Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Department of General Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China.
Cell Oncol (Dordr). 2022 Dec;45(6):1421-1434. doi: 10.1007/s13402-022-00731-3. Epub 2022 Nov 4.
Integrin alpha 2 (ITGA2, also known as CD49b or VLA-2) is the alpha subunit of a transmembrane receptor for collagens and related proteins. Previously, we found that ITGA2 may regulate immune cell infiltration in pancreatic cancer by inducing PD-L1 expression. As yet, however, whether ITGA2 regulates immune cell infiltration in pancreatic cancer by other mechanisms remains unclear.
RNA sequencing was performed to identify differentially expressed genes in ITGA2-silenced pancreatic cancer cells. Protein-protein interactions were detected via co-immunoprecipitation. The infiltration level of immune cells was assessed using an immunofluorescence staining assay.
We found that ITGA2 can activate the cytosolic DNA-sensing pathway and promote STING expression in pancreatic cancer cells. In addition, we found that ITGA2 induces DNMT1 degradation by disrupting the interaction between DNMT1 and Kindlin2 in pancreatic cancer cells. As a DNA methyltransferase, we found that DNMT1 overexpression induced by ITGA2 silencing significantly up-regulated the methylation level of the STING gene promoter. Finally, ITGA2 silencing combined with DNMT1 inhibitor treatment induced immune cell infiltration in pancreatic cancer.
Our data indicate that ITGA2 induces STING expression by interacting with DNMT1 and inducing the degradation of DNMT1. ITGA2 silencing combined with DNMT1 inhibitor treatment may be a novel therapeutic strategy for pancreatic cancer.
整合素 alpha2（ITGA2，也称为 CD49b 或 VLA-2）是细胞外基质蛋白胶原和相关蛋白的跨膜受体的 alpha 亚基。此前，我们发现 ITGA2 可能通过诱导 PD-L1 表达来调节胰腺癌中的免疫细胞浸润。然而，ITGA2 是否通过其他机制调节胰腺癌中的免疫细胞浸润尚不清楚。
通过 RNA 测序鉴定 ITGA2 沉默的胰腺癌细胞中差异表达的基因。通过共免疫沉淀检测蛋白质-蛋白质相互作用。通过免疫荧光染色测定评估免疫细胞的浸润水平。
我们发现 ITGA2 可激活胰腺癌细胞中的胞质 DNA 感应途径并促进 STING 表达。此外，我们发现 ITGA2 通过破坏胰腺癌细胞中 DNMT1 和 Kindlin2 之间的相互作用诱导 DNMT1 降解。作为一种 DNA 甲基转移酶，我们发现 ITGA2 沉默诱导的 DNMT1 过表达显著上调了 STING 基因启动子的甲基化水平。最后，ITGA2 沉默联合 DNMT1 抑制剂治疗诱导了胰腺癌中的免疫细胞浸润。
我们的数据表明，ITGA2 通过与 DNMT1 相互作用并诱导其降解来诱导 STING 表达。ITGA2 沉默联合 DNMT1 抑制剂治疗可能是一种治疗胰腺癌的新策略。
