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Role of Telomeric RAP1 in radiation sensitivity modulation and its interaction with CSC marker KLF4 in Colorectal cancer.

端粒 RAP1 在结直肠癌放射敏感性调节中的作用及其与 CSC 标志物 KLF4 的相互作用。

  • 影响因子:2.03
  • DOI:10.1080/09553002.2020.1721609
  • 作者列表:"Anuja K","Kar M","Chowdhury AR","Shankar G","Padhi S","Roy S","Akhter Y","Rath AK","Banerjee B
  • 发表时间:2020-01-27
Abstract

:Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.

摘要

目的: 放射治疗主要作为治疗结直肠癌 (CRC) 局部肿瘤的治疗方式之一。疾病治疗中的障碍可归因于肿瘤干细胞 (CSCs) 在肿瘤中生存的放射耐受。了解 CSCs 的放射抗性特性可能有助于完成靶向放疗治疗,提高无病生存率。端粒 RAP1 有助于调节各种转录因子,导致异常细胞增殖和肿瘤细胞迁移。因此,我们研究了 RAP1 在放射抗性细胞中维持抗性表型和获得性干性的作用。主要方法: 通过细胞存活和 DNA 损伤分析对 HCT116 来源的放射抗性细胞 (HCT116RR) 进行表征。通过 western blotting 和 Real-time PCR 观察 RAP1 沉默细胞的 DNA 损伤和 CSC 标记物的表达。进行分子对接和免疫共沉淀研究,研究 RAP1 和 KLF4 的相互作用,然后在 CRC 患者中进行 RAP1 蛋白状态分析。关键发现: 我们建立了放射抗性细胞,其表现出对放疗的耐受性和 CSC 标记物的表达升高以及 rap1。RAP1 沉默显示辐射后 DNA 损伤增强,CSC 标记物表达降低。我们观察到 RAP1 和 KLF4 蛋白之间存在强烈的物理相互作用。此外,在 CRC 患者的肿瘤中观察到较高的 RAP1 表达。数据集分析还发现 RAP1 高表达与不良预后相关。意义: 我们得出结论,较高的表达 ofRAP1 暗示其可能通过调节 DNA 损伤和 CSC 表型促进 CRC 细胞的放射抗性。

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相关文献
影响因子:2.03
发表时间:2020-01-27
DOI:10.1080/09553002.2020.1721609
作者列表:["Anuja K","Kar M","Chowdhury AR","Shankar G","Padhi S","Roy S","Akhter Y","Rath AK","Banerjee B"]

METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.

翻译标题与摘要 下载文献
影响因子:2.69
发表时间:2020-01-18
DOI:10.1016/j.bbrc.2020.01.048
作者列表:["Li Y","Wang Z","Jin J","Zhu SX","He GQ","Li SH","Wang J","Cai Y"]

METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.

翻译标题与摘要 下载文献
影响因子:2.46
发表时间:2020-01-01
DOI:10.1097/COC.0000000000000609
作者列表:["Appelt AL","Andersen RF","Lindebjerg J","Jakobsen A"]

METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.

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