HMGA1 expression levels are elevated in pancreatic intraepithelial neoplasia cells in the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer

Abstract

Background:Pancreatic cancer is currently the third leading cause of cancer deaths in the United States and it is predicted to become the second by the year 2030. High-mobility group A1 protein (HMGA1) is an oncogenic transcription factor, localised and active in cell nuclei, that is linked to tumour progression in many human cancers, including pancreatic cancer. Overexpression of HMGA1 renders cancer cells resistant to chemotherapy. Although the Ptf1a-Cre; LSL-KrasG12D transgenic mouse is perhaps the most widely utilised animal model for human pancreatic cancer, expression levels of HMGA1 in pancreata from this mouse model have not been characterised.Methods:Quantitative immunohistochemical analysis was used to determine nuclear HMGA1 levels in pancreatic tissue sections from Ptf1a-Cre; LSL-KrasG12D mice aged 5, 11, and 15 months. The H Score method was used for quantitative analysis.Results:The HMGA1 levels were significantly elevated in pancreatic intraepithelial neoplasia (PanIN) epithelia compared with untransformed acinar tissues or fibroinflammatory stroma.Conclusions:The PanINs have long been regarded as precancerous precursors to pancreatic adenocarcinoma. Significantly elevated HMGA1 levels observed in the nuclei of PanINs in Ptf1a-Cre; LSL-KrasG12D mice validate this animal model for investigating the role that HMGA1 plays in cancer progression and testing therapeutic approaches targeting HMGA1 in human cancers.

NMR-based metabolic profiling of urine, serum, fecal, and pancreatic tissue samples from the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer

“…In this study, NMR based metabonomics has been used to explore the potential of metabolic profiling for identification of potential biomarkers for detection of precancerous pancreatic intraepithelial neoplasia (PanIN) that precede pancreatic cancer [ 4 , 31 – 33 ]. The transgenic Ptf1a-Cre; LSL-KrasG12D mouse model used in this study has been extensively characterized and shown to display extensive PanIN that eventually progress to PDAC [ 4 , 31 – 33 ].…”

“…In this study, NMR based metabonomics has been used to explore the potential of metabolic profiling for identification of potential biomarkers for detection of precancerous pancreatic intraepithelial neoplasia (PanIN) that precede pancreatic cancer [ 4 , 31 – 33 ]. The transgenic Ptf1a-Cre; LSL-KrasG12D mouse model used in this study has been extensively characterized and shown to display extensive PanIN that eventually progress to PDAC [ 4 , 31 – 33 ]. The Ptf1a-Cre; LSL-KrasG12D mouse model of pancreatic cancer is considered to recapitulate important characteristics of human pancreatic cancer, including spontaneous pancreatic tumor formation that is preceded by a precancerous PanIN stage [ 4 , 31 , 33 ].…”

“…The transgenic Ptf1a-Cre; LSL-KrasG12D mouse model used in this study has been extensively characterized and shown to display extensive PanIN that eventually progress to PDAC [ 4 , 31 – 33 ]. The Ptf1a-Cre; LSL-KrasG12D mouse model of pancreatic cancer is considered to recapitulate important characteristics of human pancreatic cancer, including spontaneous pancreatic tumor formation that is preceded by a precancerous PanIN stage [ 4 , 31 , 33 ]. Another common feature is that mutations of the Kras gene are found in > 90% of human pancreatic adenocarcinoma tumors [ 34 – 36 ] as well as in > 95% of PanINs have been reported to have Kras mutations [ 37 ] and the Ptf1a-Cre; LSL-KrasG12D mouse model was constructed to cause activation of PanIN initiation and pancreatic tumor formation based on the introduction of the G12D Kras mutation with activation restricted to expression in the pancreatic tissue [ 4 ], presumably mimicking spontaneous somatic cell Kras mutations that occur in the initiation of human pancreatic cancer [ 28 , 37 ].…”

Spatial variations in gut permeability are linked to type 1 diabetes development in non-obese diabetic mice

“…All dissections and intestinal histologies were performed as described previously 22–29. Details regarding the histological procedures can be found in online supplementary material.…”

Linc‑pint inhibits early stage pancreatic ductal adenocarcinoma growth through TGF‑β pathway activation

“…Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. Treatment outcomes for PDAC are generally poor due to the existence of distant tumor metastasis in 80–90% of patients at the time of diagnosis, since metastasis is a contraindication for surgical resection (3). Therefore, early tumor detection is crucial.…”