Inhibiting Proliferation and Enhancing Chemosensitivity to Taxanes in Osteosarcoma Cells by RNA Interference-Mediated Downregulation of Stathmin Expression

Wang, Rui; Dong, Ke; Lin, Fang; Wang, Xi; Gao, Peng; Wei, Sanhua; Cheng, Shi-Yin; Zhang, Huizhong

doi:10.2119/2007-00046.wang

Cited by 56 publications

(32 citation statements)

References 27 publications

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“…The growing evidence has shown that miR-21 is an oncogenic miRNA and is highly expressed in a variety of malignant tumors (24,25). It is still a challenging question as to how the expression of miRNAs is regulated.…”

Section: Discussionmentioning

confidence: 99%

Foxo3a Regulates Apoptosis by Negatively Targeting miR-21

Wang

2010

Journal of Biological Chemistry

100

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MicroRNAs are a class of small non-coding RNAs and participate in the regulation of apoptotic program. Although miR-21 is able to inhibit apoptosis, its expression regulation and downstream targets remain to be fully elucidated. Here we report that the transcriptional factor Foxo3a initiates apoptosis by transcriptionally repressing miR-21 expression. Our results showed that doxorubicin could simultaneously induce the translocation of Foxo3a to the cell nuclei and a reduction in miR-21 expression. Knockdown of Foxo3a resulted in an elevation in miR-21 levels, whereas enforced expression of Foxo3a led to a decrease in miR-21 expression. In exploring the molecular mechanism by which Foxo3a regulates miR-21, we observed that Foxo3a bound to the promoter region of miR-21 and suppressed its promoter activity. These results indicate that Foxo3a can transcriptionally repress miR-21 expression. In searching for the downstream targets of miR-21 in apoptosis, we found that miR-21 suppressed the translation of Fas ligand (FasL), a pro-apoptotic factor. Furthermore, Foxo3a was able to up-regulate FasL expression through down-regulating miR-21. Our data suggest that Foxo3a negatively regulates miR-21 in initiating apoptosis. miRNAs 2 are a class of small non-coding RNAs that mediate post-transcriptional gene silencing. Recently, the work on miRNAs renovates our understanding about apoptotic regulation. They can be classified as either pro-or anti-apoptotic miRNAs (1, 2). For example, miR-1 participates in the initiation of apoptosis (3), whereas miR-21 is able to inhibit apoptosis (4). miRNAs are expressed at a constant level under physiological condition, and their functions depend on their expression levels. It remains a challenging question as to how their expression is regulated in the apoptotic program.The forkhead family of transcription factors is characterized by the presence of a conserved 100-amino acid DNA binding domain and participate in regulating diverse cellular functions such as apoptosis, differentiation, metabolism, proliferation, and survival (5). Foxo3a is a substrate of protein kinase Akt, and its transcriptional output is controlled via phosphorylation. In the absence of cellular stimulation and when Akt is inactive, Foxo3a is localized within the nucleus where it performs transcription of target genes. However, upon phosphorylation by Akt at Thr-32, Ser-253, and Ser-315, it binds to 14-3-3 and cannot exert the transcriptional function (6).Fas ligand (FasL) is a potential transcriptional target of Foxo3a, but the transcriptional output can be either activation or suppression. It has been reported that Foxo3a can stimulate FasL expression, thereby triggering apoptosis (6). However, there is also evidence showing that Foxo3a decreases the expression of FasL (7). The molecular mechanism by which Foxo3a regulates FasL expression remains further elusive. miR-21 has been shown to regulate apoptosis by targeting a variety of apoptotic factors. It contributes to glioma malignancy by down-regulating matrix meta...

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Section: Discussionmentioning

confidence: 99%

Foxo3a Regulates Apoptosis by Negatively Targeting miR-21

Wang

2010

Journal of Biological Chemistry

100

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“…In our previous study, stathmin was also found to be overexpressed in osteosarcoma and ovarian carcinoma cells, and the overexpression of this gene signiWcantly correlated with prognosis of patients (Zhang et al 2004;Wei et al 2008). Moreover, we found that small interfering RNA (siRNA) or antisense-mediated downregulation of stathmin expression could lead to proliferation inhibition and chemosensitivity enhancement in human osteosarcoma cells (Zhang et al 2006;Wang et al 2007). Therefore, stathmin might be involved in the tumor carcinogenesis, proliferation, metastasis and chemmoresistance, while the high levels of this molecule are signiWcantly correlated with tumor progression and patient outcome (Belletti et al 2008;McGrogan et al 2008) .…”

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confidence: 82%

Expression of stathmin/op18 as a significant prognostic factor for cervical carcinoma patients

Wang

Lin

et al. 2008

J Cancer Res Clin Oncol

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“…[33][34][35] Previously, we have described bi-shRNA STMN1 BIV cleavage product detection both in vitro and in vivo, but not in patients. 21 Data presented in this report are the first demonstration that STMN1 expression can be knocked down by RNAi approach in humans.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Trial of Bi-shRNA STMN1 BIV in Refractory Cancer

Barve

Wang²,

Kumar

et al. 2015

Molecular Therapy

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Stathmin1 (STMN1) is a microtubule modulator that is expressed in multiple cancers and correlates with poor survival. We previously demonstrated in vivo safety of bifunctional (bi) shRNA STMN1 bilamellar invaginated vesicle (BIV) and that systemic delivery correlated with antitumor activity. Patients with superficial advanced refractory cancer with no other standard options were entered into trial. Study design involved dose escalation (four patients/cohort) using a modified Fibonacci schema starting at 0.7 mg DNA administered via single intratumoral injection. Biopsy at baseline, 24/48 hours and resection 8 days after injection provided tissue for determination of cleavage product using next-generation sequencing (NGS) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), 5' RLM rapid amplification of cDNA ends (RACE) assay. Serum pharmacokinetics of circulating plasmid was done. Twelve patients were entered into three dose levels (0.7, 1.4, 7.0 mg DNA). No ≥ grade 3 toxic effects to drug were observed. Maximum circulating plasmid was detected at 30 seconds with less than 10% detectable in all subjects at 24 hours. No toxic effects were observed. Predicted cleavage product was detected by both NGS (n = 7/7 patients analyzed, cohorts 1, 2) and RLM RACE (n = 1/1 patients analyzed cohort 3). In conclusion, bi-shRNA STMN1 BIV is well tolerated and detection of mRNA target sequence-specific cleavage product confirmed bi-shRNA BIV mechanism of action.

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Inhibiting Proliferation and Enhancing Chemosensitivity to Taxanes in Osteosarcoma Cells by RNA Interference-Mediated Downregulation of Stathmin Expression

Cited by 56 publications

References 27 publications

Foxo3a Regulates Apoptosis by Negatively Targeting miR-21

Foxo3a Regulates Apoptosis by Negatively Targeting miR-21

Expression of stathmin/op18 as a significant prognostic factor for cervical carcinoma patients

Phase 1 Trial of Bi-shRNA STMN1 BIV in Refractory Cancer

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