从miR-122调控IGF-1R信号通路探讨基于 “毒、瘀、虚”论治中药复方抗肝癌的作用机制

miR-122 is a miRNA specific expressed by liver, IGF-1R is a target gene regulated by miR-122. New studies suggest the expression of miR-122 inhibited lead to activation of IGF-1R pathway,that is associated with liver cells malignant transformation and oncogenesis.Increasing the expression of miR-122 and inhibit the activation of IGF-1R pathway is a new molecular target for anti- Hepatocellular carcinoma(HCC) remedy..Our recent study confirmed that Compound phyllanthus Urinsria Ⅱ(CPUⅡ)which based on the TCM pathogenesis of “evil,blood stasis, asthenia”and has the function of“clearing away heat, eliminating toxin, activating blood circulation to dissipate blood stasis, invigoratory vital energy,strengthen spleen and invigoratory kidney”,can obviously inhibit hepatoma Huh7 cells proliferation by suppressing the activation of IGF-1R pathway, but whether the effect is achieved by enhanced expression of miR-122 was not clear. The project intends to establish humahepatoma huh7 cells model, nude mice HCC xenograft model and 2-AAF induced HCC model, Using RNA interference technology, from molecule, cell ,histology and animal to inquire into the new mechanism of anti-cancer with TCM therapy by increasing the expression of miR-122 and inhibiting the activation of IGF-1R pathway, and provide new scientific basis for clinical application.

miR-122由肝脏特异表达，IGF-1R是miR-122调控的靶基因。新的研究证实miR-122的表达抑制，导致IGF-1R 信号通路的高度活化，是肝癌发生发展的关键病理机制。增强miR-122的表达抑制IGF-1R信号通路活化，是药物抗肝癌治疗新的分子靶点。 . 课题组的前期研究显示：针对肝癌“毒、瘀、虚”的主要发病机制，具有清热活血、健脾补肾作用的叶下珠复方Ⅱ号，可以通过抑制IGF-1R表达和下游信号通路的活化，抑制肝癌Huh7细胞增殖，但该作用是否通过增强miR-122表达来实现尚不清楚。本课题通过肝癌huh7细胞、裸鼠肝癌移植瘤模型和2-AAF诱导的大鼠肝癌模型，采用siRNA等技术，从分子、细胞、组织及整体动物水平，阐明叶下珠复方Ⅱ号通过增强miR-122表达、抑制IGF-1R信号通路活化，从而发挥抗肝癌作用的新机制，为清热活血、健脾补肾法的临床应用提供新的科学依据。

miR-122为肝脏特异表达，IGF-1R是miR-122调控的靶基因。目前的研究显示体内单一miR-122基因的表达抑制，即可导致肝癌的发生，证实非编码基因miR-122在维持肝脏内环境稳定和抑制肝癌发生过程中的关键作用，其分子机制与miR-122表达抑制导致IGF-1R信号通路的过度活化密切相关。而通过恢复miR-122的表达，可以显著抑制IGF-1R信号通路活化，阻断肝癌的发生发展，为肝癌的预防和治疗提供了新的靶点。. 本项目研究结果显示：针对肝癌“毒、瘀、虚”发病机制的叶下珠复方Ⅱ号，通过增强miR-122的表达、抑制IGF-1R信号通路活化，从而抑制肝癌Huh7细胞增殖和诱导其凋亡；对miR-122表达抑制肝癌Huh7细胞裸鼠移植瘤及Hep3B细胞裸鼠移植瘤生长，均具有明显的抑制作用；对2-AAF诱导的大鼠肝癌癌前病变模型，采用叶下珠复方Ⅱ号干预治疗，可以明显抑制大鼠肝组织纤维化病变和结节形成，作用机制与提高miR-122表达，从而抑制IGF-1R信号通路活化有关。上述研究结果进一步阐释了清热活血、健脾补肾法的抗癌作用机制，丰富了其抗肿瘤作用的科学内涵，为其临床应用提供了新的依据。