Decreased Levels of miR-224 and the Passenger Strand of miR-221 Increase MBD2, Suppressing Maspin and Promoting Colorectal Tumor Growth and Metastasis in Mice

Yuan, Kefei; Xie, Ke; Fox, John; Zeng, Huawei; Gao, Hongwei; Huang, Canhua; Wu, Min

doi:10.1053/j.gastro.2013.06.008

Cited by 81 publications

(78 citation statements)

References 29 publications

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“…Chromatin IP assay was carried out as described previously. 31 Immunoprecipitated DNA was quantitated by real-time quantitative PCR. Primer sets were chosen to amplify approximately 100 to 150 base pairs on the promoter of SOCS3.…”

Section: Discussionmentioning

confidence: 99%

HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3

Yuan

et al. 2016

Cell Death Differ

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Interleukin-6 (IL-6) has been demonstrated to be involved in Hepatitis B virus (HBV)-associated hepatocarcinogenesis through activation of the STAT3 pathway. The sustained activation of the IL-6/STAT3 pathway is frequently associated with repression of SOCS3, which is both a target gene and a negative regulator of STAT3. However, the silencing mechanism of SOCS3 in hepatocellular carcinoma (HCC) remains to be elucidated. Here, we showed that the repression of SOCS3 and sustained activation of IL-6/STAT3 pathway in HBV-producing HCC cells were caused by HBV-induced mitochondrial ROS accumulation. Mechanistic studies revealed that ROS-mediated DNA methylation resulted in the silencing of SOCS3. Decreased SOCS3 expression significantly promoted the proliferation of HCC cells and growth of tumor xenografts in mice. Further studies revealed that HBVinduced ROS accumulation upregulated the expression of the transcription factor, Snail, which bound to the E-boxes of SOCS3 promoter and mediated the epigenetic silencing of SOCS3 in association with DNMT1 and HDAC1. In addition, we found that the expression of Snail and SOCS3 were inversely correlated in HBV-associated HCC patients, suggesting that SOCS3 and/or Snail could be used as prognostic markers in HCC pathogenesis. Taken together, our data show that HBV-induced mitochondrial ROS production represses SOCS3 expression through Snail-mediated epigenetic silencing, leading to the sustained activation of IL-6/STAT3 pathway and ultimately contributing to hepatocarcinogenesis. Cell Death and Differentiation (2016) 23, 616-627; doi:10.1038/cdd.2015.129; published online 22 January 2016 Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer death in the world.1 Chronic HBV infection and chronic liver disease that progress from hepatitis to cirrhosis are major risk factors for the development of HCC. Options for the treatment of HCC are quite limited because the molecular, cellular and environmental mechanisms that drive HBV-associated HCC pathogenesis are poorly understood.Pro-inflammatory cytokines contribute significantly to the pathogenesis of many tumor types.2 Among them, elevated IL-6 is closely related to HCC development and progression.3 Elevated IL-6 was found in patients with viral and alcoholic hepatitis and liver cirrhosis. In these conditions, IL-6 is expressed mainly by myeloid cells/leukocytes. 4 Recent studies have confirmed that upregulation of IL-6 in human HCC, where it is expressed by the cancer cells, also has a central role in a gene expression network via an autocrine signaling pathway that drives tumor development and progression.5 However, it remains unknown whether IL-6 autocrine signaling can be stimulated by HBV during hepatocarcinogensis.Reactive oxygen species (ROS) are continuously generated by cells to regulate cellular responses such as proliferation, differentiation and apoptosis. 6 Chronic virus infection may enhance ROS production and cause oxidative stress in host cells.7 Continued oxidative...

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Section: Discussionmentioning

confidence: 99%

HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3

Yuan

et al. 2016

Cell Death Differ

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“…The role of miR-224 during CRC initiation and progression remains controversial [15, 16, 17, 18, 19, 20, 21]: MiR-224 is overexpressed in inflammatory bowel disease-associated CRC [21], it promotes CRC tumor growth in mice by repressing PHLPP1 and PHLPP2 [19], and ectopic miR-224 expression decreases the chemoradiosensitivity of CRC [22], all of which suggests an oncogenic function. Yet, reports that methotrexate-resistant colon cancer cells express lower miR-224 [23], and that miR-224 suppresses tumor growth and metastasis in vivo [20] suggest that an opposite role in CRC may be true.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, reports that methotrexate-resistant colon cancer cells express lower miR-224 [23], and that miR-224 suppresses tumor growth and metastasis in vivo [20] suggest that an opposite role in CRC may be true. The latter study also showed lower miR-224 expression in metastatic CRC cell lines versus non-metastatic cell lines, and in metastatic tumors in the lung versus primary CRC tumors [20]. …”

Section: Discussionmentioning

confidence: 99%

The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis

Ling

Pickard

Ivan

et al. 2015

Gut

120

106

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Objective MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis. Design We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by qRT-PCR. We tested metastatic activity of selected miRNAs, and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analyzed in six sets of CRC cases (n=449) including The Cancer Genome Atlas consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression. Results MiR-224 expression increases consistently with tumor burden and microsatellite stable (MSS) status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target, and observed negative correlation (Spearman Rs=−0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037 respectively), and shorter metastasis-free survival (hazard ratio 6.51, 95% CI 1.97-21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (hazard ratio 4.12, 95% CI 1.1-15.41, p=0.0175). Conclusion MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for CRC patient survival.

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“…Of note, extensive deep RNA sequencing in failing human hearts identified miR-21* to be expressed in the human heart and increased during heart failure (41). Others have shown functional roles for star miRNAs also in other pathologies, such as colorectal and prostate cancer or obesity/metabolic syndrome (42)(43)(44). RNA deep sequencing studies in Drosophila melanogaster identified that a large number of miRNA* sequences are not degraded but are able to bind to Ago2-RISC complexes (45)(46)(47).…”

Section: Methodsmentioning

confidence: 99%

Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy

et al. 2014

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In response to stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and pathological growth of cardiomyocytes (hypertrophy), which contribute to heart failure. Alterations in microRNA (miRNA) levels are associated with dysfunctional gene expression profiles associated with many cardiovascular disease conditions; however, miRNAs have emerged recently as paracrine signaling mediators. Thus, we investigated a potential paracrine miRNA crosstalk between cardiac fibroblasts and cardiomyocytes and found that cardiac fibroblasts secrete miRNA-enriched exosomes. Surprisingly, evaluation of the miRNA content of cardiac fibroblast-derived exosomes revealed a relatively high abundance of many miRNA passenger strands ("star" miRNAs), which normally undergo intracellular degradation. Using confocal imaging and coculture assays, we identified fibroblast exosomal-derived miR-21_3p (miR-21*) as a potent paracrineacting RNA molecule that induces cardiomyocyte hypertrophy. Proteome profiling identified sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) as miR-21* targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of miR-21* in a mouse model of Ang II-induced cardiac hypertrophy attenuated pathology. These findings demonstrate that cardiac fibroblasts secrete star miRNA-enriched exosomes and identify fibroblast-derived miR-21* as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target.

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Decreased Levels of miR-224 and the Passenger Strand of miR-221 Increase MBD2, Suppressing Maspin and Promoting Colorectal Tumor Growth and Metastasis in Mice

Cited by 81 publications

References 29 publications

HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3

HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3

The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis

Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy

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