TY  - JOUR
AU  - Kayal, Yasmin
AU  - Barash, Uri
AU  - Naroditsky, Inna
AU  - Ilan, Neta
AU  - Vlodavsky, Israel
TI  - Heparanase 2 (Hpa2)- a new player essential for pancreatic acinar cell differentiation.
JO  - Cell death & disease
VL  - 14
IS  - 7
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DKFZ-2025-02475
SP  - 465
PY  - 2023
N1  - #DKFZ-MOST-Ca198#
AB  - Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic activity. Mutations of HPSE2 were identified in patients diagnosed with urofacial syndrome (UFS), a rare genetic disorder that exhibits abnormal facial expression and bladder voiding dysfunction, leading to renal damage and eventually renal failure. In order to reveal the role of HPSE2 in tissue homeostasis, we established a conditional Hpa2-KO mouse. Interestingly, the lack of Hpa2 was associated with a marked decrease in the expression of key pancreatic transcription factors such as PTF1, GATA6, and Mist1. This was associated with a two-fold decrease in pancreas weight, increased pancreatic inflammation, and profound morphological alterations of the pancreas. These include massive accumulation of fat cells, possibly a result of acinar-to-adipocyte transdifferentiation (AAT), as well as acinar-to-ductal metaplasia (ADM), both considered to be pro-tumorigenic. Furthermore, exposing Hpa2-KO but not wild-type mice to a carcinogen (AOM) and pancreatic inflammation (cerulein) resulted in the formation of pancreatic intraepithelial neoplasia (PanIN), lesions that are considered to be precursors of invasive ductal adenocarcinoma of the pancreas (PDAC). These results strongly support the notion that Hpa2 functions as a tumor suppressor. Moreover, Hpa2 is shown here for the first time to play a critical role in the exocrine aspect of the pancreas.
KW  - Mice
KW  - Animals
KW  - Pancreas: pathology
KW  - Acinar Cells: metabolism
KW  - Pancreatic Neoplasms: pathology
KW  - Pancreatitis: metabolism
KW  - Cell Differentiation
KW  - Inflammation: pathology
KW  - Carcinoma, Pancreatic Ductal: pathology
KW  - heparanase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37491420
C2  - pmc:PMC10368643
DO  - DOI:10.1038/s41419-023-05990-y
UR  - https://inrepo02.dkfz.de/record/306246
ER  -