Abstract:
BACKGROUND:Ovarian cancer (OC) is the most lethal gynecological malignancy and the second leading cause of cancer-related death in women. Treatment with PARP inhibitors (PARPi), such as Olaparib, has been recently introduced for OC patients, but resistance may occur and underlying mechanisms are still poorly understood. The aim of this study is to identify target genes within the tumor cells that might cause resistance to Olaparib. We focused on Neuropilin 1 (NRP1), a transmembrane receptor expressed in OC and correlated with poor survival, which has been also proposed as a key molecule in OC multidrug resistance. METHODS:Using three OC cell lines (UWB, UWB-BRCA and SKOV3) as model systems, we evaluated the biological and molecular effects of Olaparib on OC cell growth, cell cycle, DNA damage and apoptosis/autophagy induction, through MTT and colony forming assays, flow cytometry, immunofluorescence and Western blot analyses. We evaluated NRP1 expression in OC specimens and cell lines by Western blot and qRT-PCR, and used RNA interference to selectively inhibit NRP1. To identify miR-200c as a regulator of NRP1, we used miRNA target prediction algorithms and Pearsons' correlation analysis in biopsies from OC patients. Then, we used a stable transfection approach to overexpress miR-200c in Olaparib-resistant cells. RESULTS:We observed that NRP1 is expressed at high levels in resistant cells (SKOV3) and is upmodulated in partially sensitive cells (UWB-BRCA) upon prolonged Olaparib treatment, leading to poor drug response. Our results show that the selective inhibition of NRP1 is able to overcome Olaparib resistance in SKOV3 cells. Moreover, we demonstrated that miR-200c can target NRP1 in OC cells, causing its downmodulation, and that miR-200c overexpression is a valid approach to restore Olaparib sensitivity in OC resistant cells. CONCLUSIONS:These data demonstrate that miR-200c significantly enhanced the anti-cancer efficacy of Olaparib in drug-resistant OC cells. Thus, the combination of Olaparib with miRNA-based therapy may represent a promising treatment for drug resistant OC, and our data may help in designing novel precision medicine trials for optimizing the clinical use of PARPi.
journal_name
J Exp Clin Cancer Resjournal_title
Journal of experimental & clinical cancer research : CRauthors
Vescarelli E,Gerini G,Megiorni F,Anastasiadou E,Pontecorvi P,Solito L,De Vitis C,Camero S,Marchetti C,Mancini R,Benedetti Panici P,Dominici C,Romano F,Angeloni A,Marchese C,Ceccarelli Sdoi
10.1186/s13046-019-1490-7subject
Has Abstractpub_date
2020-01-02 00:00:00pages
3issue
1eissn
0392-9078issn
1756-9966pii
10.1186/s13046-019-1490-7journal_volume
39pub_type
杂志文章abstract::Prostate cancer (PC) development reflects a complex sequence of biologic and molecular events. Several inheritable and somatic genetic changes have been identified. The knowledge of the molecular basis of PC can improve our understanding of the causes of this common cancer and provide information on prognosis and trea...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:
更新日期:2007-03-01 00:00:00
abstract::We measured the serum level of soluble Fas (sFas) antigen in gastric MALT (mucosa-associated lymphoid tissue) lymphoma patients to investigate immune response of B lymphoma cells in gastric MALT lymphoma. The serum sFas antigen levels in 21 patients with Helicobacter pylori (HP)-positive MALT lymphoma were 4.51+/-0.25...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:1999-09-01 00:00:00
abstract:BACKGROUND:Previous meta-analysis suggested that transdermal fentanyl was not inferior to sustained-release oral morphine in treating moderate-severe cancer pain with less adverse effects. Now, we updated the data and performed a systematic review. METHODS:Updated cohort studies on transdermal fentanyl and oral morphi...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,meta分析
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:10.1186/s13046-020-01583-1
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abstract::The aim of the present study was to assess the role of virtual cystoscopy in the identification of bladder tumors. Fifteen patients (11 men and 4 women, median age: 61 years, range: 46-74 years) with a positive finding of bladder tumor at fiber-optic cystoscopy were studied by multislice-CT. Scans were downloaded to a...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2003-03-01 00:00:00
abstract:UNLABELLED:Stem cells are a relevant source of information about cellular differentiation, molecular processes and tissue homeostasis, but also one of the most putative biological tools to treat degenerative diseases. This review focuses on human stem cells clinical and experimental applications. Our aim is to take a c...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
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journal_title:Journal of experimental & clinical cancer research : CR
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journal_title:Journal of experimental & clinical cancer research : CR
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,meta分析
doi:10.1186/1756-9966-28-1
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2002-09-01 00:00:00
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journal_title:Journal of experimental & clinical cancer research : CR
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doi:10.1186/1756-9966-28-26
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 历史文章,杂志文章
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更新日期:2003-06-01 00:00:00
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journal_title:Journal of experimental & clinical cancer research : CR
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journal_title:Journal of experimental & clinical cancer research : CR
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
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更新日期:2002-12-01 00:00:00
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journal_title:Journal of experimental & clinical cancer research : CR
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journal_title:Journal of experimental & clinical cancer research : CR
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更新日期:2000-06-01 00:00:00
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journal_title:Journal of experimental & clinical cancer research : CR
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doi:10.1186/1756-9966-28-100
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,meta分析,评审
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journal_title:Journal of experimental & clinical cancer research : CR
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journal_title:Journal of experimental & clinical cancer research : CR
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journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:1999-06-01 00:00:00
abstract:BACKGROUND:One-third of estrogen (ER+) and/or progesterone receptor-positive (PGR+) breast tumors treated with Tamoxifen (TAM) do not respond to initial treatment, and the remaining 70% are at risk to relapse in the future. Estrogen-related receptor gamma (ESRRG, ERRγ) is an orphan nuclear receptor with broad, structur...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-015-0150-9
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