KIAA1522在非小细胞肺癌中与RAS-MEK-ERK信号通路交互调控的分子机制及作用

The RAS-MEK-ERK signaling pathway plays essential roles in the development and progression of non-small cell lung cancer (NSCLC). Our prior study demonstrated that KIAA1522 was up-regulated in NSCLC, through screening of aberrantly expressed genes in the GEO databases, and immunohistochemically evaluation of 583 NSCLC tissue samples and paired non-tumor tissues. Importantly, KIAA1522 could act as an independent adverse prognostic biomarker. Both in vitro and in vivo assays show that KIAA1522 promotes NSCLC cells growth. Moreover, the following study suggests that KIAA1522 could activate RAS-MEK-ERK signaling through stabilizing RAS protein. On the other hand, RAS-MEK-ERK activates c-Jun, which may transcriptionally enhance KIAA1522 expression, indicating the reciprocal regulation of KIAA1522 and RAS-MEK-ERK signal. But the detailed mechanisms underlying the mutual regulation still need further investigation. In the present study, we are trying to address the following questions: 1. how does KIAA1522 stabilize RAS protein; 2. how can RAS-MEK-ERK signaling pathway enhance KIAA1522 expression; 3. is there any biological significance and clinical relevance of the regulation loop between KIAA1522 and RAS-MEK-ERK in NSCLC, hoping to provide new insights into the diagnosis of NSCLC and help to develop novel therapeutic strategies.

RAS-MEK-ERK信号通路的异常在非小细胞肺癌发生发展中起重要作用。前期工作中，我们通过非小细胞肺癌数据库的分析，和583例配对非小细胞肺癌-癌旁组织的免疫组化检测，发现KIAA1522在肺癌组织中上调，并且是一个独立的不良预后因子。体内外实验表明：KIAA1522促进肺癌细胞生长，且与RAS-MEK-ERK信号通路存在交互调控关系。KIAA1522通过促进RAS蛋白的稳定，激活其下游信号传递；另一方面，RAS-MEK-ERK活化还可上调KIAA1522表达。但是，详细的分子机制仍需进一步探索。本项目拟深入研究KIAA1522与RAS-MEK-ERK信号通路交互调控的分子机制，揭示：1. KIAA1522如何调控RAS蛋白稳定性；2. RAS-MEK-ERK信号通路如何调控KIAA1522表达；3. 二者交互调控的生物学作用及意义。以期为非小细胞肺癌的诊断和治疗提供新的理论依据和线索。

KIAA1522在多种类型恶性肿瘤中异常表达，但目前对其功能的研究十分有限。本项目旨在探索KIAA1522在肺腺癌发生及耐药性中的作用机制。对临床样本的检测发现KIAA1522是肺腺癌的独立预后因素，其高表达与不良预后正相关。更重要的是，KIAA1522高表达的肺腺癌患者表现出对铂类化疗的耐药性，提示其与肺腺癌的化疗耐药有关。利用KrasG12D诱导的小鼠原位肺腺癌模型及体外肺癌细胞系模型，我们证实KIAA1522促进肺腺癌的发生及对顺铂的耐药。分子机制方面，我们发现KIAA1522激活RAS-MER-ERK信号通路，从而促进肺腺癌的发生。此外，KIAA1522可活化TNFα-TNFR2-NFκB信号通路以抵抗铂类化疗药物的生长抑制作用。裸鼠皮下成瘤实验证明，NFκB小分子抑制剂能够减弱KIAA1522过表达所引起的肺腺癌细胞对铂类化疗药物的耐药性。本项目的研究结果提示，KIAA1522可以作为潜在的铂类化疗药物敏感性标志物。在KIAA1522高表达且具有铂类化疗抗性的病例中，可通过联合使用NFκB抑制剂提供疗效。