TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma

Abstract

Resistance to systemic therapy is one of the hallmarks of renal cell carcinoma (RCC). Recently, TOLLIP has emerged as a possible driver of autophagy and chemoresistance. We explored the relationship between primary and metastatic RCC tumor characteristics, patient survival, and TOLLIP expression. The tissue microarrays cohort contained 95 cores of the primary tumor, matched metastases, and matched adjacent tissues derived from 32 RCC patients. TOLLIP expression in tumor samples was evaluated using the H-score. All examined samples showed cytoplasmic TOLLIP expression, with a median value of 100 in primary tumors, 107.5 in metastases, and 220 in the control group. The expression was significantly higher in the normal adjacent tissues compared to primary or metastatic RCC (p < 0.05). We found a positive correlation between expressions of TOLLIP in the primary tumor and its metastases (p < 0.05; k = 0.48). TOLLIP expression significantly correlates with a lower overall survival rate (p = 0.047). TOLLIP functions as a ubiquitin-LC3 adaptor in the intracellular pathway associated with autophagy. Relative TOLLIP overexpression may augment autophagy-related signaling, limiting susceptibility to therapy. The blockade of TOLLIP physiological function seems to be a promising approach to overcoming resistance to systemic therapy.

Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers

“…Mechanistically, TOLLIP acts as a ubiquitin-LC3 adaptor in autophagy-related signaling. This connection provides valuable insights into how TOLLIP may augment autophagy and potentially render RCC less susceptible to therapeutic interventions [9]. In fact, this study is in line with other studies demonstrating that autophagy plays a significant role in RCC, with many autophagy-related proteins serving as prognostic markers [10].…”