AUTHOR=Rodrigues André A. Nimtz , Lopes-Santos Lucilene , Lacerda Pammela A. , Juste Mariana F. , Mariz Bruno Augusto , Cajazeiro Débora C. , Giacobbe Victoria , Borges Rafael , Casarim André , Callegari Giovanna De Sanctis , Claret Arcadipane Fernando Antônio M. , Aprahamian Ivan , Salo Tuula Anneli , De Oliveira Carine Ervolino , Coletta Ricardo D. , Augusto Taize M. , Cervigne Nilva K. 

TITLE=Heparanase 1 Upregulation Promotes Tumor Progression and Is a Predictor of Low Survival for Oral Cancer

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.742213

DOI=10.3389/fcell.2022.742213

ISSN=2296-634X

ABSTRACT=Background: Oral cancers still represent an important public health problem in the world. Oral Squamous Cell Carcinomas (OSCCs) can be quite aggressive and metastatic, with low survival rate and poor prognosis. However, that is usually related to clinical stage and histological grade, and molecular markers of prognosis for clinical practice needs yet to be defined. Heparanase (HPSE1), an endoglicosidase associated with ECM remodeling, has been implicated in several malignancies, but the clinical impacts of HPSE1 expression in OSCCs remains unknown. Method: We sought to examine HPSE1 expression in a series of primary OSCCs, and further investigate whether its overexpression plays a relevant role in OSCC tumorigenesis. Immunohistochemistry and real-time quantitative PCR were carried out in OSCC tissue samples and cell lines. A loss-of-function strategy using shRNA and a gain-of-function using ORF-vector targeting HPSE1 was employed to investigate in vitro endogenous modulation of HPSE1 and its effects on oral cancer proliferation, apoptosis, adhesion, epithelial-mesenchymal transition (EMT), angiogenesis, migration and invasion. Results: We showed that HPSE1 is frequently upregulated in OSCC samples and cell lines, and in combination with advanced T stage is an unfavorable prognostic indicator of disease-specific survival. Also, abrogation of HPSE1 in OSCC cells significantly promoted apoptosis, and inhibited proliferation, migration, invasion and EMT, by significantly decreased the expression of N-caderin and Vimentin. In addition, conditioned media from HPSE1 downregulated cells lead to reduced vascular endothelial growth. Conclusions: Our findings confirm the overexpression of HPSE1 in OSCCs, suggest that HPSE1 expression correlates with disease progression, as it is associated with several important biological processes for oral tumorigenesis, and may serve as a prognostic marker and therapeutic target for patients with OSCC.