Hypoxia inducible factor 1 alpha (HIF1A) is a tumor suppressor in pancreatic cancer cells, and strategies to restore its activity could be developed for the treatment of pancreatic ductal adenocarcinomas (PDAC), according to the results of a study published in Gastroenterology.

PDACs are hypovascular, resulting in the upregulation of HIF1A, which promotes survival of cells under low oxygen conditions. Researchers studied the role of HIF1A in the development of pancreatic tumors in mice. They also performed studies with the human pancreatic cancer cell lines PATU-8988T, BxPC-3, PANC-1, and MiaPACA-2, which have no or low metastatic activity, and PATU-8988S, AsPC-1, SUIT-2, and Capan-1, which have high-metastatic activity.

Investigators found that Pdx1-Cre (KPC) mice with labeled pancreatic epithelial cells (EKPC) with pancreas-specific deletion of HIF1A developed more advanced pancreatic neoplasias and PDACs with more invasion and metastasis and had significantly shorter survival times than EKPC mice. Pancreatic cancer cells from these tumors had higher invasive and metastatic activity in culture than cells from tumors of EKPC mice.


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HIF1A-knockout pancreatic cancer cells had increased expression of protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B). In human PDAC tumors, there was an inverse correlation between levels of HIF1A and PPP1R1B, and higher expression of PPP1R1B correlated with shorter survival times of patients. Metastatic human pancreatic cancer cell lines had increased levels of PPP1R1B and lower levels of HIF1A compared with non-metastatic cancer cell lines; knockdown of PPP1R1B significantly reduced the ability of pancreatic cancer cells to form lung metastases in mice. PPP1R1B promoted degradation of p53 by stabilizing phosphorylation of MDM2 at Ser166.

One noted limitation is that this study was performed in mice and human cell lines and tissues. The authors acknowledge the need for further studies of this pathway in human pancreatic tumor progression.

“Our study identifies PPP1R1B as a potential target to mitigate pancreatic cancer metastasis and provides a detailed molecular understanding of how inhibiting HIF1A may influence the outcome of pancreatic cancer unfavorably in clinical setting,” the researchers concluded.

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Reference

Tiwari A, Tashiro K, Dixit A, et al. Loss of HIF1A from pancreatic cancer cells increases expression of PPP1R1B and degradation of p53 to promote invasion and metastasis [published online August 3, 2020].  Gastroenterology. doi: 10.1053/j.gastro.2020.07.046