USP33 is a Biomarker of Disease Recurrence in Papillary Thyroid Carcinoma

Abstract

Background/Aims: To investigate the clinical significance and functional mechanisms of deubiquitinase USP33 in papillary thyroid carcinoma (PTC). Methods: Immunohistochemistry staining was conducted to explore the expression of USP33 in PTC tissues and adjacent normal thyroid tissues. Patients’ prognosis was evaluated by disease-free survival. The prognostic role of USP33 was tested by univariate and multivariate analyses. To confirm the effect of USP33 in cell proliferation and invasion, overexpression and knockdown of USP33 were performed in two PTC cell lines. Besides, cell cycle, immunoprecipitation, and apoptosis experiments were conducted to further explore the signaling pathways. Results: By analyzing series of 158 PTC tissues, we found that USP33 was down-regulated in tumor tissue compared with normal thyroid tissues, which was closely associated with lymph node metastasis (P<0.001). In particular, univariate and multivariate analyses indicated that USP33 was an independent prognostic biomarker for PTC, low USP33 expression indicated high recurrence risk. Cellular studies with TPC-1 and BCPAP cells demonstrated that USP33 can attenuate the cell capacities of proliferation, migration and invasion. Fluorescence-activated cell sorting experiment found no significant effect of USP33 on cell cycle, whereas the apoptotic caspase proteins were activated by USP33-overexpression. Moreover, the interaction between USP33 and Robo1 protein was identified, and knockdown of Robo1 enhancing the oncogenic effect upon USP33-knockdown, suggesting that USP33 may inhibit tumor progression through Robo1 signaling. Conclusions: Our data demonstrated that USP33 downregulation in PTC tissues was correlated with poor clinical outcome, which may serve as a novel biomarker and potential therapeutic target.

Transcriptional characterization of conjunctival melanoma identifies the cellular tumor microenvironment and prognostic gene signatures

“…These results underline the potential of a transcriptional analysis to categorize clinical outcome. While most of the genes predicting outcome of CM have already been described as prognostic factors in other malignancies, such as CENPK [41][42][43][44][45][46] , INHA [47][48][49][50] , RPS6KL1 51 , CASP3 (Caspase 3) 52 , SERPINB1 (Serpin Family B Member 1) 53 , USP33 (Ubiquitin Specific Peptidase 33) [54][55][56][57][58][59] , TRPV4 60 and ACO2 61 , some of the predicting factors have not yet been associated to cancer prognosis, such as GPN1, SNRNP48, AAR2 and SNORA73B. Among the mentioned factors, GPN1 was the gene with the highest correlation coefficient with good clinical outcome in CM.…”

Pellino‐2 in nonimmune cells: novel interaction partners and intracellular localization

“…The cell surface receptor ROBO-1 belongs to the family of immunoglobulin-like cell adhesion molecules and has been involved in neuronal migration and axonal guidance [23], as well as immune cell migration [24,25]. Although little is known about the ubiquitination of ROBO-1, the deubiquitinating enzyme USP33 has been shown to bind to the ROBO-1 cytoplasmic tail, protecting the receptor from proteasomal degradation [26,27]. It remains to be shown whether Pellino-2 leads to ROBO-1 ubiquitination and proteasomal targeted degradation.…”

<p>USP19 Enhances MMP2/MMP9-Mediated Tumorigenesis in Gastric Cancer</p>

“…21 The activity or expression of other USPs is thought to have increased in cancer cells, which could serve as prime targets for therapeutic intervention. 22,23 USP19 is known to be involved in the following: maintenance of cell proliferation; modulation of DNA damage repair by the targeting of different substrates, such as p27, HIF1α, and cIAP, for de-ubiquitination and inhibition of degradation in a DUB-independent manner; [24][25][26] and inhibition of tumor necrosis factor-α-induced cell apoptosis. 11 Pathologically, USP19 is involved in hypoxia and muscle wasting.…”

“… 21 The activity or expression of other USPs is thought to have increased in cancer cells, which could serve as prime targets for therapeutic intervention. 22 , 23 …”