Vector‐based miR‐15a/16‐1 plasmid inhibits colon cancer growth <i>in vivo</i>

Dai, Liyun; Wang, Wei; Zhang, Shuang; Jiang, Qingyuan; Wang, Ruibo; Dai, Lei; Cheng, Lin; Yang, Yang; Wei, Yuquan; Deng, Hongxin

doi:10.1042/cbi20110404

Cited by 35 publications

(25 citation statements)

References 32 publications

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“…58 Interestingly, several of the tumor types which, in addition to BC and GC, show ErbB-2 gene amplification or protein overexpression, display low levels of miR-16. 59–65 Given that miR-16 was found to act as a tumor suppressor in these cancers, 59–65 our findings raise the exciting possibility that ErbB-2 inhibition of miR-16 expression may be a common mechanism underlying ErbB-2-driven cancer growth. TZ has been found to regulate the expression of other miRNAs, which mediate its antiproliferative effects in BC.…”

Section: Discussionmentioning

confidence: 85%

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1

et al. 2016

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ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.

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Section: Discussionmentioning

confidence: 85%

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1

et al. 2016

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“…MiR-15a has been shown to be growth inhibitory in a number of cancers. [38]–[42] Subsequent qRT-PCR analysis showed miR-15a to be increased upon s-α-miR-106a∼363 expression in responsive cell lines (SK-ES-1 and RD-ES), but not in the unresponsive cell lines (TC71 and A673) (Figure 6). We thus pursued miR-15a upregulation as a possible mechanism contributing to the s-α-miR-106a∼363 growth-inhibition phenotype in Ewing Sarcoma cells.…”

Section: Resultsmentioning

confidence: 99%

“…MiR-15a has been shown to be tumor suppressive in other systems, primarily through regulation of a variety of cell cycle targets, including Wee1 and multiple cyclins. [38], [39], [41], [42] In mouse genetic models, miR-15a deletion significantly accelerates the development of Chronic Lymphocytic Leukemia, in part through de-repression of multiple miR-15a-targeted cyclins (Cyclin D1 and D3, Cyclin E), CDK6 and the anti-apoptotic factor Bcl-2. [40], [49] In prostate cancer, inhibition of miR-15a leads to increased anchorage-independent growth and migration in vitro , as well as transforming a non-tumorigenic prostate cell line in vivo .…”

Section: Discussionmentioning

confidence: 99%

Growth-Promoting Role of the miR-106a∼363 Cluster in Ewing Sarcoma

Dylla

Jedlicka

2013

PLoS ONE

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MicroRNAs (miRs) have been identified as potent regulators of both normal development and the hallmarks of cancer. Targeting of microRNAs has been shown to have preclinical promise, and select miR-based therapies are now in clinical trials. Ewing Sarcoma is a biologically aggressive pediatric cancer with little change in clinical outcomes despite improved chemotherapeutic regimens. There is a substantial need for new therapies to improve Ewing Sarcoma outcomes and to prevent chemotherapy-related secondary sequelae. Most Ewing Sarcoma tumors are driven by the EWS/Fli-1 fusion oncoprotein, acting as a gain-of-function transcription factor causing dysregulation of a variety of targets, including microRNAs. Our previous studies, and those of others, have identified upregulation of miRs belonging to the related miR-17∼92a, miR-106b∼25, and miR-106a∼363 clusters in Ewing Sarcoma. However, the functional consequences of this have not been characterized, nor has miR blockade been explored as an anti-cancer strategy in Ewing Sarcoma. To simulate a potential therapeutic approach, we examined the effects of blockade of these clusters, and their component miRs. Using colony formation as a read-out, we find that blockade of selected individual cluster component miRs, using specific inhibitors, has little or no effect. Combinatorial inhibition using miR “sponge” methodology, on the other hand, is inhibitory to colony formation, with blockade of whole clusters generally more effective than blockade of miR families. We show that a miR-blocking sponge directed against the poorly characterized miR-106a∼363 cluster is a particularly potent inhibitor of clonogenic growth in a subset of Ewing Sarcoma cell lines. We further identify upregulation of miR-15a as a downstream mechanism contributing to the miR-106a∼363 sponge growth-inhibitory effect. Taken together, our studies provide support for a pro-oncogenic role of the miR-106a∼363 cluster in Ewing Sarcoma, and identify miR-106a∼363 blockade, as well as miR-15a replacement, as possible strategies for inhibition of Ewing Sarcoma growth.

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“…We identified in silico 114 miRs (Supplementary Table 7) that target these genes regions with over 35% of these having previously been reported to have associations with CRC [54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76]. Of the top 10 most significant regions, 40% of the miRs we identified using our approach have been associated with CRC (mi R-141 , mi R-15A , mi R-15B , mi R-18A , mi R-200A , mi R-200B , mi R-203 , mi R-32 , mi R-429 and mi R-92 ).…”

Section: Resultsmentioning

confidence: 99%

Copy Number Variation in Hereditary Non-Polyposis Colorectal Cancer

Masson

Talseth‐Palmer

Evans

et al. 2013

Genes

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Hereditary non-polyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer (CRC) predisposition and by definition describes families which conform to the Amsterdam Criteria or reiterations thereof. In ~50% of patients adhering to the Amsterdam criteria germline variants are identified in one of four DNA Mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Loss of function of any one of these genes results in a failure to repair DNA errors occurring during replication which can be most easily observed as DNA microsatellite instability (MSI)—a hallmark feature of this disease. The remaining 50% of patients without a genetic diagnosis of disease may harbour more cryptic changes within or adjacent to MLH1, MSH2, MSH6 or PMS2 or elsewhere in the genome. We used a high density cytogenetic array to screen for deletions or duplications in a series of patients, all of whom adhered to the Amsterdam/Bethesda criteria, to determine if genomic re-arrangements could account for a proportion of patients that had been shown not to harbour causative mutations as assessed by standard diagnostic techniques. The study has revealed some associations between copy number variants (CNVs) and HNPCC mutation negative cases and further highlights difficulties associated with CNV analysis.

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Vector‐based miR‐15a/16‐1 plasmid inhibits colon cancer growth in vivo

Cited by 35 publications

References 32 publications

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1

MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1

Growth-Promoting Role of the miR-106a∼363 Cluster in Ewing Sarcoma

Copy Number Variation in Hereditary Non-Polyposis Colorectal Cancer

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