Rab5C enhances resistance to ionizing radiation in rectal cancer
Rab5C enhances resistance to ionizing radiation in rectal cancer
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DOI：
10.1007/s00109-019-01760-6
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发表时间：
2019-06-01
影响因子：
4.7
通讯作者：
Martins, Ilma Regina
中科院分区：
文献类型：
--
作者：
Baptisteila, Antuani Rafael;Landemberger, Michele Christine;Martins, Ilma Regina
直肠癌占被诊断的结直肠癌的三分之一。新辅助放化疗是直肠癌治疗的一种行之有效的方案，可降低局部复发的风险。然而，仅在10-40%的病例中实现病理完全缓解，并且与耐药相关的机制知之甚少。为了确定预防耐药性的潜在靶点，对新辅助治疗前从II期和III期直肠腺癌患者收集的活检标本进行蛋白质组学分析，并与新辅助治疗后手术切除的残留肿瘤组织进行比较。Ku 70、Ku 80和Rab 5C三种蛋白在放化疗后表达显著增加。为了更好地理解这些蛋白质在治疗抗性中的作用，照射直肠腺癌细胞系以产生放射治疗抗性谱系。这些细胞过度表达了在组织样本中鉴定的相同的三种蛋白质。此外，在该体外模型中，发现放射治疗抗性涉及Rab 5C对辐射响应的表皮生长因子受体（EGFR）内化的调节，影响DNA修复蛋白Ku 70和Ku 80的表达和细胞抗性。综上所述，这些发现表明EGFR和Rab 5C是直肠癌细胞致敏的潜在靶点，应该进一步研究。关键信息中心Rab 5C协调直肠腺癌的放射抗性机制Ku80.center在细胞核中，EGFR可以调节DNA修复蛋白Ku 70和Ku 80的表达。nucleus.center cell.center
Rectal cancer represents one third of the colorectal cancers that are diagnosed. Neoadjuvant chemoradiation is a well-established protocol for rectal cancer treatment reducing the risk of local recurrence. However, a pathologic complete response is only achieved in 10-40% of cases and the mechanisms associated with resistance are poorly understood. To identify potential targets for preventing therapy resistance, a proteomic analysis of biopsy specimens collected from stage II and III rectal adenocarcinoma patients before neoadjuvant treatment was performed and compared with residual tumor tissues removed by surgery after neoadjuvant therapy. Three proteins, Ku70, Ku80, and Rab5C, exhibited a significant increase in expression after chemoradiation. To better understand the role of these proteins in therapy resistance, a rectal adenocarcinoma cell line was irradiated to generate a radiotherapy-resistant lineage. These cells overexpressed the same three proteins identified in the tissue samples. Furthermore, radiotherapy resistance in this in vitro model was found to involve modulation of epidermal growth factor receptor (EGFR) internalization by Rab5C in response to irradiation, affecting expression of the DNA repair proteins, Ku70 and Ku80, and cell resistance. Taken together, these findings indicate that EGFR and Rab5C are potential targets for the sensitization of rectal cancer cells and they should be further investigated.Key messages center dot Rab5C orchestrates a mechanism of radioresistance in rectal adenocarcinoma cell.center dot Rab5C modulates EGFR internalization and its relocalization to the nucleus.center dot In the nucleus, EGFR can modulate the expression of the DNA repair proteins, Ku70 and Ku80.center dot Rab5C, Ku70, and Ku80 are overexpressed in tumor tissues that contain tumor cells that are resistant to chemoradiation treatment.