Livin-Fibronectin分子与生物力学信号偶联介导前列腺癌“抵抗-逃离”转移机制的研究

Invasion and metastasis is a major risk factor for prostate cancer mortality. According to the results discovered through our previous study apoptosis inhibitor protein Livin is an entity regarded as a facor directly involved in regulating prostate cancer metastasis by regulating the expression of the extracellular mechanical receptor-Fibronectin. Thus we speculated that Livin and Fibronectin molecules can couple extracellular biomechanical signals in order to mediate prostate cancer "resistance-flee" invasion and metastasis behavior however,exact mechanism is unknown. In our prospective study we undermine couple of maneuvers for getting deep into the molecular and biomechanical basis for prostatic carcinoma which are: (1) we analyze the correlation among prostate cancer tissue stiffness, Livin gene expression, and prostatic cancer clinical and pathological features through clinical samples. (2)By 3-D in-vitro cell culture investigation, the tumour cell foci is effected by biomechanical entitiy like extracellular matrix stiffness and the tumour cell compression because of ECM fibrosis furnishes Livin gene expression which directly or indirectly has a profound impression on invasion and metastasis of cancer cells.(3)As a result of apoptotic stress which indirectly flourishes Livin protein and causes build up of its quantity which further has a paramount clinging quality to enhance production of Fibronectin.Consequently,all this sort of biomechanical stress induced by tumour cells are culprits for gene expression and regulatory proteins which in the long run circumstances undoing predicaments for tumour cell invasion and metastasis.The objectives of our this perspective research is to descry and clearly ellaborate the bio-mechanics and molecular biology responsible for invasion and metastasis of neoplastic foci and its behaviour.Untie the blurred issues regarding its treatment which probably will add substantial edge for new therapeutic strategy.

侵袭与转移是前列腺癌的主要致死因素之一。我们前期研究发现，凋亡抑制蛋白Livin可以通过调节细胞外力学信号感受器-Fibronectin的表达直接参与调节前列腺癌的侵袭转移能力，提示Livin以及Fibronectin分子可能偶联细胞外力学信号，介导前列腺癌"抵抗-逃离"式侵袭、转移行为，但其具体机制不明。本项研究中，我们拟（1）通过对前列腺癌临床标本研究，分析前列腺癌组织硬度与Livin基因表达以及前列腺癌临床、病理特征的相关性。（2）通过灌流式细胞体外3-D培养，研究细胞外力学环境（细胞外基质硬度以及细胞承受外部压力）对Livin基因表达及细胞运动、侵袭能力的影响。（3）探讨Livin调节Fibronectin进而增加细胞外生物力学信号传递，激活肿瘤细胞内侵袭、转移相关分子信号的具体机制。从生物力学与分子生物学角度理解前列腺癌的侵袭、转移行为，为寻找前列腺癌的治疗新策略提供理论基础。

生物力学性质的变化在肿瘤发生发展中的作用越来越受到重视。前列腺组织在肿瘤发展过程中宏观和微观生物力学性质发生改变，并且随着肿瘤宏观力学性质（SI）的增高及微观力学性质（Young’s modulus）的减弱，肿瘤的恶性程度及转移能力增强，说明组织生物力学的变化与肿瘤的恶性生物学行为存在相关性；MMPs、LOX等相关蛋白水解酶介导的细胞外基质的重构，可能是导致前列腺癌组织微观力学性质变化原因，而肿瘤细胞过度增殖导致相互挤压产生的张力可能是前列腺癌宏观层面力学性质增强的原因，且fibronectin, integrinα5可能是力学信号传导通路上的重要分子；细胞外基质中含量最丰富的支架结构蛋白 Collagen I的浓度变化能够对前列腺癌PC-3细胞的粘附能力、力学性质（Young’s modulus）、侵袭能力及凋亡敏感性产生影响，说明Collagen I与前列腺癌细胞的恶性表型、力学性质存在相关性；通过实验研究表明，前列腺癌在发生发展过程中，组织及细胞生物力学性质的改变能够开启肿瘤细胞相关力学信号转导通路，通过跟以往细胞生物学及分子生物学不同的途径对肿瘤的发生发展产生影响，这为我们从多角度，跨学科的层面深入了解恶性肿瘤的发生机制是非常有帮助的。