Abstract
We aimed to examine the therapeutic potential of polysaccharide H-1-2, a bioactive component of Pseudostellaria heterophylla, against pancreatic cancer, as well as to demonstrate the underlying molecular mechanisms. Invasion and migration of pancreatic cells treated with H-1-2 were evaluated. A xenograft tumor mouse model was established to assess the effect of H-1-2 on tumor growth. Expression levels of hypoxic inducible factor-1α (HIF1α) and anterior gradient 2 (AGR2) were measured in pancreatic cells after H-1-2 treatment. Luciferase report and chromatin immunoprecipitation assays were conducted to investigate HIF1α regulation on AGR2. AGR2 expression was re-introduced into pancreatic cells to assess the role of AGR2 as a downstream effector of hypoxia after H-1-2 treatment. H-1-2 inhibited invasion and migration of pancreatic cancer cells, repressed xenograft pancreatic tumor growth, and increased survival of mice. H-1-2 repressed AGR2 expression in pancreatic cancer cells through the hypoxia response element (HRE) in its promoter region. Ectopic AGR2 expression partially negated the H-1-2 inhibitory effect on invasion and migration of pancreatic cells and on xenograft pancreatic tumors growth, and it also compromised the H-1-2 promotional effect on survival of mice. We conclude that H-1-2 suppresses pancreatic cancer by inhibiting hypoxia-induced AGR2 expression, supporting further investigation into its efficacy against pancreatic cancer in clinical settings.
Highlights
Treatments for human cancer have advanced with the aid of recent progresses in cancer biology
These findings indicated that in vitro growth of pancreatic cancer cells PANC-1 and PaCa-2 was suppressed by H-1-2
hypoxic inducible factor-1a (HIF1a) and Anterior Gradient 2 (AGR2) mRNA Are Upregulated in Pancreatic Cancer Patient Tumor Tissues We further investigated the potential downstream effectors responsible for the anti-tumor actions of H-1-2
Summary
Treatments for human cancer have advanced with the aid of recent progresses in cancer biology. Pancreatic cancer fell drastically behind other types of tumors with regard to patient prognosis and survival.[1] The overall 5-year survival rate of patients with pancreatic cancer is merely around 7%.2. About 10% of patients with pancreatic cancer are diagnosed when the disease is localized; less than 10% of diagnosed patients could be cured with surgical interventions. Even among patients with localized cancer, the 5-year survival rate is only one in five. While multiple prominent morbidities associated with tumor, e.g., biliary sepsis, obstruction of gastric outlet and bile duct, tumor cachexia, and venous thromboembolism, are thought to contribute to the poor outcome, epidemiological investigations suggest that pancreatic tumor cells often mobilize and develop micrometastases at relatively early stages, thereby acquiring resistance to currently available adjuvant radiotherapy and/or chemotherapy.[3] it is thought that pancreatic cancer fosters aggressive phenotypes at relatively early stages, different from other gastrointestinal cancers
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