ITGA2通过DNMT1-p15信号轴调控胰腺癌对CDK4/6抑制剂敏感性的机制研究

传统的化疗药物对胰腺癌基本无效，新型靶向药物有望为胰腺癌提供新的治疗选择。CDK4/6抑制剂已被用于乳腺癌等多种肿瘤的临床治疗，但研究发现CDK4/6抑制剂单药不能有效抑制胰腺癌进展。据文献报道，上调p15的表达可增强胰腺癌对CDK4/6抑制剂的敏感性；我们前期研究发现ITGA2在胰腺癌中高表达，且ITGA2沉默可通过上调p15的表达增强胰腺癌对CDK4/6抑制剂的敏感性。同时，预实验结果还表明ITGA2与DNMT1存在蛋白质水平的相互作用且显著增强了DNMT1与p15基因启动子区域的结合。因此，我们提出以下假设：ITGA2沉默可通过DNMT1-p15信号轴增强胰腺癌对CDK4/6抑制剂敏感性。本研究拟在前期研究基础上，在体内体外进一步探究上述假设的具体分子机制。本实验的成功实施将为改善胰腺癌对CDK4/6抑制剂的敏感性、确立胰腺癌新的联合治疗方案提供理论依据。

The traditional chemotherapy drugs have no treatment effect on pancreatic cancer, and new targeted drugs are expected to provide new treatment options for pancreatic cancer. CDK4/6 inhibitor has been used in the clinical treatment of breast cancer and other tumors; however, previous studies had found that CDK4/6 inhibitor treatment alone couldn't effectively inhibit the progression of pancreatic cancer. According to previous studies, upregulation of p15 expression could enhance the sensitivity of pancreatic cancer to CDK4/6 inhibitor; our previous results showed that ITGA2 was overexpressed in pancreatic cancer, and ITGA2 silencing could enhance the sensitivity of pancreatic cancer to CDK4/6 inhibitor through upregulation of p15 expression. In addition, preliminary experimental results indicated that ITGA2 interacted with DNMT1 and enhanced the binding of DNMT1 to p15 promoter. Therefore, we made the following hypothesis: ITGA2 silencing could enhance the sensitivity of pancreatic cancer to CDK4/6 inhibitor through DNMT1-p15 signal axis. On the basis of previous results, our study intends to further explore the specific molecular mechanism of the above hypothesis in vivo and in vitro. This study will provide a theoretical basis for improving the sensitivity of pancreatic cancer to CDK4/6 inhibitor and establishing a new combined therapy choice for pancreatic cancer.