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1.
Int J Radiat Oncol Biol Phys ; 106(1): 174-181, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525407

RESUMO

PURPOSE: We aimed to study radiation-induced gene expression changes and to identify differences in gene expression between patients with and without response to radiation therapy (RT) for invasive breast cancer with the purpose of exploring whether a predictive signature could be developed. Such a signature could assist in optimizing individualized locoregional treatment. METHODS AND MATERIALS: RNA-seq using next-generation sequencing was performed on fresh frozen samples from pretreatment biopsies and post-RT surgery specimens from patients with low-risk breast cancer treated within the multicenter preoperative accelerated partial breast irradiation trial. Patients were treated with preoperative RT (10 × 4 Gy in 10 days or 5 × 6 Gy in 5 days) and a lumpectomy 6 weeks thereafter. The response of the tumor to RT was evaluated by pathologic assessment. To analyze the gene expression data, unsupervised and supervised clustering was performed. Gene expression profiles were compared between biopsies of responders and nonresponders and between samples before and after RT. RESULTS: Ninety-four samples from 77 patients were analyzed: 68 pretreatment biopsies and 26 post-RT surgery specimens. Six patients had a (near) complete pathologic response, 3 patients had a good response, 32 patients had a partial response, and 22 patients had no or very limited response. Comparing patients with and without response to RT, 25 genes were significantly differentially expressed and were not linked to a pathway. Comparison of samples before and after RT identified significant changes in gene expression. Genes involved in p53 signaling, TNFA1 signaling, apoptosis, epithelial mesenchymal transition, and inflammatory response were upregulated. Genes involved in mitotic spindle, G2M checkpoint, and E2F targets were downregulated. CONCLUSIONS: Radiation-induced gene expression changes mainly involved p53 signaling, cell cycle regulation, DNA repair, and inflammatory response. No clinically significant differences could be identified in gene expression between patients with and without response to RT.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Terapia Neoadjuvante , RNA Neoplásico/análise , Transcriptoma , Biópsia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Feminino , Secções Congeladas , Perfilação da Expressão Gênica/métodos , Humanos , Mastectomia , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Medicina de Precisão , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Tolerância a Radiação/genética , Análise de Sequência de RNA , Resultado do Tratamento
2.
Mutat Res ; 816-818: 111679, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31715522

RESUMO

Glioblastoma (GBM) is the most lethal type of primary brain tumor. Currently, even with optimal and multimodal cancer therapies, the survival rate of GBM patients remains poor. One reason for inadequate response of GBM tumors to radiotherapy is radioresistance (RR). Thus, there is a critical need for new insights about GBM treatment to increase the chance of treatment. microRNAs (miRNAs) are important regulatory molecules that can effectively control GBM radiosensitivity (RS) by affecting radiation-related signal transduction pathways such as apoptosis, proliferation, DNA repair and cell cycle regulation. miRNAs provide new clinical perspectives for developing effective GBM treatments. A growing body of literature has demonstrated that GBM RS can be modified by modulating the expression of miRNAs such as miR-7, miR-10b, miR-124, miR-128, miR-320, miR-21, miR-203, and miR-153. This paper highlights the miRNAs and the underlying molecular mechanisms that are involved in the RS of GBM. Besides highlighting the role of miRNAs in different signaling pathways, we explain the mechanisms that affect RS of GBM for modulating radiation response at the clinical level.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , MicroRNAs/genética , Tolerância a Radiação/genética , Transdução de Sinais/genética , Animais , Neoplasias Encefálicas/radioterapia , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/radioterapia , Humanos , Tolerância a Radiação/efeitos da radiação , Transdução de Sinais/efeitos da radiação
3.
Cancer Radiother ; 23(8): 883-890, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31615730

RESUMO

Radiotherapy is one of the most common form of treatment in oncology care. Indeed, radiotherapy proved to be very effective in treating a wide range of malignancies. Nevertheless, certain tumours are intrinsically radioresistant or may evolve to become radioresistant. Resistance to radiotherapy is often associated with dysregulated DNA damage response and repair. Recently, a number of strategies have been developed to improve radiotherapy efficacy by targeting the DNA damage response and repair pathways. Ongoing clinical trials showed the potential of some of these approaches in enhancing radiotherapy, but also highlighted the possible limitations. Here, we will describe (i) the main mechanisms involved in double-strand break repair; (ii) available strategies that target these DNA repair processes to improve radiotherapy and (iii) the clinical outcomes and challenges that have emerged so far.


Assuntos
Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Neoplasias/radioterapia , Tolerância a Radiação/genética , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Humanos , Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico , Reparo de DNA por Recombinação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
4.
J Exp Clin Cancer Res ; 38(1): 392, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488179

RESUMO

BACKGROUND: Radioresistance remains a challenge to the successful treatment of various tumors. Intrinsic factors like alterations in signaling pathways regulate response to radiation. RhoC, which has been shown to modulate several tumor phenotypes has been investigated in this report for its role in radioresistance. In vitro and clinical sample-based studies have been performed to understand its contribution to radiation response in cervical cancer and this is the first report to establish the role of RhoC and its effector ROCK2 in cervical cancer radiation response. METHODS: Biochemical, transcriptomic and immunological approaches including flow cytometry and immunofluorescence were used to understand the role of RhoC and ROCK2. RhoC variants, siRNA and chemical inhibitors were used to alter the function of RhoC and ROCK2. Transcriptomic profiling was performed to understand the gene expression pattern of the cells. Live sorting using an intracellular antigen has been developed to isolate the cells for transcriptomic studies. RESULTS: Enhanced expression of RhoC conferred radioprotection on the tumor cells while inhibition of RhoC resulted in sensitization of cells to radiation. The RhoC overexpressing cells had a better DNA repair machinery as observed using transcriptomic analysis. Similarly, overexpression of ROCK2, protected tumor cells against radiation while its inhibition increased radiosensitivity in vitro. Further investigations revealed that ROCK2 inhibition abolished the radioresistance phenotype, conferred by RhoC on SiHa cells, confirming that it is a downstream effector of RhoC in this context. Additionally, transcriptional analysis of the live sorted ROCK2 high and ROCK2 low expressing SiHa cells revealed an upregulation of the DNA repair pathway proteins. Consequently, inhibition of ROCK2 resulted in reduced expression of pH2Ax and MRN complex proteins, critical to repair of double strand breaks. Clinical sample-based studies also demonstrated that ROCK2 inhibition sensitizes tumor cells to irradiation. CONCLUSIONS: Our data primarily indicates that RhoC and ROCK2 signaling is important for the radioresistance phenotype in cervical cancer tumor cells and is regulated via association of ROCK2 with the proteins of DNA repair pathway involving pH2Ax, MRE11 and RAD50 proteins, partly offering insights into the mechanism of radioresistance in tumor cells. These findings highlight RhoC-ROCK2 signaling involvement in DNA repair and urge the need for development of these molecules as targets to alleviate the non-responsiveness of cervical cancer tumor cells to irradiation treatment.


Assuntos
Reparo do DNA , Tolerância a Radiação/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Quinases Associadas a rho/metabolismo , Proteína de Ligação a GTP rhoC/genética , Proteína de Ligação a GTP rhoC/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Ligação Proteica , Transcriptoma , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia
5.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502570

RESUMO

Radioresistance is a material obstacle for effective treatment of colorectal cancer (CRC). Thus, the discovery of a novel biomarker for determining the CRC radiosensitivity is necessary. Recent studies have confirmed that miR-183-3p regulates cell phenotypes and tumor growth in various cancers. However, the role and mechanism of this micro-ribonucleic acid in CRC radiosensitivity remains unclear. Here, the abundances of miR-183-5p and ATG5 mRNAwere detected by a real-time quantitative reverse transcription polymerase chain reaction. Kaplan-Meier survival analysis was carried out to explore the correlation between miR-183-5p and patient prognosis. Cell viability was evaluated by the MTT assay. Survival fraction analysis through colony formation was performed to assess the cell radiation response. Bioinformatic, luciferase and western blot assays were employed to verify the targeted interaction between miR-183-5p and ATG5. The results showed that an elevated abundance of miR-183-5p and a reduced ATG5 level in CRC were associated with the poor prognosis. The knockdown of miR-183-5p enhanced the sensitivity of CRC cells to radiation, inflected by the decreased cell viability and survival fraction. Mechanically, ATG5 was targeted by miR-183-5p. The addition of ATG5 conferred the radiosensitivity of the CRC cells, which was revered by miR-183-5p restoration. Furthermore, miR-183-5p knockdown hindered the tumor growth by repressing ATG5 in vivo after radiation treatment. In summary, the output data indicated that miR-183-5p heightened the radiation response of the CRC cells by targeting ATG5, promising a novel therapeutic target for CRC patients with radioresistance.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Neoplasias Colorretais/radioterapia , MicroRNAs/genética , Tolerância a Radiação/genética , Idoso , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Commun ; 10(1): 3959, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477729

RESUMO

Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFß is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy.


Assuntos
Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Experimentais/terapia , Radioterapia/métodos , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Terapia Combinada , Perfilação da Expressão Gênica/métodos , Interferon gama/imunologia , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Tolerância a Radiação/genética
7.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491955

RESUMO

Japonica and indica are two important subspecies in cultivated Asian rice. Irradiation is a classical approach to induce mutations and create novel germplasm. However, little is known about the differential response between japonica and indica rice after γ radiation. Here, we utilized the RNA sequencing and Weighted Gene Co-expression Network Analysis (WGCNA) to compare the transcriptome differences between japonica Nipponbare (NPB) and indica Yangdao6 (YD6) in response to irradiation. Japonica subspecies are more sensitive to irradiation than the indica subspecies. Indica showed a higher seedling survival rate than japonica. Irradiation caused more extensive DNA damage in shoots than in roots, and the severity was higher in NPB than in YD6. GO and KEGG pathway analyses indicate that the core genes related to DNA repair and replication and cell proliferation are similarly regulated between the varieties, however the universal stress responsive genes show contrasting differential response patterns in japonica and indica. WGCNA identifies 37 co-expressing gene modules and ten candidate hub genes for each module. This provides novel evidence indicating that certain peripheral pathways may dominate the molecular networks in irradiation survival and suggests more potential target genes in breeding for universal stress tolerance in rice.


Assuntos
Raios gama , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Redes Reguladoras de Genes , Oryza/genética , Oryza/efeitos da radiação , Transcriptoma , Biologia Computacional/métodos , Dano ao DNA/genética , Perfilação da Expressão Gênica , Ontologia Genética , Tolerância a Radiação/genética , Plântula/genética , Plântula/efeitos da radiação
8.
Semin Oncol ; 46(3): 246-253, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492437

RESUMO

Primary organ-confined prostate cancer is curable with external-beam radiotherapy. However, prostate cancer expresses a unique radiobiological phenotype, and its ablation requires doses at the high-end range of clinical radiotherapy. At this dose level, normal tissue radiosensitivity restricts the application of curative treatment, and mandates the use of the most advanced high-precision treatment delivery techniques to spare critical organs at risk. The efficacy and tolerance of dose-escalated conventional fractionated radiotherapy and of the biological equivalent doses of moderate and extreme hypofractionation are reviewed. Current studies indicate that novel risk-adapted techniques to spare normal organs at risk are still required to deploy high-biological equivalent dose extreme hypofractionation, while affording preservation of quality of life and cost-effectiveness.


Assuntos
Próstata/efeitos da radiação , Neoplasias da Próstata/radioterapia , Doses de Radiação , Relação Dose-Resposta à Radiação , Humanos , Masculino , Próstata/patologia , Neoplasias da Próstata/patologia , Tolerância a Radiação/genética
9.
Int J Radiat Oncol Biol Phys ; 105(4): 824-833, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31404579

RESUMO

PURPOSE: Defective mismatch repair system (dMMR) has been shown to have a favorable impact on outcome in patients with colorectal cancer treated with surgery or immunotherapy, with adjuvant chemotherapy being discouraged unless there is nodal involvement. Its impact on radiosensitivity is unknown in patients with colorectal cancer. METHODS AND MATERIALS: Patients treated for locally advanced rectal cancer between 2000 and 2016 were studied. Reported points included age, sex, clinical and radiologic tumor stages at diagnosis, modalities of neoadjuvant treatment, posttreatment pathologic staging, tumor regression score, and local, distant relapse-free, and overall survival. An inverse probability of treatment weighting propensity score analysis was performed to evaluate the association of mismatch repair proficiency with surgical and clinical outcomes. RESULTS: Among the 296 patients included, 23 (7.8%) had dMMR. Median follow-up was 43.0 months (interquartile range, 27.9-66.7). Patients with dMMR were significantly younger than the others. After inverse probability of treatment weighting propensity score matching, dMMR patients had higher pathologic downstaging rate (P < .0001), higher tumor regression grade (P = .024), and a longer recurrence-free survival (P < .0001). CONCLUSIONS: dMRR was associated with significant tumor downstaging after neoadjuvant chemoradiation and with increased recurrence-free survival. dMMR patients may have more radiosensitive tumors.


Assuntos
Quimiorradioterapia Adjuvante , Reparo de Erro de Pareamento de DNA/fisiologia , Terapia Neoadjuvante/métodos , Neoplasias Retais/genética , Neoplasias Retais/terapia , Fatores Etários , Idoso , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Pontuação de Propensão , Tolerância a Radiação/genética , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Fatores Sexuais , Resultado do Tratamento
10.
Breast Cancer Res ; 21(1): 89, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391072

RESUMO

BACKGROUND: Understanding the molecular alterations associated with breast cancer (BC) progression may lead to more effective strategies for both prevention and management. The current model of BC progression suggests a linear, multistep process from normal epithelial to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Up to 20% ADH and 40% DCIS lesions progress to invasive BC if left untreated. Deciphering the molecular mechanisms during BC progression is therefore crucial to prevent over- or under-treatment. Our previous work demonstrated that miR-671-5p serves as a tumor suppressor by targeting Forkhead box protein M1 (FOXM1)-mediated epithelial-to-mesenchymal transition (EMT) in BC. Here, we aim to explore the role of miR-671-5p in the progression of BC oncogenic transformation and treatment. METHODS: The 21T series cell lines, which were originally derived from the same patient with metastatic BC, including normal epithelia (H16N2), ADH (21PT), primary DCIS (21NT), and cells derived from pleural effusion of lung metastasis (21MT), and human BC specimens were used. Microdissection, miRNA transfection, dual-luciferase, radio- and chemosensitivity, and host-cell reactivation (HCR) assays were performed. RESULTS: Expression of miR-671-5p displays a gradual dynamic decrease from ADH, to DCIS, and to IDC. Interestingly, the decreased expression of miR-671-5p detected in ADH coexisted with advanced lesions, such as DCIS and/or IDC (cADH), but not in simple ADH (sADH). Ectopic transfection of miR-671-5p significantly inhibited cell proliferation in 21NT (DCIS) and 21MT (IDC), but not in H16N2 (normal) and 21PT (ADH) cell lines. At the same time, the effect exhibited in time- and dose-dependent manner. Interestingly, miR-671-5p significantly suppressed invasion in 21PT, 21NT, and 21MT cell lines. Furthermore, miR-671-5p suppressed FOXM1-mediated EMT in all 21T cell lines. In addition, miR-671-5p sensitizes these cell lines to UV and chemotherapeutic exposure by reducing the DNA repair capability. CONCLUSIONS: miR-671-5p displays a dynamic decrease expression during the oncogenic transition of BC by suppressing FOXM1-mediated EMT and DNA repair. Therefore, miR-671-5p may serve as a novel biomarker for early BC detection as well as a therapeutic target for BC management.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Tolerância a Radiação/genética , Regiões 3' não Traduzidas , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Dano ao DNA , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Proteína Forkhead Box M1/genética , Genes Reporter , Humanos , Modelos Biológicos , Interferência de RNA
11.
Int J Radiat Oncol Biol Phys ; 105(4): 698-712, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31381960

RESUMO

The advent of affordable and rapid next-generation DNA sequencing technology, along with the US Supreme Court ruling invalidating gene patents, has led to a deluge of germline and tumor genetic variant tests that are being rapidly incorporated into clinical cancer decision-making. A major concern for clinicians is whether the presence of germline mutations may increase the risk of radiation toxicity or secondary malignancies. Because scarce clinical data exist to inform decisions at this time, the American Society for Radiation Oncology convened a group of radiation science experts and clinicians to summarize potential issues, review relevant data, and provide guidance for adult patients and their care teams regarding the impact, if any, that genetic testing should have on radiation therapy recommendations. During the American Society for Radiation Oncology workshop, several main points emerged, which are discussed in this manuscript: (1) variants of uncertain significance should be considered nondeleterious until functional genomic data emerge to demonstrate otherwise; (2) possession of germline alterations in a single copy of a gene critical for radiation damage responses does not necessarily equate to increased risk of radiation-induced toxicity; (3) deleterious ataxia-telangiesctasia gene mutations may modestly increase second cancer risk after radiation therapy, and thus follow-up for these patients after indicated radiation therapy should include second cancer screening; (4) conveying to patients the difference between relative and absolute risk is critical to decision-making; and (5) more work is needed to assess the impact of tumor somatic alterations on the probability of response to radiation therapy and the potential for individualization of radiation doses. Data on radiosensitivity related to specific genetic mutations is also briefly discussed.


Assuntos
Testes Genéticos , Mutação , Neoplasias/genética , Neoplasias/radioterapia , Radio-Oncologistas , Tolerância a Radiação/genética , Adulto , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Tomada de Decisão Clínica , Consenso , Reparo do DNA/genética , Genes BRCA1 , Genes BRCA2 , Variação Genética , Mutação em Linhagem Germinativa , Pesquisas sobre Serviços de Saúde , Heterozigoto , Humanos , Neoplasias Induzidas por Radiação/genética , Segunda Neoplasia Primária/genética , Síndrome , Terminologia como Assunto
12.
Int J Mol Sci ; 20(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349558

RESUMO

In the era of precision medicine, radiotherapy strategies should be determined based on genetic profiles that predict tumor radiosensitivity. Accordingly, pre-clinical research aimed at discovering clinically applicable genetic profiles is needed. However, how a given genetic profile affects cancer cell radiosensitivity is unclear. To address this issue, we performed a pilot in vitro study by utilizing EGFR mutational status as a model for genetic profile. Clonogenic assays of EGFR mutant (n = 6) and wild-type (n = 9) non-small cell lung carcinoma (NSCLC) cell lines were performed independently by two oncologists. Clonogenic survival parameters SF2, SF4, SF6, SF8, mean inactivation dose (MID), D10, D50, α, and ß were obtained using the linear quadratic model. The differences in the clonogenic survival parameters between the EGFR mutant and wild-type cell lines were assessed using the Mann-Whitney U test. As a result, for both datasets, the p values for SF2, SF4, D50, α, and α/ß were below 0.05, and those for SF2 were lowest. These data indicate that a genetic profile of NSCLC cell lines might be predictive for their radiation response; i.e., EGFR mutant cell lines might be more sensitive to low dose- and low fraction sized-irradiation.


Assuntos
Mutação , Doses de Radiação , Tolerância a Radiação/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Ensaio Tumoral de Célula-Tronco , Raios X
13.
Int J Mol Sci ; 20(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277435

RESUMO

High-intensity ultraviolet-B (UV-B) irradiation is a complex abiotic stressor resulting in excessive light exposure, heat, and dehydration, thereby affecting crop yields. In the present study, we identified quantitative trait loci (QTLs) for resistance to high-intensity UV-B irradiation in soybean (Glycine max [L.]). We used a genotyping-by-sequencing approach using an F6 recombinant inbred line (RIL) population derived from a cross between Cheongja 3 (UV-B sensitive) and Buseok (UV-B resistant). We evaluated the degree of leaf damage by high-intensity UV-B radiation in the RIL population and identified four QTLs, UVBR12-1, 6-1, 10-1, and 14-1, for UV-B stress resistance, together explaining 20% of the observed phenotypic variation. The genomic regions containing UVBR12-1 and UVBR6-1 and their syntenic blocks included other known biotic and abiotic stress-related QTLs. The QTL with the highest logarithm of odds (LOD) score of 3.76 was UVBR12-1 on Chromosome 12, containing two genes encoding spectrin beta chain, brain (SPTBN, Glyma.12g088600) and bZIP transcription factor21/TGACG motif-binding 9 (bZIP TF21/TGA9, Glyma.12g088700). Their amino acid sequences did not differ between the mapping parents, but both genes were significantly upregulated by UV-B stress in Buseok but not in Cheongja 3. Among five genes in UVBR6-1 on Chromosome 6, Glyma.06g319700 (encoding a leucine-rich repeat family protein) had two nonsynonymous single nucleotide polymorphisms differentiating the parental lines. Our findings offer powerful genetic resources for efficient and precise breeding programs aimed at developing resistant soybean cultivars to multiple stresses. Furthermore, functional validation of the candidate genes will improve our understanding of UV-B stress defense mechanisms.


Assuntos
Locos de Características Quantitativas/genética , Tolerância a Radiação/genética , Soja/genética , Soja/efeitos da radiação , Raios Ultravioleta , Mapeamento Cromossômico , Cromossomos de Plantas/genética , Cruzamentos Genéticos , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Ligação Genética , Genoma de Planta , Endogamia , Escore Lod , Fenótipo , Folhas de Planta/efeitos da radiação , Polimorfismo de Nucleotídeo Único/genética , Estresse Fisiológico/genética , Estresse Fisiológico/efeitos da radiação , Sintenia/genética
14.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261893

RESUMO

BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative disorders involving devastating loss of dopaminergic neurons in the substantia nigra. Early steps in PD pathogenesis include mitochondrial dysfunction, and mutations in mitochondrial genes have been linked to familial forms of the disease. However, low penetrance of mutations indicates a likely important role for environmental factors in PD risk through gene by environment interactions. Herein, we study how genetic deficiencies in mitochondrial dynamics processes including fission, fusion, and mitophagy interact with environmental exposures to impact neurodegeneration. METHODS: We utilized the powerful model organism Caenorhabditis elegans to study ultraviolet C radiation (UVC)- and 6-hydroxydopamine-induced degeneration of fluorescently-tagged dopaminergic neurons in the background of fusion deficiency (MFN1/2 homolog, fzo-1), fission deficiency (DMN1L homolog, drp-1), and mitochondria-specific autophagy (mitophagy) deficiency (PINK1 and PRKN homologs, pink-1 and pdr-1). RESULTS: Overall, we found that deficiency in either mitochondrial fusion or fission sensitizes nematodes to UVC exposure (used to model common environmental pollutants) but protects from 6-hydroxydopamine-induced neurodegeneration. By contrast, mitophagy deficiency makes animals more sensitive to these stressors with an interesting exception-pink-1 deficiency conferred remarkable protection from 6-hydroxydopamine. We found that this protection could not be explained by compensatory antioxidant gene expression in pink-1 mutants or by differences in mitochondrial morphology. CONCLUSIONS: Together, our results support a strong role for gene by environment interactions in driving dopaminergic neurodegeneration and suggest that genetic deficiency in mitochondrial processes can have complex effects on neurodegeneration.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Dinâmica Mitocondrial , Doença de Parkinson/genética , Tolerância a Radiação/genética , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos da radiação , Dinaminas/genética , GTP Fosfo-Hidrolases/genética , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/genética , Raios Ultravioleta/efeitos adversos
15.
Int J Radiat Oncol Biol Phys ; 105(2): 275-284, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201893

RESUMO

PURPOSE: To estimate the effect of radiation therapy (RT) on nonbreast second malignant neoplasms (SMNs) in young women survivors of stage I-IIIA breast cancer. METHODS AND MATERIALS: Women aged 20 to 44 years who received a diagnosis of stage I-IIIA breast cancer (1988-2008) were identified in the Surveillance, Epidemiology, and End Results 9 registries. Bootstrapping approach and competing-risk proportional hazards models were used to evaluate the effect of RT on nonbreast SMN risk. The analysis was repeated in racial subgroups. Radiotolerance score analysis of normal airway epithelium was performed using Gene Expression Omnibus (GEO) data sets. RESULTS: Within records of 30,003 women with primary breast cancer, 20,516 eligible patients were identified, including 2,183 African Americans (AAs) and 16,009 Caucasians. The 25-year cumulative incidences of SMN were 5.2% and 3.6% (RT vs no-RT) for AAs, with 12.8-year and 17.4-year (RT vs no-RT) median follow-up (hazard ratio [HR] = 1.81; 95% bootstrapping confidence interval [BCI], 1.02-2.50; P < .05), respectively, and 6.4% and 5.9% (RT vs no-RT) for Caucasians with 14.3-year and 18.1-year (RT vs no-RT) median follow-up (HR = 1.10; 95% BCI, 0.61-1.40; P > .05), respectively. The largest portion of excess RT-related SMN risk was lung cancer (AA: HR = 2.08, 95% BCI, 1.02-5.39, P < .05; Caucasian: HR = 1.50, 95% BCI, 0.84-5.38, P > .05). Subpopulation Treatment Effect Pattern Plot (STEPP) analysis revealed higher post-RT nonbreast SMN risk in those 20 to 44 years of age, with larger HRs for RT in AAs. Radiotolerance score (RTS) of normal airway epithelium from young AA women was significantly lower than that from young Caucasian women (P = .038). CONCLUSIONS: With a projected 25-year follow-up, RT is associated with elevated risk of nonbreast SMNs, particularly second lung cancer, in young women survivors of stage I-IIIA breast cancer. Nonbreast SMNs associated with RT are higher in AA women than Caucasian women.


Assuntos
Afro-Americanos , Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Neoplasias Induzidas por Radiação , Segunda Neoplasia Primária/etiologia , Adulto , Afro-Americanos/estatística & dados numéricos , Fatores Etários , Neoplasias da Mama/patologia , Sobreviventes de Câncer , Carcinoma Ductal de Mama/patologia , Feminino , Seguimentos , Expressão Gênica , Humanos , Incidência , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Neoplasias Induzidas por Radiação/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Modelos de Riscos Proporcionais , Tolerância a Radiação/genética , Programa de SEER , Estatísticas não Paramétricas , Estados Unidos/epidemiologia , Adulto Jovem
16.
BMC Med Genomics ; 12(1): 73, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138194

RESUMO

BACKGROUND: Radioresistance is one of the main obstacle limiting the therapeutic efficacy and prognosis of patients, the molecular mechanisms of radioresistance is still unclear. The purpose of this study was to identify the key genes and miRNAs and to explore their potential molecular mechanisms in radioresistant nasopharyngeal carcinoma. METHODS: In this study, we analysis the differentially expressed genes and microRNA based on the database of GSE48501 and GSE48502, and then employed bioinformatics to analyze the pathways and GO terms in which DEGs and DEMS target genes are involved. Moreover, Construction of protein-protein interaction network and identification of hub genes. Finally, analyzed the biological networks for validated target gene of hub miRNAs. RESULTS: A total of 373 differentially expressed genes (DEGs) and 14 differentially expressed microRNAs (DEMs) were screened out. The up-regulated gene JUN was overlap both in DEGs and publicly available studies, which was potentially targeted by three miRNAs, including hsa-miR-203, hsa-miR-24 and hsa-miR-31. Moreover, Pathway analysis showed that both up-regulated gene and DEMs target genes were enriched in TGF-beta signaling pathway, Hepatitis B, Pathways in cancer and p53 signaling pathway. Finally, we further constructed protein-protein interaction network (PPI) of DEGs and analyzed the biological networks for above mentioned common miRNAs, the result indicated that JUN was a core hub gene in PPI network, hsa-miR-24 and its target gene were significantly enriched in P53 signaling pathway. CONCLUSIONS: These results might provide new clues to improve the radiosensitivity of Nasopharyngeal Carcinoma.


Assuntos
Biologia Computacional , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Tolerância a Radiação/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Mapeamento de Interação de Proteínas , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/metabolismo
17.
Mol Med Rep ; 20(1): 81-94, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115568

RESUMO

It has been demonstrated that microRNAs (miRNAs) serve important roles in various biological processes, such as tumorigenesis. In the present study, the role of miR­30a­3p in the pathogenesis of esophageal carcinoma (EC) was investigated. Reverse transcription­quantitative polymerase chain reaction was performed to determine the levels of miR­30a­3p expression in EC tissues and cell lines. Then, the effects of miR­30a­3p on the migration, invasion and radiosensitivity of EC cells were investigated using scratch­wound, Transwell and radiosensitivity assays, respectively. A dual­luciferase reporter assay was performed to determine potential interactions between miR­30a­3p and the 3'­untranslated region (3'­UTR) of insulin­like growth factor 1 receptor (IGF­1R). The results demonstrated that the levels of miR­30a­3p expression in EC tissues and cell lines were significantly decreased compared with those in paired healthy tissues and a human esophageal epithelial cell line. Upregulation of miR­30a­3p expression significantly suppressed migration, invasion and epithelial­mesenchymal transition (EMT), and enhanced radiosensitivity in EC cells. Analysis of luciferase activity demonstrated that miR­30a­3p interacted with the 3'­UTR of IGF­1R, and knockdown of IGF­1R induced similar effects on the migration, invasion, EMT and radiosensitivity of EC cells. The results indicated that miR­30a­3p suppressed metastasis and enhanced the radiosensitivity of EC cells via downregulation IGF­1R, suggesting that miR­30a­3p may be a potential therapeutic target in the treatment of EC.


Assuntos
Carcinoma/radioterapia , Neoplasias Esofágicas/radioterapia , Tolerância a Radiação/genética , Receptor IGF Tipo 1/genética , Idoso , Carcinogênese/genética , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Fator de Crescimento Insulin-Like I/genética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica
18.
Virchows Arch ; 475(1): 39-47, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31056731

RESUMO

Our study was done in order to identify novel molecular markers to predict which locally advanced rectal cancers (LARCs) might be resistant to neoadjuvant chemoradiotherapy (nCRT). Seventy-four patients with LARCs treated with nCRT were collected. Pathological evaluation after nCRT was performed according to the tumor regression grading (TRG) system. Next-generation sequencing kit including 279 exons of 59 genes was performed on Illumina Miseq Platform. Sanger sequencing was performed to confirm some mutations. Four of the tumors (4/74, 5.4%) had BRAF mutation, which presented in one TRG 2 tumor and three TRG 3 tumors but was not observed in TRG 0-1 tumors. Higher mutational frequency of BRAF gene in TRG 3 tumors (3/12, 25%) was found in comparison with the TRG 0-2 tumors (1/62, 1.6%; p = 0.012). Eight tumors (8/74, 10.8%) harbored SMAD4 mutations, which was mutated across all TRG groups. However, SMAD4 mutated more in TRG 3 tumors (4/12, 33.3%) compared with that in TRG 0-2 tumors (4/62, 6.5%; p = 0.020). The patients with BRAF-mutated LARCs had shorter progression-free survival (PFS) (p = 0.045) and shorter overall survival (OS) (p = 0.000) than the BRAF wild-type (WT) ones. The patients with SMAD4-mutated tumors had shorter PFS than the WT cases (p = 0.008). BRAF and SMAD4 genetic mutations might be important molecular markers to predict resistance to nCRT and poor prognosis in LARCs. More cases are needed to confirm these findings in the near future.


Assuntos
Biomarcadores Tumorais/genética , Quimiorradioterapia Adjuvante , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Terapia Neoadjuvante , Proteínas Proto-Oncogênicas B-raf/genética , Tolerância a Radiação/genética , Neoplasias Retais/terapia , Proteína Smad4/genética , Adulto , Idoso , Quimiorradioterapia Adjuvante/efeitos adversos , Análise Mutacional de DNA , Progressão da Doença , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Terapia Neoadjuvante/efeitos adversos , Gradação de Tumores , Estadiamento de Neoplasias , Fenótipo , Intervalo Livre de Progressão , Neoplasias Retais/genética , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
19.
Med Sci Monit ; 25: 3469-3475, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31075090

RESUMO

BACKGROUND The aim of this study was to investigate the role of deubiquitinase [ovarian tumor domain-containing protein 5 (OTUD5)] in regulating Akt ubiquitination and its effect on the radiosensitivity of cervical cancer. MATERIAL AND METHODS Cervical cancer C33A cells were cultured, and then 2 groups of cells (overexpressed cells and silenced cells) were established by overexpressing and silencing OTUD5 gene. Next, quantitative polymerase chain reaction (qPCR) was employed to detect the expression level of OTUD5 in cells in each group. Co-immunoprecipitation and Western blot (WB) analysis were applied to measure the expression level of phosphorylated protein kinase B (Akt) and the level of ubiquitination. The sensitivity of cells to radiotherapy in each group was detected via clone-forming efficiency assay. After that, Statistical Product and Service Solutions (SPSS) 17.0 software was employed for analyses. The t test, one-way analysis of variance (ANOVA), and p test were used. P<0.05 suggested that a difference was statistically significant. RESULTS The levels of phosphorylated Akt and ubiquitination in OTUD5-overexpressed C33A cells were lower than those in the OTUD5-silenced group and control group. The sensitivity of OTUD5-overexpressed C33A cells to radiotherapy was higher than that of the OTUD5-silenced group and control group. CONCLUSIONS OTUD5 affects the radiosensitivity of cervical cancer through the regulation of Akt deubiquitination.


Assuntos
Endopeptidases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Enzimas Desubiquitinantes/metabolismo , Endopeptidases/fisiologia , Feminino , Inativação Gênica , Humanos , Neoplasias Ovarianas/genética , RNA Interferente Pequeno , Tolerância a Radiação/genética , Tolerância a Radiação/fisiologia , Transdução de Sinais , Ubiquitinação , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/radioterapia
20.
Mol Med Rep ; 20(1): 613-621, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115576

RESUMO

Radiotherapy is a useful treatment for malignant tumors, including lung carcinoma; however, non­small cell lung carcinoma (NSCLC) is frequently insensitive to radiation. It has been reported that heat shock protein 27 (HSPB1) is a radioresistance­associated protein in nasopharyngeal carcinoma. In the present study, the role of HSPB1 in NSCLC cells induced by irradiation was investigated. The viability of cells was determined by a Cell Counting Kit­8 assay. The apoptotic activity, cell cycle distribution and mitochondrial membrane potential (MMP) of cells were evaluated via flow cytometry. Reverse transcription­quantitative polymerase chain reaction and western blot analyses were employed to measure the expression of various genes and proteins. It was observed that knockdown of HSPB1 with small interfering RNA (si­HSPB1) markedly decreased the viability of A549 NSCLC cells and induced cell cycle arrest in the G2/M phase following exposure to 6 Gy irradiation. Furthermore, it was revealed that si­HSPB1 significantly downregulated cyclin B1 and cyclin G1 expression. Additionally, si­HSPB1 promoted apoptosis and depolarized the MMP of cells exposed to 6 Gy irradiation. The expression levels of B­cell lymphoma­2 (Bcl­2), mitochondrial cytochrome c (cyto c) and pro­caspase­8 were downregulated, whereas those of Bcl­2 associated X protein (Bax), cytosolic cyto c and cleaved­caspase­8 were upregulated. Collectively, silencing of HSPB1 increased the radiosensitivity of NSCLC cells by reducing cell viability, depolarizing the MMP, arresting the cell cycle in the G2/M phase and promoting cell apoptosis. Therefore, HSPB1 may be a novel target for increasing radiosensitivity in the treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Choque Térmico HSP27/genética , Proteínas de Neoplasias/genética , Tolerância a Radiação/genética , Células A549 , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Ciclo Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica , Humanos , Potencial da Membrana Mitocondrial/genética
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