MiR-99b-5p expression and response to tyrosine kinase inhibitor treatment in clear cell renal cell carcinoma patients

Lukamowicz-Rajska, Magdalena; Mittmann, Christiane; Prummer, Michael; Zhong, Qing; Bedke, Jens; Hennenlotter, Jörg; Stenzl, Arnulf; Mischo, Axel; Bihr, Svenja; Schmidinger, Manuela; Vogl, Ursula Maria; Blume, Iris; Karlo, Christoph; Schraml, Peter; Moch, Holger

doi:10.18632/oncotarget.12618

Cited by 30 publications

(20 citation statements)

References 47 publications

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“…Our results confirm other study data regarding miRNAs as helpful tools for this current issue in the application of TKIs in the first-line treatment of mRCC patients [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 48 ]. However, the different results between those studies and our data should be mentioned.…”

Section: Discussionsupporting

confidence: 90%

“…Similar to our approach, five working groups used a two-stage design to identify potential predictive miRNAs in nephrectomy specimens. Such an approach consisted of an initial array- or sequencing-based screening step to discover deregulated miRNAs associated with a therapeutic response to a TKI in either fresh-frozen RCC or FFPE RCC samples followed by a second RT-qPCR validation step for selected miRNAs [ 21 , 22 , 23 , 24 , 25 ]. Moreover, Gamez-Pozo et al [ 48 ] examined miRNAs in peripheral blood samples from mRCC patients as predictors of resistance to sunitinib.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, microRNAs (miRNAs, miRs) as small, non-protein-coding transcripts could be considered as suitable biomarkers because of their important role as posttranscriptional regulators in all network processes of carcinogenesis and metastasis [ 20 ]. Several studies that have identified differentially expressed miRNAs in nephrectomy specimens of RCC patients with subsequent tumor relapse while under TKI therapy have confirmed this assumption [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. However, different definitions of the clinical endpoints of progression-free survival or time to progression were used in these studies to classify two groups with different responses to sunitinib or other TKIs.…”

Section: Introductionmentioning

confidence: 91%

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miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

Ralla

Busch

Flörcken

et al. 2018

Cancers

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Approximately 20–30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51; pazopanib, n = 6; sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

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miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

Ralla

Busch

Flörcken

et al. 2018

Cancers

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“…Successful independent validation of potentially predictive miRNAs remains a challenge. Overlap of results is rare in published studies of miRNAs as predictors of response to sunitinib in mRCC (8,(28)(29)(30). This could be partly due to tumor heterogeneity, various technologies used for miRNA analysis, limited numbers of enrolled patients, and failure to include a validation cohort.…”

Section: Discussionmentioning

confidence: 99%

MiR-376b-3p Is Associated With Long-term Response to Sunitinib in Metastatic Renal Cell Carcinoma Patients

Kovacova

Juráček

Poprach

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: Sunitinib is a tyrosine kinase inhibitor routinely used as first-line therapy in metastatic renal cell carcinoma (mRCC). Emerging evidence suggests that microRNAs (miRNAs) could be suitable biomarkers with predictive potential in mRCC. The aim of this study was to identify miRNA-based predictive biomarkers of therapy response to avoid unnecessary therapy to non-responding patients. Patients and Methods: High-throughput miRNA microarray profiling was performed on a cohort of 47 patients treated with sunitinib. Validation of candidate miRNAs was carried out on an independent cohort of 132 mRCC patients using qRT-PCR. Results: Out of 158 miRNAs (65 down-regulated, 93 up-regulated), six miRNAs were chosen for independent validation and miR-376b-3p was confirmed to be differentially expressed in tumors of patients with primary resistance versus long-term response (p<0.0002). Conclusion: A predictive miRNA associated with progression-free survival in metastatic renal cell carcinoma patients treated with sunitinib was identified. Renal cell carcinoma (RCC) accounts for more than 3% of adult solid tumors and is fatal for around 40% of patients (1). The metastatic form of this disease (mRCC) is routinely treated with tyrosine kinase inhibitors (TKIs) of the VEGF pathway to prevent formation of new blood vessels that support tumors with nutrients. Sunitinib is routinely used as a first-line therapy, followed by other therapeutic options and TKI variants in the second-and third-line treatment after first line failure, which is inevitable in most patients (2, 3). However, duration of response is variable, ranging from a few months to more than two years since a proportion of the patients have primary resistance to treatment, some develop it faster than others (4). The financial burden of therapy together with many unpleasant side-effects affecting the quality of life of patients are the main drivers behind the attempts to identify predictive biomarkers reliably differentiating patients who would benefit from the first-line sunitinib from those who should be immediately redirected to other therapeutic options. MicroRNAs (miRNAs) are a class of short non-coding RNAs, 18-25 nucleotides long, post-transcriptionally regulating gene expression of more than half of protein-coding human genes. Complementary binding to the 3'untranslated region of their target mRNAs (5), miRNAs are pivotal regulators of many vital cellular processes and their deregulation leads to over-or 353 This article is freely accessible online.

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“…In mammals, five members of this family are known: RelA (p65), RelB, c-Rel, NF-kB1 (p105/p50), and NF-kB2 (p100/p52). The functional role of NF-kB1 in RCC has been investigated in recent years but is far from being fully elucidated [4][5][6][7] . The Nf-κB1 gene encodes the p105 protein, which undergoes cleavage to remove the carboxy-terminal portion by the 26S proteasome, generating the p50 protein that is capable of binding to DNA but lacks transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

Avaliação >i<in vitro>/i< e >i<in vivo>/i< do impacto do silenciamento do gene NF-kB1 no ciclo celular, capacidade proliferativa e na radiossensibilidade do adenocarcinoma renal

Ikegami¹

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Avaliação in vitro e in vivo do impacto do silenciamento do gene NF-κB1 no ciclo celular, capacidade proliferativa e na radiossensibilidade do adenocarcinoma renal AMANDA IKEGAMI Dissertação apresentada como parte dos requisitos para obtenção do Grau de Mestre em Ciências na área de Tecnologia Nuclear -Aplicações Orientadora: Profª Drª Maria Helena Bellini São Paulo 2019 INSTITUTO DE PESQUISAS ENERGÉTICAS E NUCLEARES Autarquia associada à Universidade de São Paulo Avaliação in vitro e in vivo do impacto do silenciamento do gene NF-κB1 no ciclo celular, capacidade proliferativa e na radiossensibilidade do adenocarcinoma renal AMANDA IKEGAMI Dissertação apresentada como parte dos requisitos para obtenção do Grau de Mestre em Ciências na área de Tecnologia Nuclear -Aplicações Orientadora: Profª Drª Maria Helena Bellini São Paulo 2019 AGRADECIMENTOS À Profª Drª Maria Helena Bellini Marumo pela oportunidade concedida, orientação e contribuição para meu desenvolvimento intelectual, profissional e pessoal. Ao Instituto de Pesquisas Energéticas e Nucleares por colocar à disposição o espaço necessário ao desenvolvimento do trabalho. À Fundação de Amparo à Pesquisa do Estado de São Paulo que forneceu apoio financeiro ao projeto (processo n.2014/19265-7). À Comissão Nacional de Energia Nuclear pela concessão da bolsa de mestrado (memorando n. 95/SEFESP edital 01/2016). A todos os envolvidos, professores e colegas de pesquisa, que contribuíram para a realização e finalização deste projeto. RESUMO IKEGAMI, Amanda. Avaliação in vitro e in vivo do impacto do silenciamento do gene NF-κB1 no ciclo celular, capacidade proliferativa e na radiossensibilidade do adenocarcinoma renal. 2019. 71 p. Dissertação (Mestrado em Tecnologia Nuclear) Instituto de Pesquisas Energéticas e Nucleares -IPEN-CNEN/SP. São Paulo. O carcinoma de células renais (CCR) é responsável por, aproximadamente, 1 a 3% das neoplasias malignas humanas e, dentre os tumores urológicos, é o mais agressivo. A heterogeneidade biológica, a resistência aos fármacos e os efeitos colaterais à quimioterapia são os maiores obstáculos ao tratamento eficaz do CCR. Várias moléculas vêm sendo correlacionadas com o fenótipo agressivo deste tumor, sendo uma delas o fator de transcrição NF-κB. Estudos demonstraram a ativação de NF-κB no CCR e muitos apontaram NF-κB1 (p50) como uma molécula importante na progressão tumoral e metástase. Neste trabalho, foi utilizada a técnica de silenciamento gênico de interferência por RNA -Short hairpin RNA (shRNA) -para diminuir a expressão de NF-κB1 em células murinas de carcinoma de células renais (Renca). Verificou-se que, in vitro, a diminuição da expressão do gene NF-κB1 reduz a capacidade proliferativa das células Renca e aumenta a taxa de apoptose tardia/necrose e a quantidade de células na fase G2/M do ciclo celular. Além disso, as análises de Western blot revelaram aumento significativo da expressão proteica de Ciclina B1 e Bax. A regulação negativa da p50 também alterou a capacidade clonogênica das células que, conjugada à irradiação ioni...

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MiR-99b-5p expression and response to tyrosine kinase inhibitor treatment in clear cell renal cell carcinoma patients

Cited by 30 publications

References 47 publications

miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

miR-9-5p in Nephrectomy Specimens is a Potential Predictor of Primary Resistance to First-Line Treatment with Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

MiR-376b-3p Is Associated With Long-term Response to Sunitinib in Metastatic Renal Cell Carcinoma Patients

Avaliação >i<in vitro>/i< e >i<in vivo>/i< do impacto do silenciamento do gene NF-kB1 no ciclo celular, capacidade proliferativa e na radiossensibilidade do adenocarcinoma renal

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