GATA2-Mediated Transcriptional Activation of Notch3 Promotes Pancreatic Cancer Liver Metastasis

Abstract

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 in vitro and in vivo 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.

Melatonin suppresses tumor proliferation and metastasis by targeting GATA2 in endometrial cancer

“…GATA2 is highly expressed in prostate cancer, pancreatic cancer, glioma, and colorectal cancer, and its overexpression promotes cancer cell proliferation, EMT, and cancer stemness; inhibits apoptosis; and increases tumorigenicity and resistance to standard therapies. 17,[44][45][46] High GATA2 expression is positively correlated with tumor stage, disease recurrence, and distal metastasis in prostate and colorectal cancer. [47][48][49] In the animal experiments in Figure 7B,D, we determined that the expression level of GATA2 was lower and the tumor volume was larger.…”

“…However, other studies have reported that GATA2 promotes cancer progression. GATA2 is highly expressed in prostate cancer, pancreatic cancer, glioma, and colorectal cancer, and its overexpression promotes cancer cell proliferation, EMT, and cancer stemness; inhibits apoptosis; and increases tumorigenicity and resistance to standard therapies 17,44–46 . High GATA2 expression is positively correlated with tumor stage, disease recurrence, and distal metastasis in prostate and colorectal cancer 47–49 .…”

The real-world study of the clinical characteristics, diagnosis, and treatment of advanced pancreatic cancer in China

“…Liver metastasis is the most common form of pancreatic cancer and is associated with poor prognosis. [25,26] In contrast, patients with pancreatic cancer and lung metastasis exhibit much longer survival. [27,28] In this cohort, the incidences of liver, lung, and lymph node metastases were 75.8%, 10.1%, and 10.4%, respectively.…”

A Novel Metabolic Detour for Pancreatic Cancer Survival

“…Pancreatic cancer is one of the most lethal tumor types, and novel therapeutic approaches against PDA should be developed to meet unmet clinical needs ( Jiang et al, 2022 ; Lin et al, 2022 ). Over the last decade, tumor energy metabolism has been a target for PDA therapeutics, but tumor metabolic plasticity has been behind their failure ( Jiang et al, 2022 ; Park et al, 2021 ).…”