DataSheet_1_SEMA3C Supports Pancreatic Cancer Progression by Regulating the Autophagy Process and Tumor Immune Microenvironment.pdf

To date, driver genes for pancreatic cancer treatment are difficult to pursue therapeutically. Targeting mutated KRAS, the most renowned driver gene in pancreatic cancer, is an active area of study. We discovered a gene named SEMA3C was highly expressed in pancreatic cancer cell lines and patients with a G12D mutation in KRAS. High expression of SEMA3C in patients was significantly associated with the decreased survival of pancreatic cancer patients based on the TCGA database. In pancreatic cancer cells, SEMA3C knockdown or inhibition exhibited growth/colony inhibition and cell cycle arrest. In addition, SEMA3C inhibition sensitized KRAS or MEK1/2 inhibition in pancreatic cancer cells. Overexpression of SEMA3C resulted in the induction of autophagy, whereas depletion of SEMA3C compromised induction of autophagy. SEMA3C modified the PD-L1 expression in tumor and immune cells and is correlated with the M2-like macrophage marker ARG1/CD163 expression, which could reshape the tumor microenvironment. Inhibition of SEMA3C decreased tumor formation in the xenograft model in vivo. Taken together, our data suggest that SEMA3C plays a substantial role in promoting cancer cell survival by regulating the autophagy process and impacting the tumor environment immune response. SEMA3C can be used as a novel target or marker with therapeutic or diagnostic potential in pancreatic cancer especially in tumors harboring the specific KRAS G12D mutation.

迄今为止，胰腺癌治疗的驱动基因难以进行临床治疗研究。针对胰腺癌中最为知名的驱动基因KRAS突变体，已成为研究的热点。本研究发现，名为SEMA3C的基因在胰腺癌细胞系和KRAS G12D突变患者中高表达。根据TCGA数据库，SEMA3C在患者中的高表达与胰腺癌患者的生存率显著降低相关。在胰腺癌细胞中，SEMA3C的敲低或抑制表现出生长/集落抑制和细胞周期停滞。此外，SEMA3C的抑制增强了KRAS或MEK1/2抑制在胰腺癌细胞中的敏感性。SEMA3C的过表达诱导自噬，而SEMA3C的耗竭则损害了自噬的诱导。SEMA3C调节肿瘤和免疫细胞中的PD-L1表达，并与M2样巨噬细胞标记物ARG1/CD163的表达相关，这可以重塑肿瘤微环境。在异种移植模型中，SEMA3C的抑制降低了肿瘤的形成。综合以上数据，我们的研究结果表明，SEMA3C通过调节自噬过程和影响肿瘤环境的免疫反应，在促进癌细胞存活中起着重要作用。SEMA3C可以作为胰腺癌新型治疗靶点或标志物，具有治疗或诊断潜力，尤其是在携带特定KRAS G12D突变的肿瘤中。