A pan-cancer analysis reveals role of clusterin (CLU) in carcinogenesis and prognosis of human tumors

Abstract

Clusterin (CLU) is a chaperone-like protein that has been demonstrated to have a direct relationship with cancer occurrence, progression, or metastasis. Clusterin was downregulated in tumor tissues using three datasets of tongue squamous carcinoma from the Gene Expression Omnibus. We further retrieved datasets from The Cancer Genome Atlas and Gene Expression Omnibus to thoroughly investigate the carcinogenic consequences of Clusterin. Our findings revealed that decreased Clusterin expression in malignancies was associated with a worse overall survival prognosis in individuals with multiple tumors; Clusterin gene deep deletions were found in almost all malignancies and were connected to most cancer patient’s prognosis, Clusterin DNA methylation level was dependent on tumor type, Clusterin expression was also linked to the invasion of cancer-associated CD8+ T-cells and fibroblasts in numerous cancer forms. Moreover, pathway enrichment analysis revealed that Clusterin primarily regulates biological processes such as cholesterol metabolism, phospholipid binding, and protein-lipid complex formation. Overall, our pan-cancer research suggests that Clusterin expression levels are linked to tumor carcinogenesis and prognosis, which contributes to understanding the probable mechanism of Clusterin in tumorigenesis as well as its clinical prognostic significance.

Clusterin and Its Isoforms in Oral Squamous Cell Carcinoma and Their Potential as Biomarkers: A Comprehensive Review

“…According to a study conducted by Fu et al (2023) [41], CLU expression has been demonstrated to be decreased in most cancer types. One phenomenon observed in the prognosis of most cancer patients is that the CLU gene is always found to have a significant deletion in all malignancies.…”

“…Although limited studies have reported decreased CLU expression in tumors, there are still a few reports suggesting a reduction in CLU levels in specific cancers, including prostate cancer [39], neuroblastoma [40], and OSCC [10,12]. A pan-cancer analysis has also demonstrated a significant decrease in CLU expression in various cancerous tumors [41]. In fact, due to the dual role of clusterin as a tumor suppressor and a tumor promoter, currently, it remains uncertain whether cancer specifically expresses only the anti-apoptotic form of CLU or if pro-apoptotic nCLU isoforms are consistently suppressed in different types of cancers.…”

“…However, the expression of sCLU has been observed to vary across a wide range of malignancies. OS prognosis study data from Fu et al (2023) [41] suggest varied conclusions regarding different types of cancer, CLU gene expression, which leads to a worse prognosis, is inconsistent across different cancers. The question that remains here concerns the uncertainty as to whether sCLU, which is anti-apoptotic, is the only type of CLU expressed in cancer or if nCLU is suppressed in various tumor types.…”

Clusterin: a marker and mediator of chemoresistance in colorectal cancer

“…Moreover, the abundance, intracellular localisation and histological distribution of CLU expression have been associated with the progression of CRC [ 38 , 62 – 65 ] (Table 1 ). Conversely, a recent pan-cancer analysis by Fu and colleagues of CLU expression revealed decreased expression across most cancers compared to the matched normal tissue, including CRC [ 66 ]. However, this could be attributed to the opposing functions of the CLU isoforms which as previously mentioned, play very different roles in the cell.…”

“…1 ). Again, Fu et al [ 66 ] noted conflicting results from their pan-cancer analysis regarding CLU expression and overall survival, with high CLU expression conferring a survival advantage in some cancers, and a disadvantage to others (including CRC). Therefore, this suggests that monitoring expression levels of the sCLU isoform specifically may be a useful biomarker for the detection of disease as well as potential as a surveillance tool, in a similar approach to monitoring of circulating tumour DNA for the detection of disease relapse.…”