CTRC通过调控自噬参与胰腺癌发生发展的作用机制研究

Pancreatic ductal adenocarcinoma (PDAC), with its extreme high mortality and poor prognosis, is one of the most lethal cancers worldwide. However, little is known about the molecular mechanism of PDAC. We have analyzed the protein expression differences between normal pancreatic tissues and PDAC tissues using mass spectrum analysis. Chymotrypsin C (CTRC)was identified down regulated in PDAC among 44 differentially expressed proteins. Besides, down-regulation of CTRC in pancreatic ductal epithelial cells could inhibit autophagy under stress conditions. Hence, we speculate that, when the external stimulation occurs, down-regulated CTRC in pancreatic epithelial cells cannot repair damage and induce apoptosis through autophagy, leading to the malignant transformation, thus contributing to the occurrence of pancreatic cancer. In the present study, we are to clarify correlation between CTRC and PDAC prognosis by tissue array. We will verify down-regulated CTRC induced autophagy inhibition could lead to cell malignant transformation under stress conditions. Finally, we will screen the interacting proteins of CTRC and uncover the regulation mechanisms of CTRC on autophagy. Our research will shed lights on new mechanisms of malignant transformation of pancreatic epithelial cells and eventually provide new therapeutic targets for the treatment of PDAC.

胰腺癌（胰腺导管腺癌，PDAC）是高度恶性、预后极差的肿瘤，其发病机制尚不清楚。我们利用质谱筛选出44个在胰腺癌和癌旁组织中具有统计学意义的差异表达蛋白，证实糜蛋白酶C(CTRC)在胰腺癌组织和细胞系中表达下调，且CTRC表达下调抑制了胰腺导管上皮细胞在应激条件下的自噬作用。我们推测：当外界刺激发生时，CTRC表达下调的胰腺导管上皮细胞无法通过自噬作用修复损伤、诱导凋亡，导致其恶性转化，从而促进了胰腺癌的发生。本研究拟通过组织芯片明确CTRC与胰腺癌预后的相关性；利用免疫组化染色分析临床标本连续切片中CTRC与细胞自噬相关分子的表达相关性；验证在应激条件下CTRC下调诱发的胰腺导管上皮细胞自噬作用减弱导致的细胞恶性转化；筛选CTRC相互作用蛋白，揭示CTRC调控细胞自噬的机制，并初步阐明CTRC表达下调机理。本研究将为胰腺导管上皮细胞恶性演变提供新的机理，为胰腺癌早期干预提供新的治疗靶点。

胰腺癌（胰腺导管腺癌，PDAC）是高度恶性、预后极差的肿瘤，其发病机制尚不清楚。我们利用质谱筛选出44个在胰腺癌和癌旁组织中具有统计学意义的差异表达蛋白，证实糜蛋白酶C(CTRC)在胰腺癌组织和细胞系中表达下调，且CTRC表达下调抑制了胰腺导管上皮细胞在应激条件下的自噬作用。我们推测：当外界刺激发生时，CTRC表达下调的胰腺导管上皮细胞无法通过自噬作用修复损伤、诱导凋亡，导致其恶性转化，从而促进了胰腺癌的发生。本研究拟通过组织芯片明确CTRC与胰腺癌预后的相关性；利用免疫组化染色分析临床标本连续切片中CTRC与细胞自噬相关分子的表达相关性；验证在应激条件下CTRC下调诱发的胰腺导管上皮细胞自噬作用减弱导致的细胞恶性转化；筛选CTRC相互作用蛋白，揭示CTRC调控细胞自噬的机制，并初步阐明CTRC表达下调机理。本研究将为胰腺导管上皮细胞恶性演变提供新的机理，为胰腺癌早期.干预提供新的治疗靶点