胰腺癌星状细胞活化分泌TenascinC调节肿瘤生长的分子机制研究

Pancreatic cancer is characterized by serious progress, poor prognosis and chemo resistance. The fibroblast，collagen and fibronectin constitute tumor micro- environmental extracellular matrix,(ECM) of pancreatic cancer. Pancreatic stellate cell(PSC) locates in ECM and actives during the tumor development.TenascinC(TNC) is secreted only by activated PSC and probably makes the function in modulating tumor progression in pancreatic cancer. Previous study has demonstrated some biological properties of TNC, including tumor proliferation and molecules expressions in pancreatic cancer. So far, few study has reported about the intrinsic mechanism by which TNC affects the pancreatic cancer progression.In present project,we will investigate the molecular mechanism of PSC/TNC in enhancing tumor cell invasion and proliferation, regulating tumor cell differentiation, inhibiting tumor angiogenesis and apoptosis, and inducing chemoresistance in pancreatic cancer. We will elucidate that TNC, as the specific secreted factor in ECM, play an important role in distigushing the diagnosis, assessing the therapeutic regimen and acting as a potential therapeutic target for pancreatic cancer.

胰腺癌高度恶性，对放化疗不敏感，死亡率高。确定胰腺癌诊断标记物、治疗靶点和治疗方案，是改善预后关键。胰腺癌组织周围聚集大量的成纤维细胞、胶原和纤维黏连蛋白结缔组织，与胰腺癌细胞相互作用肿影响瘤生长。胰腺癌星状细胞(pancreatic stellate cell PSC)活化后分泌腱糖蛋白C（TenascinC TNC）作为胰腺癌微环境中特异表达的功能蛋白，具有重要生物活性,可能与肿瘤生长有关，但是其生物学功能还不清楚。我们对部分胰腺癌标本研究时发现PSC活化蛋白α-平滑肌蛋白和TNC表达异常升高，并且与肿瘤生长具有相关性。TNC某些生物学特性在以往的初步细胞学试验中得到验证，如对肿瘤增殖的影响及其相关信号分子等。本项目观察PSC/TNC对胰腺癌的生长的影响，及其及相关分子机制，拟证实TNC为胰腺癌诊断的标记物，可以对优化胰腺癌治疗方案有评估价值和可能成为胰腺癌分子治疗的有效靶点。

胰腺癌高度恶性，对放化疗不敏感，死亡率高。确定胰腺癌诊断标志物、治疗靶点和治疗方案，是改善预后关键。胰腺癌星状细胞及癌细胞分泌腱糖蛋白C（Tenascin-C, TNC）作为胰腺癌微环境中特异表达的功能蛋白，具有重要生物活性，与胰腺癌细胞相互作用影响瘤生长、转移。我们研究发现TNC在癌组织中高表达并与与胰腺癌的肿瘤分期呈相关性。TNC激活JNK信号通路调控上皮间质转化（EMT）、金属基质蛋白酶9（MMP9）和黏着斑的形成，从而促进肿瘤的转移；TNC激活ERK1/2的磷酸化，增加NF-κB的表达和核转运，从而抑制细胞凋亡；TNC激活AKT信号通路，通过调控β-catenin和p27Kip1影响cyclin D1-CDK4复合物的形成，从而促进G1/S期转化、细胞增殖；TNC还可激活ABCG2表达促进其核转移，从而增强肿瘤细胞对吉西他滨的耐受性。通过对TNC在胰腺癌转移、增殖及凋亡的研究，丰富了对胰腺癌发生发展机制的认识。吉西他滨是用于胰腺癌治疗的一线药物，通过研究TNC对胰腺癌细胞吉西他滨耐药调节作用，可为胰腺癌的诊治提出新的靶点和思路。