Altered p53 regulation of miR-148b and p55PIK contributes to tumor progression in colorectal cancer

Wang, G; Cao, Xiaoyan; Lai, Senyan; Luo, Xuelai; Feng, Yechen; Wu, Jingjing; Ning, Qin; Xia, Xi; Wang, J; Gong, Jianping; Hu, Junbo

doi:10.1038/onc.2014.30

Cited by 33 publications

(33 citation statements)

References 27 publications

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“…For example, miR‐148b is a tumour suppressor of colorectal cancer through targeting the cholecystokinin‐2 receptor gene (Song et al ., ) and coordinates breast cancer progression by targeting integrin signalling molecules such as ITGA5, ROCK1, PIK3CA and NRAS (Cimino et al ., ). MiR‐148b also targets the isoform of phosphatidylinosotol 3‐kinase (p55PIK), which plays important roles in regulating cell cycle, thus miR‐148b overexpression abolishes p55PIK stimulation of cell cycle progression in colorectal cancer cell lines and suppresses tumour growth in vivo (Wang et al ., ). In addition, miR‐148b can act as a fine tuner in regulating the antigen‐presenting capacity of dendritic cells by targeting calcium/calmodulin dependent protein kinase II (Liu et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Sung

et al. 2016

J Tissue Eng Regen Med

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Repairing large calvarial bone defects remains a challenging task. Previously, it was discovered that that miR-148b, when acting in concert with bone morphogenetic protein 2 (BMP-2), enhanced the osteogenesis of human adipose-derived stem cells (hASCs) and improved calvarial bone healing in nude mice. However, the molecular target of miR-148b remained elusive. Here it is revealed that miR-148b directly targets NOG, whose gene product (noggin) is an antagonist to BMPs and negatively regulates BMP-induced osteogenic differentiation and bone formation. A new Cre/loxP-based baculovirus system was employed to drive prolonged BMP-2 and miR-148b overexpression in hASCs, wherein the BMP-2 overexpression induced noggin expression but the concurrent miR-148b expression downregulated noggin, thus relieving the negative regulatory loop and ameliorating hASC osteogenesis without hindering hASC proliferation or triggering appreciable cytotoxicity. Implantation of the engineered hASCs coexpressing BMP-2 and miR-148b into nude mice enabled substantial repair of critical-size calvarial bone defects (4 mm diameter) at 12 weeks post-transplantation, filling 83% of the defect area, 75% of bone volume and restoring the bone density to 89% of the original bone density. Such superior healing effects indicate the potential of the Cre/loxP-based baculovirus-mediated BMP-2/miR-148b expression for calvarial bone repair. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 97%

Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Sung

et al. 2016

J Tissue Eng Regen Med

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“…Three different isoforms of the regulatory subunit, p85a, p85b, and p55g, are encoded by PIK3R1, PIK3R2, and PIK3R3, respectively (31). Although the oncogenic role of p55g has been established in several cancers (33)(34)(35), understanding of its expression and regulation mechanism in cervical cancer is limited.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway

Mei

Zhang

et al. 2017

Clinical Cancer Research

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Purpose: Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented.Experimental Design: The loss of heterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-PCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analyses were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation-specific PCR. The tumorsuppressing effects of miR-181a2/181b2 were determined in vitro and in vivo. The target gene and signaling pathway that mediated the function of miR-181a2/181b2 were also identified.Results: Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Underexpression of miR-181a2/ 181b2 was detected in 46% of cervical cancer and was induced by the LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro. They also effectively impeded tumor formation and growth in vivo. miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55g) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway.Conclusions: We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the underexpression of miR-181a2/181b2, leading to the elevated activation of the PI3K pathway.

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“…Once loaded onto the Argonaute protein, the mature miRNAs bind to the 3= untranslated region (UTR) of mRNAs through a highly conserved seed sequence (nucleotides 2 to 8), thereby inhibiting translation or enhancing degradation of the mRNA molecules (31). Cellular miRNAs regulate many processes, including cell survival and proliferation, in part by mediating the actions of tumor suppressors and signaling pathways (33); for example, p53 and ATM activation has been shown to impact specific miRNAs (34)(35)(36). As a result, aberrant patterns of expression of particular miRNAs are associated with specific cancers (33).…”

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confidence: 99%

Epstein-Barr Virus EBNA1 Protein Regulates Viral Latency through Effects on let-7 MicroRNA and Dicer

Mansouri

Pan

Blencowe

et al. 2014

J Virol

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The EBNA1 protein of Epstein-Barr virus (EBV) plays multiple roles in EBV latent infection, including altering cellular pathways relevant for cancer. Here we used microRNA (miRNA) cloning coupled with high-throughput sequencing to identify the effects of EBNA1 on cellular miRNAs in two nasopharyngeal carcinoma cell lines. EBNA1 affected a small percentage of cellular miRNAs in both cell lines, in particular, upregulating multiple let-7 family miRNAs, including let-7a. The effects of EBNA1 on let-7a were verified by demonstrating that EBNA1 silencing in multiple EBV-positive carcinomas downregulated let-7a. Accordingly, the let-7a target, Dicer, was found to be partially downregulated by EBNA1 expression (at the mRNA and protein levels) and upregulated by EBNA1 silencing in EBV-positive cells. Reporter assays based on the Dicer 3= untranslated region with and without let-7a target sites indicated that the effects of EBNA1 on Dicer were mediated by let-7a. EBNA1 was also found to induce the expression of let-7a primary RNAs in a manner dependent on the EBNA1 transcriptional activation region, suggesting that EBNA1 induces let-7a by transactivating the expression of its primary transcripts. Consistent with previous reports that Dicer promotes EBV reactivation, we found that a let-7a mimic inhibited EBV reactivation to the lytic cycle, while a let-7 sponge increased reactivation. The results provide a mechanism by which EBNA1 could promote EBV latency by inducing let-7 miRNAs. IMPORTANCE The EBNA1 protein of Epstein-Barr virus (EBV) contributes in multiple ways to the latent mode of EBV infection that leads to lifelong infection.In this study, we identify a mechanism by which EBNA1 helps to maintain EBV infection in a latent state. This involves induction of a family of microRNAs (let-7 miRNAs) that in turn decreases the level of the cellular protein Dicer. We demonstrate that let-7 miRNAs inhibit the reactivation of latent EBV, providing an explanation for our previous observation that EBNA1 promotes latency. In addition, since decreased levels of Dicer have been associated with metastatic potential, EBNA1 may increase metastases by downregulating Dicer. E pstein-Barr virus (EBV) is a gammaherpesvirus that infects most people worldwide and is associated with several types of B-cell lymphomas, as well as nasopharyngeal carcinoma (NPC) and gastric carcinoma (1, 2). The EBV life cycle consists of both latent and lytic modes of infection in B lymphocytes and epithelial cells. Although EBV mainly exists in a latent mode of infection in B cells, it occasionally reactivates to the lytic state for cell-to-cell spread. In addition, lytic reactivation of EBV in epithelial cells of the orthopharynx is necessary for the production of viral particles required for host-to-host transmission of the virus. Lytic infection begins with the expression of BZLF1 (or Zta), followed by the expression of BRLF1 (or Rta). Together these proteins activate the cascade of subsequent lytic gene expression and enable the generation of lin...

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Altered p53 regulation of miR-148b and p55PIK contributes to tumor progression in colorectal cancer

Cited by 33 publications

References 27 publications

Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Improved calvarial bone repair by hASCs engineered with Cre/loxP-based baculovirus conferring prolonged BMP-2 and MiR-148b co-expression

Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway

Epstein-Barr Virus EBNA1 Protein Regulates Viral Latency through Effects on let-7 MicroRNA and Dicer

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