Effects of VEGF suppression by small hairpin RNA interference combined with radiotherapy on the growth of cervical cancer

Qi, Lei; Liu, Xing; Wei, Xiaorong; Song, Shigang

doi:10.4238/2014.july.7.2

Cited by 17 publications

(11 citation statements)

References 23 publications

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“…37 Similarly, VEGF has been shown to promote the growth of other solid tumors such as colorectal cancer and cervical cancer. 27,35 Thus, we hypothesize that the reduction in systemic VEGF levels induced by propranolol may be one mechanism underlying propranolol's efficacy in vivo.…”

Section: Discussionmentioning

confidence: 99%

Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

Shepard

Bugarini

Edwards

et al. 2019

Journal of Neurosurgery

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OBJECTIVEVon Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by CNS hemangioblastomas (HBs) and clear cell renal cell carcinomas (RCCs) due to hypoxia-inducible factor activation (pseudohypoxia). Because of the lack of effective medical therapies for VHL, HBs and RCCs account for significant morbidity and mortality, ultimately necessitating numerous neurological and renal surgeries. Propranolol is an FDA-approved pan-beta adrenergic antagonist with antitumor effects against infantile hemangiomas (IHs) and possibly VHL HBs. Here, the authors investigated the antitumor efficacy of propranolol against pseudohypoxia-driven VHL-HBs and VHL-RCCs.METHODSPatient-derived VHL-associated HBs (VHL-HBs) or 786-O-VHL−/− RCC cells were treated with clinically relevant concentrations of propranolol in vitro and assessed with viability assays, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. In vivo confirmation of propranolol antitumor activity was confirmed in athymic nude mice bearing 786-O xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) were analyzed for incidental propranolol intake. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis.RESULTSPropranolol decreased HB and RCC viability in vitro with IC50 (half maximal inhibitory concentration) values of 50 µM and 200 µM, respectively. Similar to prior reports in infantile hemangiomas, propranolol induced apoptosis and paradoxically increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-O cells. While intracellular VEGF protein levels were not affected by propranolol treatment, propranolol decreased HIF expression in 786-O cells (7.6-fold reduction, p < 0.005). Propranolol attenuated tumor progression compared with control (33% volume reduction at 7 days, p < 0.005) in 786-O xenografted tumor-bearing mice. Three patients (harboring 25 growing CNS HBs) started propranolol therapy during the longitudinal VHL-HB study. HBs in these patients tended to grow slower (median growth rate 27.1 mm3/year vs 13.3 mm3/year) during propranolol treatment (p < 0.0004).CONCLUSIONSPropranolol decreases VHL-HB and VHL-related RCC viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogates 786-O xenograft tumor progression in vivo, and retrospective clinical data suggest that propranolol curtails HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors.

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Section: Discussionmentioning

confidence: 99%

Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

Shepard

Bugarini

Edwards

et al. 2019

Journal of Neurosurgery

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“…However, we found a considerable number of patients suffering from radiation insensitivity in clinical practice and the 5-year survival rate was limited. Although there are constant technological innovations on radiotherapy equipment, its effect remains unsatisfactory, especially with respect to its negative effects of local recurrence and distant metastasis (19). Therefore, it is crucial to find predictive markers of radiation sensitivity.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis

Pan

Yang

et al. 2015

Oncology Reports

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Abstract. Evidence has demonstrated that microRNAs (miRNAs) are important in the regulation of cellular radiosensitivity of various types of human cancer. The aim of this study was to examine the role of miR-18a in regulating the radiosensitivity of cervical cancer, in order to understand the underlying mechanism and to assess the potential of miR-18a as a biomarker for predicting radiosensitivity. The expression of miR-18a was investigated in 48 cervical cancer patients. The results revealed that miR-18a expression was significantly higher in radiosensitive patients than in radioresistant patients by RT-qPCR (P<0.05). Transient transfection experiments showed that miR-18a was upregulated by the miR-18a mimic and downregulated by the miR-18a inhibitor in the SiHa and HeLa cells. Without irradiation treatment, a similar growth was observed in the cells with or without transfection of miR-18a. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Hoechst staining assays showed that miR-18a had no effect on the proliferation and apoptosis of cervical cancer cells after transfection. However, the upregulation of miR-18a suppressed the level of ataxia-telangiectasia mutated and attenuated DNA double-strand break repair after irradiation, which re-sensitized the cervical cancer cells to radiotherapy by promoting apoptosis. Taken together, these results demonstrated that miR-18a is a potential molecule predictor of radiosensitivity in cervical cancer patients and played an important role in the response to radiotherapy.

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“…A corroborating study previously confirmed that suppression of VEGFA inhibits proliferation, migration, and promotes apoptosis of ccRCC cells ( 40 ). Another study also elucidated that inhibition of VEGFA as well as its receptor and the signal transduction pathway can inhibit tumor growth in cervical cancer ( 41 ). Consistent with our work, downregulation of VEGFA was shown to restrain cell proliferation and migration as well as facilitate cell apoptosis of endometrial cancer cells ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNA IRAIN Inhibits VEGFA Expression via Enhancing Its DNA Methylation Leading to Tumor Suppression in Renal Carcinoma

Yang

Luo

et al. 2020

Front. Oncol.

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Aims: Long non-coding RNA IRAIN (lncRNA IRAIN ) plays a critical role in numerous malignancies. However, the function of lncRNA IRAIN in renal carcinoma (RC) remains enigmatic. The purpose of this study is to characterize the effects of lncRNA IRAIN on RC progression. Methods: The expression pattern of lncRNA IRAIN and the vascular endothelial growth factor A (VEGFA) in RC tissues and cells was characterized by RT-qPCR and Western blot analysis. The roles of lncRNA IRAIN and VEGFA in the progression of RC were studied by gain- or loss-of-function experiments. Bioinformatics data analysis was used to predict CpG islands in the VEGFA promoter region. MSP was applied to detect the level of DNA methylation in RC cells. The interaction between lncRNA IRAIN and VEGFA was identified by RNA immunoprecipitation and RNA-protein pull down assays. Recruitment of DNA methyltransferases (Dnmt) to the VEGFA promoter region was achieved by chromatin immunoprecipitation. The subcellular localization of lncRNA IRAIN was detected by fractionation of nuclear and cytoplasmic RNA. Cell viability was investigated by CCK-8 assay, cell migration was tested by transwell migration assay, and apoptosis was analyzed by flow cytometry. The expression of epithelial–mesenchymal transition-related and apoptotic factors was evaluated by Western blot analysis. Finally, the effect of the lncRNA IRAIN /VEGFA axis was confirmed in an in vivo tumor xenograft model. Results: LncRNA IRAIN was poorly expressed in RC tissues and cells with a primary localization in the nucleus, while VEGFA was highly expressed. Overexpression of lncRNA IRAIN or knockdown of VEGFA inhibited cell proliferation and migration and induced the apoptosis of RC cells. Bioinformatics analysis indicated the presence of CpG islands in the VEGFA promoter region. Lack of methylation at specific sites in the VEGFA promoter region was detected through MSP assay. We found that lncRNA IRAIN was able to inhibit VEGFA expression through recruitment of Dnmt1, Dnmt3a, and Dnmt3b to the VEGFA promoter region. LncRNA IRAIN was also able to suppress RC tumor growth via repression of VEGFA in an in vivo mouse xenograft model. Conclusion: Our data shows that by downregulating VEGFA expression in RC, the lncRNA IRAIN has tumor-suppressive potential.

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Effects of VEGF suppression by small hairpin RNA interference combined with radiotherapy on the growth of cervical cancer

Cited by 17 publications

References 23 publications

Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

Repurposing propranolol as an antitumor agent in von Hippel-Lindau disease

MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis

Long Non-coding RNA IRAIN Inhibits VEGFA Expression via Enhancing Its DNA Methylation Leading to Tumor Suppression in Renal Carcinoma

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