Pancreatic cancer is among the most malignant cancers, and thus early intervention is the key to better survival outcomes. However, no methods have been derived that can reliably identify early precursors of development into malignancy. Therefore, it is urgent to discover early molecular changes during pancreatic tumorigenesis. As aberrant glycosylation is closely associated with cancer progression, numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis; however, detailed glycoproteomic information, especially site-specific N-glycosylation changes in pancreatic cancer with and without drug treatment, needs to be further explored. Herein, we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans, glycosites, and intact glycopeptides in pancreatic cancer cells and patient sera. The profiling of N-glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells, whereas human sera, which contain many secreted glycoproteins, had significant changes of glycans at their specific glycosites. These results indicated the potential role for tumor-specific glycosylation as disease biomarkers. We also found that AMG-510, a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation, profoundly reduced the glycosylation level in MIA PaCa-2 cells, suggesting that KRAS plays a role in the cellular glycosylation process, and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.
胰腺癌作为最恶性的癌症之一，早期干预是提高生存率的关键。目前尚无可靠的方法对其发展为恶性肿瘤进行早期识别，因此在胰腺肿瘤发生过程中发现早期分子变化的要求迫在眉睫。异常糖基化与癌症进展密切相关，对将糖基化变化作为胰腺癌诊断的生物标记物已有较多研究，但详细的糖组学信息，尤其是胰腺癌在药物治疗前后的位点特异性N-糖基化变化研究，仍需进一步深入。本研究采用综合性固相化学酶糖组学手段，对胰腺癌细胞和患者血清中的聚糖、糖基化位点和完整糖肽展开分析。癌症细胞中N-聚糖的分析结果显示，原位肿瘤MIA PaCa-2细胞分泌的糖蛋白增加，然而含有较多分泌糖蛋白的人类血清在其特定糖基化位点上的聚糖却发生了显著变化。上述结果表明，肿瘤特异性糖基化可作为胰腺癌诊断的潜在生物标志物。此外，本研究发现抗KRAS G12C突变的小分子抑制剂AMG-510可显著降低MIA PaCa-2细胞的糖基化水平，这表明KRAS在细胞糖基化过程中发挥抑制作用，将有助于AMG-510的抗肿瘤作用。.
胰腺癌作为最恶性的癌症之一，早期干预是提高生存率的关键。目前尚无可靠的方法对其发展为恶性肿瘤进行早期识别，因此在胰腺肿瘤发生过程中发现早期分子变化的要求迫在眉睫。异常糖基化与癌症进展密切相关，对将糖基化变化作为胰腺癌诊断的生物标记物已有较多研究，但详细的糖组学信息，尤其是胰腺癌在药物治疗前后的位点特异性N-糖基化变化研究，仍需进一步深入。本研究采用综合性固相化学酶糖组学手段，对胰腺癌细胞和患者血清中的聚糖、糖基化位点和完整糖肽展开分析。癌症细胞中N-聚糖的分析结果显示，原位肿瘤MIA PaCa-2细胞分泌的糖蛋白增加，然而含有较多分泌糖蛋白的人类血清在其特定糖基化位点上的聚糖却发生了显著变化。上述结果表明，肿瘤特异性糖基化可作为胰腺癌诊断的潜在生物标志物。此外，本研究发现抗KRAS G12C突变的小分子抑制剂AMG-510可显著降低MIA PaCa-2细胞的糖基化水平，这表明KRAS在细胞糖基化过程中发挥抑制作用，将有助于AMG-510的抗肿瘤作用。
Keywords: Biomarker; Glycoproteomics; Glycosylation; Mass spectrometry; Pancreatic cancer.