MiR-145, a new regulator of the DNA Fragmentation Factor-45 (DFF45)-mediated apoptotic network

Zhang, Jianjun; Guo, Haiyan; Qian, Guofeng; Ge, Shengfang; Hui-feng, JI; Hu, Xiaobo; Chen, Wantao

doi:10.1186/1476-4598-9-211

Cited by 68 publications

(53 citation statements)

References 39 publications

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“…Accordingly, miR-145 suppressed tumor cell growth, cell apoptosis and survival by targeting Fli1 23 IRS1, 15 c-Myc 24 and DFF45. 25 Additionally, miR-145 impacted tumor migration, invasion and metastasis by targeting mucin1, 26 p70S6K1 14 and NUDT1. 16 Furthermore, it also affected p53-mediated cell cycle arrest by targeting p21.…”

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confidence: 99%

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Zhu

Xie

et al. 2014

Intl Journal of Cancer

104

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Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Because of the absence of early symptoms, most patients are diagnosed at an advanced stage. Chemotherapy is one of the most frequently used treatment modalities for advanced-stage ovarian cancer patients. Although initial responsiveness to first-line chemotherapy consisting of a platinum-containing compound in combination with paclitaxel (PTX) is high, up to 80% of patients eventually relapse and become platinum/taxane resistant. Therefore, a better understanding of the mechanisms involved in MDR ovarian cancer and more effective therapeutic approaches are immediately required.1 Multiple mechanisms that mediate intrinsic or acquired resistance to paclitaxel have been identified. A major contributor to resistance is the active export of drugs by transmembrane polysubstrate efflux pumps that prevent drugs from reaching their intracellular targets, and a highly studied member of this family is multidrug resistance-1 (MDR1). MDR1 encodes for the membrane transporter P-glycoprotein (P-gp), whose substrates included a wide array of toxins and commonly used chemotherapeutic agents, including taxanes and anthracyclines. 2 Cell cycle dysregulation is another common molecular finding in ovarian cancer, and the cyclin-dependent kinases (Cdks) represent attractive targets in this pathway. For example, inhibition of Cdk6, one of the powerful cell cycle progression regulators, showed encouraging effects in animal experiments and clinical trials. MicroRNAs (miRNAs) are small, noncoding RNA molecules that negatively regulate a large number of proteinencoding genes via either mRNA degradation or translational silencing. Evidence is emerging for roles of miRNAs in modulating drug sensitivity/resistance of cells, 4,5 specifically for one class of miRNAs that target survival pathways or pathways that regulate apoptosis sensitivity, such ...

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confidence: 99%

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Zhu

Xie

et al. 2014

Intl Journal of Cancer

104

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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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“…DNA fragmentation factor 45 is a caspase-3 or caspase-7 substrate that must be cleaved before apoptotic DNA fragmentation can proceed. DNA fragmentation factor 45 forms a heterodimer with DFF40, a 40 kDa endonuclease, and acts both as its specific inhibitor and as a chaperone in its appropriate folding [7,8]. When caspase-3 is activated by apoptotic stimuli, it cleaves DFF45 at two sites, which causes the release and activation of DFF40, leading to the generation of double-stranded breaks in internucleosomal chromatin regions and chromatin condensation [11].…”

Section: Discussionmentioning

confidence: 99%

“…DNA fragmentation factor-45 (DFF45) is the substrate of caspase-3, a key point effector molecule in apoptosis, and thus has an important role in apoptotic DNA fragmentation, which contributes to malignant transformation and metastasis [7,8]. Recent clinical studies have convincingly linked DFF45 with tumor progression and poor clinical outcomes in many cancer types, including neuroblastoma, esophageal carcinoma, ovarian endometriomas [9][10][11], and endometrial and ovarian carcinoma [10,[12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological significance of DNA fragmentation factor 45 and thyroid transcription factor 1 expression in benign and malignant lesions of the gallbladder

Yuan

Yang²,

Zou³

et al. 2013

pjp

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Gallbladder cancer (GBC) is one of the most aggressive tumors; we examined the expression level of DNA fragmentation factor 45 (DFF45) and thyroid transcription factor 1 (TTF-1) in benign and malignant lesions of the gallbladder by immunohistochemistry. The results were correlated with clinicopathological features and prognosis. DNA fragmentation factor 45 and TTF-1 expression was significantly higher in gallbladder adenocarcinomas than in the corresponding peritumoral tissues (χ 2 DFF45 = 6.92, χ 2 TTF-1 = 8.68, ps < 0.01), polyps (χ 2 DFF45 = 4.49, χ 2 TTF-1 = 5.35, ps < 0.05), and chronic cholecystitis (χ 2 DFF45 = 12.98, χ 2 TTF-1 = 17.74, ps < 0.01). Negative expression of DFF45 and TTF-1 was significantly associated with tumor differentiation, tumor mass, lymph node metastasis and invasion of adenocarcinomas (p < 0.05). Univariate Kaplan-Meier analysis showed that elevated expression levels of DFF45 and TTF-1 (p < 0.05) were closely associated with increased overall survival. In addition, the average survival time of patients with DFF45(+) TTF-1(+) tumors was significantly higher than those with DFF45(-) TTF-1(-) tumors (p < 0.05). Finally, multivariate Cox regression analysis showed that negative expression of DFF45 and TTF-1 was an independent prognostic predictor in gallbladder adenocarcinoma (p < 0.05). The expression of DFF45 and/or TTF-1 is closely related to the carcinogenesis, progression, clinical behavior and prognosis of gallbladder adenocarcinomas. DNA fragmentation factor 45 and TTF-1 could be progression-associated genes correlating with good prognosis in GBC.

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MiR-145, a new regulator of the DNA Fragmentation Factor-45 (DFF45)-mediated apoptotic network

Cited by 68 publications

References 39 publications

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

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

Clinicopathological significance of DNA fragmentation factor 45 and thyroid transcription factor 1 expression in benign and malignant lesions of the gallbladder

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