Investigation of the clinical significance and prospective molecular mechanisms of cystatin genes in patients with hepatitis B virus‑related hepatocellular carcinoma

Abstract

The present study aimed to investigate the clinical significance and prospective molecular mechanism of cystatin (CST) genes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The role of CST genes in the molecular mechanism of HCC was revealed through bioinformatics analysis. The clinical significance of CST genes was investigated using GSE14520-derived data from patients with HBV-related HCC. Gene set enrichment analysis (GSEA) was used to identify pathways in which the CST genes were enriched, as well as the association between these pathways and HCC. The expression levels of CST1, CST2, CST5, CSTA and CSTB genes were higher in HCC tissue compared with in normal tissue; conversely, CST3 and CST7 were reduced in HCC tissue. Subsequent receiver operating characteristic analysis of the CST genes demonstrated that CST7 and CSTB genes may function as potential diagnostic markers for HCC. Furthermore, the expression levels of CST6 and CST7 were strongly associated with recurrence-free survival and overall survival of patients with HBV-related HCC. GSEA of the CST genes revealed that CST7 was significantly enriched in tumor evasion and tolerogenicity, cancer progenitors, liver cancer late recurrence, liver cancer progression and several liver cancer subclasses. In addition, CST genes demonstrated homology in terms of protein structure and were revealed to be strongly co-expressed. The present findings suggested that CST7 and CSTB genes may serve as potential prognostic and diagnostic biomarkers for HCC.

Transcriptomic Profiling Identifies Neutrophil-Specific Upregulation of Cystatin F as a Marker of Acute Inflammation in Humans

“…The cystatins consist of three families of proteins that bind reversibly with high-affinity to inhibit multiple cathepsin family members ( 8 ) Cystatin F is unique among the cystatins in that its expression is limited to leukocytes ( 9 ) and because it is secreted in an inactive form that can be internalized and subsequently activated in target cells ( 10 , 11 ). In the context of malignancy, increased levels of CST7 have been correlated with a poorer prognosis in liver metastasis following colorectal cancer ( 12 ) and with improved survival in the context of pancreatic ductal adenocarcinoma ( 13 ) and hepatocellular carinoma ( 14 ). Additionally, in the context of neuroinflammation, CST7 is upregulated during CNS demyelination and is associated with areas of remyelination ( 15 , 16 ).…”

“…If neutrophilic cystatin F is secreted, then it may act to suppress cathepsin C in other cells. Furthermore, if cystatin F is secreted by neutrophils in a tumor microenvironment ( 14 ), then it may contribute to pro-tumor immunosuppression. We identified a dataset (GSE101584) for tumor-associated neutrophils in a mouse cancer model ( 29 ) and found a significant increase in CST7 expression compared to that in naïve neutrophils.…”

Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

“…Survival analysis indicated that CST6 correlated with the OS and recurrence-free survival (RFS) of patients with hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) [ 116 ]. CST6 may function as a prognostic biomarker for HCC, with a high CST6 expression being associated with poor survival of patients, in correlation with a previous report claiming that cystatin M/E could be a pancreatic tumor promotor [ 119 ].…”

“…CST6 may function as a prognostic biomarker for HCC, with a high CST6 expression being associated with poor survival of patients, in correlation with a previous report claiming that cystatin M/E could be a pancreatic tumor promotor [ 119 ]. Taken together, data suggest that cystatin M/E may participate in diverse molecular mechanisms and exert distinct effects in different types of cancer [ 116 ].…”

Identification of Cysteine Protease Inhibitor CST2 as a Potential Biomarker for Colorectal Cancer

“…In CRC cells, p53-induced upregulation of CST5 promoted the induction of mesenchymal-epithelial transition [34]. Recently, CST5 had been shown to inhibit the proliferation, migration, and tumor formation of xenografted CRC cell lines [35], as well as exhibit higher expression levels in hepatocellular carcinoma tissue compared to normal tissue [36]. Thus, CSTs cannot be merely regarded as a cysteine protease inhibitor considering its vital role in tumorigenesis.…”