He Ruizhe, Shi Juanjuan, Xu Dapeng, Yang Jian, Shen Yang, Jiang Yong-Sheng, Tao Lingye, Yang Minwei, Fu Xueliang, Yang Jian-Yu, Liu Dejun, Huo Yanmiao, Shen Xuqing, Lu Ping, Niu Ningning, Sun Yong-Wei, Xue Jing, Liu Wei
State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Lett. 2022 Jul 10;538:215693. doi: 10.1016/j.canlet.2022.215693. Epub 2022 Apr 23.
Owing to the lack of early diagnosis, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal tumours. Because acinar-to-ductal metaplasia (ADM) is a critical process to pancreatic regeneration and PDAC initiation, we applied GSE65146, a dataset composed of transcripts at different time points in wild-type and Kras mutant mice upon pancreatitis induction, to obtain regeneration- and tumour initiation-related genes. By overlapping with genes differentially expressed in human PDAC, we defined the initiation- and progression-related genes, and the most prognostic gene, SULF2, was selected for further verification. By using multiple PDAC genetically engineered murine models (GEMMs), we further verified that the expression of SULF2 was increased at the ADM and PDAC stages. Functionally, SULF2 was able to promote the dedifferentiation of acinar cells as well as the metastatic ability of PDAC. Additionally, our study revealed that SULF2 could enhance TGFβ-SMAD signalling via GDF15. More importantly, serum SULF2 was elevated in patients with PDAC, and in combination with CA19-9, it provided a better method for PDAC diagnosis. Herein, our study screened out key genes for the initiation and progression of PDAC, providing potential indicators for the diagnosis of the disease.
由于缺乏早期诊断，胰腺导管腺癌（PDAC）仍然是最致命的肿瘤之一。因为腺泡-导管化生（ADM）是胰腺再生和PDAC起始的关键过程，我们应用了GSE65146，这是一个由野生型和Kras突变小鼠在胰腺炎诱导后不同时间点的转录本组成的数据集，以获得与再生和肿瘤起始相关的基因。通过与人类PDAC中差异表达的基因进行重叠，我们定义了与起始和进展相关的基因，并选择了最具预后价值的基因SULF2进行进一步验证。通过使用多种PDAC基因工程小鼠模型（GEMMs），我们进一步验证了SULF2在ADM和PDAC阶段的表达增加。在功能上，SULF2能够促进腺泡细胞的去分化以及PDAC的转移能力。此外，我们的研究表明SULF2可以通过GDF15增强TGFβ-SMAD信号通路。更重要的是，PDAC患者血清中的SULF2升高，并且与CA19-9联合使用时，它为PDAC诊断提供了更好的方法。在此，我们的研究筛选出了PDAC起始和进展的关键基因，为该疾病的诊断提供了潜在指标。
