IKIP在直肠癌术前放疗敏感性预测中的作用及分子机制

Rectal cancer is one of the most common cancers in China. Preoperative chemoradiotherapy, known as neoadjuvant CRT has been increasingly used for rectal cancer. Neoadjuvant CRT followed by total mesorectal excision (TME) has improved the rate of sphincter preservation and local pelvic control. However, response to radiotherapy differs among individual rectal cancer patients. About 30% of rectal cancer patients respond to neoadjuvant CRT. For nonresponders, neoadjuvant CRT not only brings extra expenditure and postoperative complications, but also results in a delay to therapy. It is important to identify a set of discriminating biomarkers that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Our previous work was carried out by DNA microarray analysis. To identify the radio sensitivity-related genes, global expression profiles of responders and nonresponders were assayed. Quantitative reverse transcription PCR (qRT-PCR) assays were used to measure the dsregulated genes and to assess their association with disease-free survival. In both qRT-PCR and IHC analysis, responders had higher level of IKIP expression compared with paired non-responders, the upregulation of IKIP was correlated with long Disease-free survival of rectal cancer, which indicated that the levels of IKIP expression were associated with the response to the radiotherapy and prognosis. This project was to further verify the correlation of IKIP upregulation with the response to radiotherapy and prognosis by a large-scale validation, and to investigate the impact of IKIP on the rectal cancer cell and its potentional molecular mechanism.

直肠癌是消化道常见恶性肿瘤之一,其发病率在我国逐年上升，术前辅助放化疗是重要的治疗方法。但是,直肠癌患者中术前放疗敏感人群仅占30%，术前放疗对不敏感的病人不仅增加手术并发症和费用，且耽误了手术和术后治疗的时间，因此寻找与放疗敏感性相关的生物学标志物对病例进行筛选, 避免无效、过度的治疗, 对于直肠癌个体化治疗有重要临床意义。我们利用人类全基因组表达谱芯片对放疗敏感和放疗抗性的直肠癌放疗前组织进行检测，筛选出差异表达的基因，运用Realtime PCR及免疫组化对关键基因进行验证，结果发现IKIP在放疗敏感组表达显著高于放疗抗性组，IKIP高表达组无疾病复发存活高于低表达组，说明IKIP与术前放疗敏感性及预后显著相关。本研究旨在在前期工作的基础上，一方面通过扩大样本验证IKIP与直肠癌术前放疗敏感性及术后复发的相关性。另一方面深入研究IKIP在放疗敏感性中发挥作用的分子机理。

直肠癌是消化道常见恶性肿瘤之一,其发病率在我国逐年上升，术前辅助放化疗是重要的治疗方法。但是,直肠癌患者中术前放疗敏感人群仅占30%，术前放疗对不敏感的病人不仅增加手术并发症和费用，且耽误了手术和术后治疗的时间，因此寻找与放疗敏感性相关的生物学标志物对病例进行筛选, 避免无效、过度的治疗, 对于直肠癌个体化治疗有重要临床意义。我们利用人类全基因组表达谱芯片对放疗敏感和放疗抗性的直肠癌放疗前组织进行检测，筛选出差异表达的基因，运用Realtime PCR及免疫组化对关键基因进行验证，结果发现IKIP在放疗敏感组表达显著高于放疗抗性组，IKIP高表达组无疾病复发存活高于低表达组，说明IKIP与术前放疗敏感性及预后显著相关。本研究在前期工作的基础上，一方面通过扩大样本验证了IKIP与直肠癌术前放疗敏感性及术后复发的相关性。另一方面研究了IKIP在放疗敏感性中发挥作用的分子机理。我们研究表明，IKIP与直肠癌术前放疗敏感性正相关，与术后预后正相关。过表达IKIP增强了CRC细胞的放疗敏感性。IKIP增强CRC细胞放疗敏感性可能是通过促进了CRC细胞凋亡及细胞周期的改变引起。IKIP表达受P53调控.我们的研究首次证实IKIP在术前放疗敏感性预测及术后预后预测中的意义，可作为潜在的放疗敏感性相关的生物学标志物。明确了IKIP在直肠癌中的表达及在放疗敏感性中所起到的作用，初步探索了调节IKIP表达的信号传导通路，部分阐释了IKIP在直肠癌放疗敏感性中发挥作用的分子机理。