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High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer. | LitMetric

High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer.

Cancer Lett

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA. Electronic address:

Published: August 2021

AI Article Synopsis

  • Pancreatic cancer has the worst survival rates among all cancers, with patients often diagnosed at advanced stages, highlighting the need for better treatments.
  • The study examines the role of RHAMM, a protein not found in normal pancreases but linked to pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PNET), in cancer progression using genetically modified mice.
  • Findings reveal that a truncated form of RHAMM (HMMR) promotes the advancement of PDAC and PNET, especially in models with p53 mutations, suggesting that RHAMM could be a key factor in worsening pancreatic cancer outcomes.

Article Abstract

Pancreatic cancer has the lowest survival rate out of all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages, hence an urgent need for a better therapeutic development of this devastating disease. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm mice. However, we found that Rhamm mice expressed a truncated HMMR protein at higher abundance levels than wild-type RHAMM. While HMMR did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRAS mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRAS mice with heterozygous p53 knockout. Kras PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMR was not apparent in these short lifespan mice. In addition, HMMR shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMR , which lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC), accelerated pancreatic cancer progression.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235875PMC
http://dx.doi.org/10.1016/j.canlet.2021.05.011DOI Listing

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