Role of anti-oncomirs miR-143 and -145 in human colorectal tumors

Akao, Yukihiro; Nakagawa, Yoshihito; Hirata, Ichiro; Iio, Akio; Itoh, Tomohiro; Kojima, Keitaro; Nakashima, Remi; Kitade, Yukio; Naoe, Tomoki

doi:10.1038/cgt.2009.88

Cited by 236 publications

(188 citation statements)

References 25 publications

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“…Overexpression microRNA-143 regulates MLL-AF4 oncogene expression L Dou et al of miRNAs can result in downregulation of tumor suppressor genes, whereas their decreased expression can lead to oncogene upregulation. Expression of miR-143 was previously shown to be reduced in colon cancer and various cancer cell lines (Akao et al, 2007;Akao et al, 2010). In this study, miR-143 was significantly downregulated in samples from MLL-AF4 B-cell ALL patients compared with healthy individuals.…”

Section: Discussionmentioning

confidence: 48%

Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

Dou

Zheng

et al. 2011

Oncogene

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Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL-AF4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11)-positive ALL patients (MLL-AF4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3 0 untranslated regions may modulate MLL-AF4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL-AF4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL-AF4 expression in MLL-AF4 ALL samples. Restoration of miR-143 in MLL-AF4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL-AF4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL-AF4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL-AF4-negative primary blasts, which was directly associated with expression of the MLL-AF4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL-AF4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL-AF4 B-cell ALL.

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Section: Discussionmentioning

confidence: 48%

Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

Dou

Zheng

et al. 2011

Oncogene

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“…1B). MiR-145, as a positive control, was known to have potent antiproliferative activity in colorectal cancer (21)(22)(23). miR-124, miR-137 or miR-145 inhibited the growth of HCT116 cells.…”

Section: Growth Inhibition Of Colorectal Cancer Cells By Mir-124 Mirmentioning

confidence: 99%

miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect

et al. 2012

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Abstract. Colorectal cancer represents one of the most challenging diseases. Increasing evidence indicates that aberrant expression of microRNAs (miRNAs) is related to pathogenesis of colorectal cancer. Cancer cells reprogram metabolic pathways to sustain higher proliferation rates. Whether mechanisms underlying the role of miRNA in colorectal cancer are involved in metabolic reprogramming and the mechanisms through which miRNAs alter cancer metabolism are as yet unknown. Herein, we show that miR-124, miR-137 and miR-340 are associated with poor prognosis of colorectal cancer. Expression of these miRNAs inhibits the growth of colorectal cancer cells. PKM (pyruvate kinase isozyme) alternative splicing proteins (PTB1/ hnRNAPA1/hnRNAPA2), which control the inclusion of exon 9 (PKM1) or exon 10 (PKM2), are targeted by miR-124, miR-137 and miR-340. Consequently, miR-124, miR-137 and miR-340 switch PKM gene expression from PKM2 to PKM1. High ratios of PKM1/PKM2 inhibit the glycolysis rate, but elevate the glucose flux into oxidative phosphorylation. These results demonstrate that miRNAs (miR-124, miR-137 and miR-340) impair colorectal cancer growth by counteracting the Warburg effect due to regulating alternative splicing of the PKM gene. IntroductionColorectal cancer (CRC) is the third most common type of cancer. About 608,700 deaths from CRC occurred in 2008, accounting for 8% of all cancer deaths (1). About 30% of recurrent CRC patients have liver metastasis, and >70% of them are not candidates for curative resection (2). In the past few years, accumulating evidence has suggested that microRNAs (miRNAs) are involved in the pathogenesis of CRC (3). The pattern of miRNA expression is related with cancer type, stage and other clinical variables, which makes miRNA a promising prognostic and therapeutic tool (4,5).In order to support high rates of proliferation, cancer cells consume additional nutrients and divert those nutrients into macromolecular synthesis pathways. Cancer cells prefer to metabolize glucose by glycolysis, intentionally avoid oxidative phosphorylation even when oxygen is abundant -the Warburg effect (6). Therefore, many cancer cells are characterized with increased lactate production and decreased O 2 consumption (7). Active glycolysis coupled with increased glucose intake will provide sufficient intermediate metabolites, such as NADPH, acetyl-CoA and ribose, for biosynthetic process (8,9).Pyruvate kinase (PK), which converts phosphoenolpyruvate into pyruvate, is one of rate-limiting enzymes in glycolytic pathway. PKM is alternatively spliced to either M1 (PKM1) or M2 (PKM2) isoform, which contains exon 9 or exon 10, respectively (10,11). The single exon difference endows the enzymes with distinct expression patterns and functions. PKM2 is exclusively expressed in embryonic, proliferating and cancer cells, which promotes glycolysis even in an aerobic environment. PKM1 is expressed in normal differentiated tissues, which promotes oxidative phosphorylation (12,13). The expression PKM2 is critical for ca...

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“…The ectopic expression of miR-145 in such cells exhibits a growth inhibitory effect [1,18]. In human malignant melanoma (HMM), it is suggested that a higher expression level of miR-145 is associates with longer survival after recurrence [19].…”

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confidence: 99%

Comparative Study of Anti-Oncogenic MicroRNA-145 in Canine and Human Malignant Melanoma

et al. 2012

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ABSTRACT. is aberrantly expressed in most of human cancers and plays a significant role in carcinogenesis and cancer progression. In the current study, we focused on how miR-145 plays a role in canine and human malignant melanomas. MiR-145 was significantly downregulated in canine malignant melanoma tissues and canine melanoma cell lines, as well as human melanoma cell lines tested. The ectopic expression of miR-145 showed a significant growth inhibition in both canine and human melanoma cells tested, and the effect was achieved partly by suppressing c-MYC in canine melanoma LMeC and in human melanoma A2058 and Mewo cells. At the same time, a suppressive tendency on cell migration in canine melanoma KMeC cells and significant suppression of cell migration in human melanoma A2058 cells by suppressing FASCIN1 were also found. These findings suggest that miR-145 acts as a tumor suppressor in both canine and human malignant melanomas.

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Role of anti-oncomirs miR-143 and -145 in human colorectal tumors

Cited by 236 publications

References 25 publications

Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect

Comparative Study of Anti-Oncogenic MicroRNA-145 in Canine and Human Malignant Melanoma

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