State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, China.
J Immunol Res. 2021 Mar 1;2021:6694392. doi: 10.1155/2021/6694392. eCollection 2021.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is known for its high resistance and low response to treatment. Tumor immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Karyopherin alpha 2 (KPNA2), a member of the nuclear transporter family, is elevated in multiple human cancers and accelerates carcinogenesis. However, the specific role of KPNA2 in PDAC remains unclear. In this study, we found that expression of KPNA2 was significantly upregulated in PDAC compared to adjacent nontumor tissue and its high expression was correlated with poor survival outcome by analyzing the GEO datasets. Similar KPNA2 expression pattern was also found in both human patient samples and KPC mouse models through IHC staining. Although KPNA2 knockdown failed to impair the vitality and migration ability of PDAC cells , the tumor growth was significantly impeded and the expression of immune checkpoint ligand PD-L1 was reduced by silencing KPNA2. Furthermore, we uncovered that KPNA2 modulated the expression of PD-L1 by mediating nuclear translocation of STAT3. Collectively, our data suggested that KPNA2 has the potential to serve as a promising biomarker for diagnosis in PDAC.
胰腺导管腺癌（PDAC）是最致命的恶性肿瘤之一，以其对治疗的高度耐药性和低反应性而闻名。肿瘤免疫逃逸是设计有效抗癌治疗策略的主要障碍。核转运蛋白家族的成员核转运蛋白α 2（KPNA2）在多种人类癌症中升高，并加速了癌变。然而，KPNA2 在 PDAC 中的具体作用尚不清楚。在这项研究中，我们通过分析 GEO 数据集发现，与相邻非肿瘤组织相比，KPNA2 的表达在 PDAC 中显著上调，其高表达与不良生存结局相关。通过免疫组化染色，我们在人类患者样本和 KPC 小鼠模型中也发现了相似的 KPNA2 表达模式。尽管 KPNA2 敲低未能损害 PDAC 细胞的活力和迁移能力，但沉默 KPNA2 可显著抑制肿瘤生长并降低免疫检查点配体 PD-L1 的表达。此外，我们发现 KPNA2 通过介导 STAT3 的核易位来调节 PD-L1 的表达。总之，我们的数据表明 KPNA2 有可能成为 PDAC 诊断的有前途的生物标志物。
