PRDX1 and PRDX6 are repressed in papillary thyroid carcinomas via BRAF V600E-dependent and -independent mechanisms

Abstract

Many clinical studies highlight the dichotomous role of PRDXs in human cancers, where they can exhibit strong tumor-suppressive or tumor-promoting functions. Recent evidence suggests that lower expression of PRDXs correlates with cancer progression in colorectal cancer (CRC) or in esophageal squamous carcinoma. In the thyroid, increased levels of PRDX1 has been described in follicular adenomas and carcinomas, as well as in thyroiditis, while reduced levels of PRDX6 has been found in follicular adenomas. We studied the expression of PRDX1 and PRDX6, in a series of thyroid tissue samples, covering different thyroid diseases, including 13 papillary thyroid carcinomas (PTCs). Our results show that PRDX1 and PRDX6 are significantly reduced in all PTCs compared to normal tissues, to non-neoplastic tissue (MNG) or follicular neoplasms. This reduction is strongly evident in PTCs harboring BRAF V600E (31% of our cases). Using TPC-1 and BCPAP and FRTL-5 cell lines, we demonstrate for the first time that the presence of BRAF V600E is responsible of the hypoexpression of PRDX1 and PRDX6 both at mRNA and protein levels. Finally, independently of BRAF status, we observe an interesting correlation between the tumor size, the presence of lymph node metastasis and the lowest PRDX1 and PRDX6 levels. Therefore, these data indicate that PRDX1 and PRDX6 expression not only may play a key role in papillary thyroid carcinogenesis via a BRAF V600E-dependent mechanism, but their determination could be considered as potential tumor marker for indicating tumor progression in PTCs, independently of BRAF status.

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated

“…PRDX6 presented reduced levels in papillary thyroid carcinomas compared to non-neoplastic tissues. A correlation between the presence of lymph node metastasis and low PRDX6 levels was also described [60]. The progression from low-grade to high-grade prostate carcinoma and metastases is mediated by down-regulation of the androgen receptor target genes, including DHCR24 (24-Dehydrocholesterol Reductase) [61].…”

The role of peroxiredoxins in cancer

“…More recently, a marked reduction in PRDX6 levels has been demonstrated in a cohort of PTCs (75). Taken together, all these studies have demonstrated that PRDX6 has a pro-tumorigenic function, promoting cell proliferation by its peroxidase activity, and facilitating invasiveness by means of its PLA2 activity (150).…”

“…Decreased PRDX1 levels in papillary thyroid carcinomas (PTCs) (74) correlate with the presence of the BRAF V600E mutation and of lymph node metastasis, suggesting that PRDX1 reduction may be caused by mutated BRAF, and this is associated with a more aggressive clinical outcome of PTCs (75). …”

Peroxiredoxin 1 – an antioxidant enzyme in cancer

“…However, Nicolussi A et al . have demonstrated that PRDX1 and PRDX6 are reduced in papillary thyroid carcinomas by BRAF V600E‐dependent and ‐independent mechanisms 117. Additionally, down‐regulation of PRDX1 suppresses growth and promotes apoptosis in bladder cancer cells through NF‐kB signalling pathway after Bifidobacterium infantis thymidine kinase/nucleoside analogue ganciclovir (BI‐TK/GCV) treatment 118.…”