ERK信号通路与let-7在哈萨克族食管癌中的调控研究

Xinjiang, northwestern China, has been one of the areas with highest incidence and mortality of esophageal cancer, and the incidence of esophageal cancer has been highest in Kazakh, which were far more than the natioinal average level. Esophageal cancer endanger the physical health of the Kazakh seriously. Extracellular Signal-regulated Kinase (abbreviated to ERK1/2), one of the members of MAPK signal pathway, plays an important role in the carcinogenesis and development of esophageal cancer. Phosphorylation (or activation) of ERK1/2 was required in the infiltration, invasion and metastasis of esophageal cancer. Let-7, one of the extensively studied microRNA moleculars, plays an typical anti-oncogene role in multiple kinds of cancers. Nevertheless, there has been little reports concerning the mechanism by which let-7 influenced biological behaviour of esophageal squamous cell carcinoma. It has been reported that there was a cascade between ERK and Let-7, i.e."ERK→Myc→lin28→ let-7→target proteins→effects". However, the correlation between ERK and Let-7 in the pathogenesis of Kazakh's esophageal cancer has been little investigated. In the current study, it is proposed to make further explorations regarding correlated regulation and control between let-7 and ERK signal pathway from esphageal cancer cell lines to nude mice exnograft models, and cancer tissues level. All the work here, obviously, committed to make further understanding about the aetiology of Kazakh's esophageal cancer, paving the way for improvement of patients' survival rates.

食管癌是我国最高发的恶性肿瘤之一，新疆是其高发区，其中哈萨克族人群发病率最高，远高于全国平均水平，在此独特地域内哈族食管癌高发的机制亟待深入研究。胞外信号调节激酶（Extracellular Signal-regulated Kinase，ERK1/2）是MAPK通路中的代表激酶，食管癌的浸润、侵袭和转移均离不开ERK的活化。Let-7是目前研究最广泛的miRNA之一，但鲜见有关let-7对食管癌恶性生物学行为影响机制的报道。ERK与let-7之间存在ERK→Myc→lin28→ let-7→靶蛋白→产生效应的作用级联，而ERK与let-7在哈族食管癌中的调控与作用机理尚未见研究报道。本课题拟从食管鳞癌细胞模型、裸鼠异位移植瘤模型和哈族食管鳞癌病人三个层面，运用多种研究方法探讨ERK信号通路与let-7在哈族食管癌中的调控作用及其机理，深入了解食管癌的发病机制，为提高患者生存率奠定基础。

食管癌是我国最高发的恶性肿瘤之一，新疆是其高发区，其中哈萨克族人群发病率最高，远高于全国平均水平，严重危害哈族身体健康。胞外信号调节激酶（Extracellular Signal-regulated Kinase，ERK1/2）是MAPK通路中的代表激酶，食管癌细胞的浸润、侵袭和转移过程均离不开ERK的活化。本研究发现磷酸化ERK2在食管癌Eca109细胞系中显著高表达，干预ERK1/2的活化水平后Eca109细胞的增殖受到显著抑制，迁移能力下降，凋亡增加，周期被阻滞在G1期；体外裸鼠成瘤实验发现抑制ERK2的表达能够抑制裸鼠移植瘤的生长；临床样本 中发现，食管鳞癌中，let-7的表达显著降低，其中哈族食管鳞癌患者let-7的表达显著低于汉、维两个民族，let-7下游靶基因HMGA2以及与浸润转移密切相关的上皮间质转化过程中重要的调控分子Snail在哈族食管鳞癌中的表达均显著高于二者在癌旁组织中的表达，并且Snail的表达与肿瘤的浸润深度明显相关，同时发现，let-7的表达与HMGA2的表达呈显著负相关，而HMGA2的表达与Snail的表达呈正相关，即哈族食管癌中let-7低表达减弱了对其靶基因HMGA2的调控，失去let-7靶向调控的HMGA2呈高表达的同时，进一步促进了上皮间质转化相关蛋白Snail的表达，进而促进了食管癌的浸润转移。