Department of Pathology, University of Turku, Turku, Finland.
Department of Pathology, Turku University Hospital, Turku, Finland.
Cancer Med. 2018 Mar;7(3):698-706. doi: 10.1002/cam4.1361. Epub 2018 Feb 14.
Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients.
术前（放）化疗（C）RT 是直肠癌患者治疗的重要组成部分，但患者对这种治疗的肿瘤反应是可变的。到目前为止，还没有临床生物标志物可用于预测对（C）RT 的反应或根据患者的预后将其分层到不同的术前治疗组。在几种癌症中已经证明了癌性蛋白磷酸酶 2A 抑制剂（CIP2A）的过表达，并且常常与降低的存活率相关。最近，高 CIP2A 表达也被表明有助于头颈部鳞状细胞癌的放射抵抗，但很少有研究研究 CIP2A 与其他恶性肿瘤的放射反应之间的关系。我们评估了 CIP2A 蛋白表达水平与直肠癌患者术前（C）RT 后肿瘤消退和生存的关系。进一步研究了 CIP2A 沉默 siRNA 对暴露于辐射的结直肠癌细胞中细胞存活的影响。与高 CIP2A 表达肿瘤的患者相比，低 CIP2A 表达肿瘤的患者对长疗程（C）RT 更频繁地表现出中度或极好的反应。在分类分析中，他们的 36 个月疾病特异性生存率（DSS）也更高。在多变量分析中，低 CIP2A 表达水平仍然是增加 DSS 的独立预测因子。siRNA 对 CIP2A 转录的抑制作用被发现可使结直肠癌细胞对辐射敏感，并降低其体外存活能力。总之，这些结果表明，通过促进癌细胞的放射敏感性，低 CIP2A 蛋白表达水平与直肠癌患者对长疗程（C）RT 的良好反应相关。
