Hemeoxygenase-1 in thyroid cancer progression

Abstract

Previous work from our group shows that Hemeoxygenase-1 (HO-1) is overexpressed in several types of tumor and the enzyme can be located in cell cytoplasm and/or nucleus. This subcellular distribu tion is caused by the cleavage of the C-terminus of HO-1 by calpain 1 (CAPN1), calpain 2 (CAPN2), cathepsin B (CTSB) and signal pep tide peptidase (SPP). In thyroid cancer (TC), HO-1 potential utility as biomarker remains underexplored. The aim of this work was to study HO-1 expression in TC and its correlation with clinical-pathological data. Tumor biopsies (N=64) and fine needle aspiration biopsies (FNAB) (N=22) were used to asses HO-1 expression by inmuno histochemistry (IHC) and inmunocytochemistry (ICC), respectively. In addition, mRNA expression of HO-1, CAPN1, CAPN2, CTSB and SPP were analyzed by using GEPIA2 and Kaplan-Meier Plotter da tabases in in silico assays. In TC biopsies, overexpression (OE) of HO-1 by IHC was found in the tumor (T) respect to non-malignant areas to the tumor (NMT) (Mann Whitney test, p<0.0001). In T, HO-1 was expressed in the cytoplasm while in NMT, nuclear expression was found. HO-1 expression correlated with histological subtype by IHC (Chi2 , p=0.0006) and Bethesda classification by ICC (Chi2 , p=0.0470). In silico studies (ISS) corroborated IHC results in papil lary TC (ANOVA, p<0.001). Stage IV female patients with HO-1 OE were associated with lower overall survival (Log rank, p=0.032). ISS showed that stage III male patients with OE of CTSB and female pa tients with OE of CAPN1 correlated with greater survival (Log rank, p=0.017; Log rank, p=0.027 respectively). However, in female and male stage IV patients, OE of CAPN2 was associated with lower survival (Log rank, p=0.0015; Log rank, p=0.039 respectively). Fur thermore, SPP OE correlated with lower survival in female patients (Log rank, p=0.041). So far our results show that HO-1, CAPN2 and SPP overexpression together could be used as unfavorable biomarkers in TC.