Overexpression of the mitochondrial chaperone tumor necrosis factor receptor‑associated protein 1 is associated with the poor prognosis of patients with colorectal cancer

Abstract

Tumor necrosis factor receptor-associated protein-1 (TRAP-1), a mitochondrial chaperone, contributes significantly to the progression of cancer. However, the understanding of its involvement in the clinicopathological characteristics and prognosis of colorectal cancer (CRC) remains limited. The aim of the present study was to assess the significance of TRAP-1 expression in CRC. The expression of TRAP-1 was evaluated in corresponding cancerous, paracancerous, lymph node and distant metastatic tissues of 256 cases of CRC by immunohistochemistry. The associations between TRAP-1 expression and the clinicopathological parameters and survival rates of patients was assessed. Out of 256 patients with CRC, TRAP-1 expression was detected in 203 (79.3%). TRAP-1 expression was significantly increased in cancerous tissue compared with that in corresponding paracancerous tissues (P<0.001). Overexpression of TRAP-1 was significantly associated with differentiation (P=0.011), depth of invasion (P=0.006), lymph node metastasis (P<0.001) and tumor-node-metastasis stage (P<0.001). In patients with high TRAP-1 expression, the 5-year overall survival (OS) rate was 38.0%, in contrast to 56.5% in patients with low TRAP-1 expression (P=0.003). Similarly, the 5-year progression-free survival (PFS) was 26.6% for patients with high TRAP-1 expression and 53.3% for patients with low TRAP-1 expression (P<0.001). Multivariate analyses indicated the TRAP-1 expression is an independent prognostic factor for poorer OS [P=0.015; hazard ratio (HR), 1.914] and PFS (P<0.001; HR, 2.534). Thus, TRAP-1 may serve as a potential biomarker for predicting the prognosis of patients with CRC. Specifically, overexpression of TRAP-1 may predict progression and poor survival in cases of CRC.

The exploration of mitochondrial‐related features helps to reveal the prognosis and immunotherapy methods of colorectal cancer

“…Interestingly, the upregulation of TRAP1 expression has different effects in different cancers, exhibiting a dual effect of carcinogenesis 72,73 or cancer inhibition 74 . Clinical experiments have shown that overexpression of TRAP1 is connected to a poor prognosis in CRC patients 75 . Apart from that, TRAP1 can regulate glycolysis metabolism and help reverse the resistance of CRC patients to EGFR inhibitors 76 .…”

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

“…While these studies identify TRAP1 as cytoprotective in mitochondrial-associated neuropathologies, other studies have highlighted a potential pro-neoplastic role of TRAP1 in cancer, where it can also display cytoprotective and other pro-tumorigenic activities. Thus, TRAP1 expression was found to be increased in hepatocellular carcinoma [ 47 ], breast cancer [ 48 ], glioma [ 49 ], small cell lung cancer [ 50 ], and kidney, prostrate, ovarian, colorectal, and esophageal cancer, and it is correlated with advanced-stage metastatic tumors with poor prognosis [ 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. In colorectal cancer and its animal models, increased TRAP1 expression was found to be localized to pro-neoplastic lesions in the tumor [ 58 , 59 ].…”

“…In colorectal cancer and its animal models, increased TRAP1 expression was found to be localized to pro-neoplastic lesions in the tumor [ 58 , 59 ]. While data supporting the importance of TRAP1 are numerous [ 24 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 59 , 60 ], these findings are challenged by other reports where TRAP1 expression inversely correlates with tumor stage [ 19 ] or is seemingly unimpactful in carcinogenesis models in TRAP1 knockout (KO) mice [ 61 ]. This has led to a general consensus that TRAP1’s role may be more context dependent.…”

“…The first indication that mitochondrial HSP90 is involved in cancer metabolism came from a study in 2012 reporting that this chaperone maintained metabolic homeostasis in neoplastic cells by inhibiting nutrient-sensing AMP kinase (AMPK), autophagy, and the unfolded protein response [ 87 ]. In the past 10 years, TRAP1 has been found to be highly expressed in a variety of neoplasms [ 24 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 59 , 60 ]. In 2013, an important observation provided a mechanistic basis for TRAP1 regulation of the balance between OxPhos and glycolysis in a variety of cell types [ 19 ].…”

The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer

“…Promising diagnostic and prognostic tools in human CRCs are reviewed in [ 67 , 68 , 69 ]. TRAP1 expression is higher in tumour tissues compared to surrounding non-malignant tissues, and elevation of TRAP1 protein levels and gene copy number correlate with malignant progression and metastasis of colorectal carcinoma [ 70 , 71 , 72 ]. TRAP1 is also known to affect mitochondrial architecture and dynamics, where TRAP1 knockdown favours mitochondrial fusion, while TRAP1 overexpression induces mitochondrial fission and subsequently enhanced migration in vitro and in tumour metastasis in vivo [ 73 ].…”