MYCL1在小细胞肺癌发生发展中的作用及分子机制研究

Small cell lung cancer (SCLC) consist 15% of all lung cancers and ranks the 6th most frequent human cancer by itself. SCLC is often diagnosed at late stages with broad metastasis and currently there is no effective therapy available for this miserable disease. Previous work, including our own analysis, demonstrated that MYCL1 was overexpressed in many SCLC through chromosome amplification and translocation and associated with poor prognosis. MYCL1, together with c-MYC, belongs to MYC family and is less studied in human cancer. In this proposal we are going to investigate the function of MYCL1 in SCLC genesis and maintenance by CRISPR/Cas9 genome editing, RNAi, human organoid culture and humanized animal models. We will also explore the potential underlying molecular mechanism by ChIP-seq and RNA-seq. Our preliminary data suggest that MYCL1 could regulate the expressions of genes related to stemness and differentiation, promote human lung organoid formation, increase proliferation while inhibit apoptosis of human SCLC cells. This study will shed light on the function and molecular mechanism of MYCL1 in cancer, which can be a potential therapeutic target of SCLC.

小细胞肺癌（SCLC）约占肺癌的15%，单独则为发病率第六的恶性肿瘤，其侵袭转移性很强，目前尚无有效治疗方案。在长期肺癌相关的基础研究与临床实践（JTO 2014；APJCP 2011）基础上，我们对临床样本和肿瘤数据库分析发现MYCL1在SCLC细胞中通过基因扩增、位移等表达上调，且与预后不良相关。但它在肿瘤发生发展中的作用和机理研究甚少。本项目拟利用CRISPR/Cas9、RNA干扰、类器官培养、人源化动物模型等技术，研究MYCL1在SCLC发生及肿瘤维持中的作用，并通过RNA-seq、ChIP-seq等分析鉴定MYCL1在SCLC中的下游基因。初步结果显示MYCL1能调控肺细胞干性和分化相关的基因表达，促进人肺类器官的形成，促进SCLC细胞的增殖、抑制其凋亡。本研究将有助于深入了了解MYCL1在肿瘤发生发展中的作用及分子机制，为潜在的靶向治疗提供理论基础。

小细胞肺癌（SCLC）约占肺癌的15%，是一种侵袭性极强的恶性神经内分泌肿瘤，五年生存率不足10%。由于临床样本及动物模型等的限制，制约梁对SCLC分子机制的了解和新型药物的开发。本项目拟在我们前期证实MYCL1在SCLC细胞中通过基因扩增、位移等表达上调，且与预后不良相关的基础上，研究但MYCL1在肿瘤发生发展中的作用和机理。为此，我们1）功构建并繁育Mycl1基因敲除鼠；2）建立人及小鼠肺组织类器官培养体系, 体外利用CRISPR/Cas9技术对类器官实现多基因组合突变；3）发现MYCL1能调控肺细胞干性和分化相关的基因表达，促进人肺类器官的形成，促进SCLC细胞的增殖、抑制其凋亡；4）利用类器官培养及CRISPR/Cas9基因编辑技术构建新型原位原发肺癌（小细胞肺癌及非小细胞肺癌）模型；5）通过RNA-seq及单细胞测序等初步探索了SCLC发生发展的分子机制。总之，本研究为肺癌研究提供了新模型，并为探索肺癌发生发展过程中相关分子机制提供了新方法，为潜在的靶向治疗提供理论基础，对于提高小细胞肺癌临床防治效果具有潜在的重要意义。