TβRIII多功能分子及其外源性融合肽s-TβRIII对涎腺腺样囊性癌演进调控及干预研究

Salivary gland adenoid cystic carcinoma (ACC) is a common malignant carcinoma of salivary gland. The high relapse rate and low long-dated survival rate of ACC is associated with (epithelial-mesenchymal transition, EMT). Recently, the type III TGF-β receptor (TβRIII, also known as betaglycan) exhibits characteristic of multiple functional sensor in human cancer disease. However, its role of in ACC disease remains largely unclear. The present proposal was designed to determine the distribution and expression changes of TβRIII in the progression of ACC and to identify its endogenous anti-cancer roles. In vivo and in vitro, we will determine that extracellular soluble betaglycan (s-TβRIII) as an isoform-selective TGF-β1 neutralizing agent exerts inhibitory effect on TGF-β signaling; and the intracellular domain of TβRIII (c-TβRIII) interacts with GIPC and β-arrestin2 to regulate downstream molecules including NF-κB and p38 by which TβRIII affects the process of EMT and drug resistance. This proposal will certainly shed a new light on the mechanism of TβRIII and its downstream signaling molecules that promote the the process of malignancy and EMT of ACC. This proposal will also evaluate the effect of s-TβRIII on the prevention and therapy for ACC. Therefore, it will expand our understanding of the role of TGF-β family members in tumor.

涎腺腺样囊性癌(ACC)是常见涎腺恶性肿瘤，术后仍具有较高的复发率和较低的远期生存率，其与上皮间质转化（EMT）发生有关。转化生长因子III型受体（TβRIII），是一种多功能细胞信号感受器，对多种肿瘤疾病进程起到重要调控作用，但在ACC疾病中的作用和功能尚不清楚。本研究在检测TβRIII在ACC肿瘤组织中表达、分布变化的基础上；通过体内外实验相为结合确定TβRIII分别可通过溶性细胞外片段s-TβRIII作为药物中和TGF-β分子，以及胞内片段c-TβRIII分别通过与GIPC和β-arrestin2信号分子共偶联对NF-κB和p38等分子有效调控，从而对ACC肿瘤细胞EMT过程以及药物耐受产生调节作用。本项目首次揭示TβRIII及下游分子信号网络促ACC恶性进程及耐药的新机制，并科学评价s-TβRIII作为药物对防控ACC疾病演进过程的效力，拓展我们对TGF-β家族信号分子的新认识。

涎腺腺样囊性癌（ACC）是常见涎腺恶性肿瘤，术后仍具有较高的复发率和较低的远期生存率，其与上皮间质转化（EMT）发生有关。转化生长因子III型受体（TβRIII或TGFBR3），是一种多功能细胞信号感受器，对多种肿瘤疾病进程起到重要调控作用，但在ACC疾病中的作用和功能尚不清楚。本研究在检测TGFBR3在ACC肿瘤组织中表达、分布变化的基础上；通过体内外实验相为结合确定TGFBR3过表达对ACC肿瘤增殖和凋亡的影响，阐明其通过与β-arrestin2信号分子共偶联对NF-κB等分子有效调控，从而对ACC肿瘤细胞增殖和凋亡发挥调节作用。本项目还进一步拓展研究了TGFBR3在口腔鳞癌（OSCC）细胞增殖、凋亡、侵袭迁移和EMT的作用及机制。TGFBR3通过激活p38信号通路促进舌鳞癌（TSCC）细胞凋亡，通过上调CDKN2b（p15）的表达诱导TSCC细胞G0/G1期阻滞，通过降低NF-κB信号通路的活性抑制TSCC细胞迁移和EMT。miR-19a和miR-424靶向调控TGFBR3介导了CAL-27细胞迁移和EMT。此外，我们还研究了SUMO化修饰和组蛋白乙酰化修饰对TSCC细胞增殖、迁移和上皮间质化的影响。该项目首次揭示TGFBR3及下游分子信号网络促ACC和OSCC恶性进程的新机制，并科学评价TGFBR3作为药物对防控ACC和OSCC疾病演进过程的效力，拓展我们对TGF-β家族信号分子的新认识。