miR-18a、miR-19a、miR-19b和miR-92a-1,是一类典型的致癌多作用子miRNA。miR-19（包括miR-19a和miR-19b）是其中最重要的致癌miRNA,在淋巴瘤、白血病、肺癌、乳腺癌、多发性骨髓瘤等肿瘤中均表达上调,成为研究的热点之一。miR-19可通过抑制靶基因如PTEN、PP2A、Bim、SOCS1等促进肿瘤的增殖、侵袭和转移,与PI3K-AKT-mTOR信号转导通路关系密切,在肿瘤的发生发展中起着非常重要的作用。