Expression of TXNIP is associated with angiogenesis and postoperative relapse of conventional renal cell carcinoma

Mate Meszaros,Maria Yusenko,Lehel Peterfi,Lilla Domonkos,Daniel Banyai,Gyula Kovacs

doi:10.1038/s41598-021-96220-y

Abstract

One of the common mediator of tumour progression is the oxidative stress induced by inflammatory tumour microenvironment (TME). Activated fibroblasts, local and immune cells produce reactive oxygen species (ROS) supporting tumour cell proliferation and pave the way for metastatic tumour growth. TXNIP regulates ROS generation by inhibiting the antioxidative function of thioredoxin (TXN). The shift of TXNIP/TXN balance towards overexpression of TXNIP is associated with proliferation of endothelial cells during tumor angiogenesis. The oxidative stress activates the hypoxia inducible factor-1 (HIF-1), which plays an important role in the biology of conventional RCC (cRCC). Under oxydative stress TXNIP interacts with NLRP3 inflammasome leading to maturation and secretion of inflammatory cytokine IL1β. To establish the role of TXNIP and downstream genes HIF1α and IL1β in the biology of cRCC, we have applied immunohistochemistry to multi-tissue arrays containing tumours of 691 patients without detectable metastases at the time of operation. We found that cRCC displaying a fine organised capillary network with nuclear translocation of TXNIP and expressing IL1β have a good prognosis. In contrary, we showed a significant correlation between cytoplasmic TXNIP expression, inefficient vascularisation by unorganized and tortuous vessels causing tumour cell necrosis and postoperative tumour relapse of cRCC.

Highlights

Conventional renal cell carcinoma makes up 80% of malignant kidney tumours
As the first Kaplan–Meier analysis revealed that patients with medium or strong cytoplasmic Thioredoxin-interacting protein (TXNIP) expression have similar disease-free survival, we have evaluated the results of cytoplasmic TXNIP immunohistochemistry in correlation to clinical and pathological parameters as negative or positive
Kaplan–Meier analysis revealed that patients having a conventional RCC (cRCC) with cytoplasmic expression of TXNIP protein have a significantly shorter disease-free survival compared to those without TXNIP expression (Fig. 3A)

Summary

Introduction

40% of the patients with cRCC have a metastasis at the time of operation or will develop metastatic disease during the postoperative course of 5 years[1]. TXNIP expression and elevated level of ROS is required for VEGF-mediated VEGFR2 activation and proliferation of endothelial cells during tumor angiogenesis[17,18]. High level of TXNIP expression was associated with a significantly shorter survival of patients with non-small cell lung cancer and invasive growth of hepatocellular c arcinoma[22,23]. To establish the role of TXNIP and downstream genes HIF1α and IL1β in the biology of cRCC, we have applied immunohistochemistry to tissue multi-arrays containing tumours of patients without detectable metastases at the time of operation

Methods

Results

Conclusion