长链非编码RNA CASC19通过调控PD-L1表达与免疫微环境促进胃癌转移的机制研究

Metastasis is the leading cause of death in gastric cancer patients and it is of great clinical significance to study the potential therapeutic targets. Combined with RNA sequencing and TCGA database, we found the metastasis-associated lncRNA CASC19. Previous work revealed that CASC19 was closely related to lymph node metastasis and prognosis. Functional experiments showed that CASC19 could inhibit apoptosis of gastric cancer cells and promote proliferation, metastasis and stem-like phenotype. We confirmed that CASC19 combined with DHX9 and formed CASC19/DHX9 complex to regulate the expression of c-MYC in gastric cancer, thereby activating the downstream pathways and promoting the development and metastasis of gastric cancer. Further analysis showed that CASC19 was significantly correlated with neutrophil infiltration and related chemokines CXCL5, CXCL6 and IL8. Overexpression of CASC19 led to the upregulation of these above chemokines and PD-L1. These results has preliminarily confirmed the role of CASC19 in regulating tumor immune microenvironment and PD-L1. However, the specific regulation and deep mechanisms of CASC19 on PD-L1 and immune cells, and whether its ability to promote gastric cancer metastasis depends on the regulation of immune microenvironment still need to be further confirmed. This study will further clarify these key issues.

肿瘤转移是胃癌患者死亡的重要原因，因此深入阐明胃癌的转移机制有重要的临床意义。结合高通量测序和数据库分析，我们筛选到胃癌转移相关lncRNA CASC19。前期工作证实CASC19与预后、淋巴结转移相关，并可抑制胃癌细胞凋亡，促进增殖、转移与干细胞样特性。我们发现CASC19可通过与DHX9结合形成CASC19/DHX9复合体来调控c-MYC的表达，进而激活c-MYC下游通路，促进胃癌的发展和转移。进一步分析显示CASC19表达与中性粒细胞浸润、参与介导的趋化因子CXCL5、CXCL6及IL8均显著相关，且过表达CASC19后上述趋化因子以及PD-L1显著上调，初步证实了CASC19调控肿瘤免疫微环境以及PD-L1的作用。但CASC19对PD-L1及免疫细胞的具体调控作用与机制，以及其促进胃癌转移能力是否依赖于对免疫微环境的调控还需进一步证实，本课题将深入阐明这些关键问题。

肿瘤转移已成为临床上胃癌治疗失败导致患者死亡的主要原因。本课题中，我们结合高通量测序及生信分析，发现胃癌高转移倾向组织有着独特的免疫微环境，且具有富集的免疫抑制信号通路。我们进而在胃癌高转移倾向的组织中筛选出了转移相关lncRNA CASC19，进一步研究发现CASC19在胃癌中可形成CASC19/DHX9复合体，通过招募DHX9结合c-MYC CRD区域，可稳定其mRNA从而上调c-MYC，进而促进胃癌发生与转移，并可通过c-MYC调控PD-L1介导的免疫逃逸进程。以上结果提示CASC19可作为提示胃癌早期转移和预后的标志物，并参与胃癌的发生发展以及免疫调控过程，本课题发现CASC19/DHX9/c-MYC这一通路在免疫治疗方面有着潜在的重要临床价值。