Notch信号在结直肠癌中调控NF-κB通路的分子机制及其对肿瘤恶性生物学行为作用的研究

Notch signal is of great importance in human malignancy. Classical Notch pathway has been widely investigated. However, recent study found that Notch signal can regulate tumor carcinogenesis and progression through non-classical pathway, among which NF-κB is an important pathway. In that concept, Notch signal could regulate tumor carcinogenesis and progression by increase or decrease the activity of NF-κB signal. But the molecular mechanism underlied the regulation of Notch to NF-κB is still not clear. Our team has intensively investigated the function of Notch signal in colorectal cancer and harvested many valuable results. Our research on the mechanism of Notch showed that Notch signal could regulate tumor carcinogenesis and progression of colorectal cancer by both transcription dependent manner and non- transcription dependent manner. The present study is going to investigate the relation between Notch signal and NF-κB signal molecules; clarify the mechanism of the regulation on tumor carcinogenesis and progression by Notch through NF-κB; construct conditional gene knockout mice to verify the function of Notch on regulate colorectal cancer carcinogenesis and progression through NF-κB. The present study has important significance on know Notch signal and the mechanism of colorectal cancer carcinogenesis and progression.

Notch信号通路在肿瘤中具有重要作用。经典Notch信号通路的作用机制已经得到广泛的研究，但是近年的研究发现，除了经典通路外,Notch信号还通过非经典通路在肿瘤的发生发展中发挥作用，其中最重要的即与NF-κB相互作用，通过增强或抑制NF-κB信号参与肿瘤的发生发展，但是其调控NF-κB通路的分子机制目前尚不清楚。我课题组深入研究了Notch信号在结结直肠癌中作用，获得了大量重要的研究成果，对其作用机制的研究发现，Notch信号可能通过转录-依赖和转录-非依赖两种方式调控NF-κB 通路参与结直肠癌发生发展。本研究将在大样本临床标本中明确Notch与NF-κB通路分子表达间的关系；阐明Notch信号调控NF-κB通路的分子机制，构建条件性基因敲除小鼠验证Notch信号通过调控NF-κB通路对结肠癌发生发展的作用。这对认识Notch信号的调控通路及结直肠癌发生发展的分子机制具有重要的意义。

Notch信号通路在肿瘤中具有重要作用。经典Notch信号通路的作用机制已经得到广泛的研究，但是近年的研究发现，除了经典通路外,Notch信号还通过非经典通路在肿瘤的发生发展中发挥作用，其中最重要的即与NF-κB相互作用，通过增强或抑制NF-κB信号参与肿瘤的发生发展，但是其调控NF-κB通路的分子机制目前尚不清楚。我课题组通过深入研究发现，Notch信号可通过转录-依赖和转录-非依赖两种方式调控NF-κB 通路参与结直肠癌发生发展。在转录-依赖调控方式中，Notch信号受体胞内段通过促进P52等转录调控NF-κB 通路，活化的NF-κB 通路又可以促进jagged-1等的转录。在转录-非依赖方式中，Notch受体胞内段与IKK 家族分子结合使其活化，导致NF-κB 通路活化，进而调控NF-κB信号。上述研究成果可进一步认识Notch信号的调控通路及结直肠癌发生发展的分子机制。