Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
These authors contributed equally to this work.
Mol Cells. 2022 May 31;45(5):329-342. doi: 10.14348/molcells.2022.2176.
The liver is the predominant metastatic site for pancreatic cancer. However, the factors that determine the liver metastasis and the specific molecular mechanisms are still unclear. In this study, we used human pancreatic cancer cell line Hs766T to establish Hs766T-L3, a subline of Hs766T with stable liver metastatic ability. We performed RNA sequencing of Hs766T-L3 and its parental cell line Hs766T, and revealed huge differences in gene expression patterns and pathway activation between these two cell lines. We correlated the difference in pathway activation with the expression of the four core transcriptional factors including STAT1, NR2F2, GATA2, and SMAD4. Using the TCGA database, we examined the relative expression of these transcription factors (TFs) in pan-cancer and their relationship with the prognosis of the pancreatic cancer. Among these TFs, we considered GATA2 is closely involved in tumor metastasis and may serve as a potential metastatic driver. Further and experiments confirmed that GATA2-mediated transcriptional activation of Notch3 promotes the liver metastasis of Hs766T-L3, and knockdown of either GATA2 or Notch3 reduces the metastatic ability of Hs766T-L3. Therefore, we claim that GATA2 may serve as a metastatic driver of pancreatic cancer and a potential therapeutic target to treat liver metastasis of pancreatic cancer.
肝脏是胰腺癌的主要转移部位。然而，决定肝脏转移的因素和具体的分子机制仍不清楚。在这项研究中，我们使用人胰腺癌细胞系 Hs766T 建立了 Hs766T-L3，这是 Hs766T 的一个具有稳定肝转移能力的亚系。我们对 Hs766T-L3 和其亲本细胞系 Hs766T 进行了 RNA 测序，揭示了这两种细胞系之间基因表达模式和通路激活的巨大差异。我们将通路激活的差异与包括 STAT1、NR2F2、GATA2 和 SMAD4 在内的四个核心转录因子的表达相关联。使用 TCGA 数据库，我们检查了这些转录因子（TFs）在泛癌中的相对表达及其与胰腺癌预后的关系。在这些 TFs 中，我们认为 GATA2 密切参与肿瘤转移，可能是潜在的转移驱动因子。进一步的实验证实，GATA2 介导的 Notch3 转录激活促进了 Hs766T-L3 的肝转移，而敲低 GATA2 或 Notch3 均可降低 Hs766T-L3 的转移能力。因此，我们认为 GATA2 可能是胰腺癌的转移驱动因子，也是治疗胰腺癌肝转移的潜在治疗靶点。
