Liver Cancer–Specific Serine Protease Inhibitor Kazal Is a Potentially Novel Biomarker for the Early Detection of Hepatocellular Carcinoma

Abstract

INTRODUCTION: Liver cancer–secreted serine protease inhibitor Kazal (LC-SPIK) is a protein that is specifically elevated in cases of hepatocellular carcinoma (HCC). We assessed the performance of LC-SPIK in detecting HCC, including its early stages, in patients with cirrhosis, hepatitis B virus (HBV), and hepatitis C virus (HCV). METHODS: We enrolled 488 patients, including 164 HCC patients (81 early HCC) and 324 controls in a blinded, prospective, case–control study. Serum LC-SPIK levels were determined by an enzyme-linked immunosorbent assay-based assay. The performance of serum LC-SPIK and α-fetoprotein (AFP), including area under the curve (AUC), sensitivity, and specificity, are compared. The performance of LC-SPIK was evaluated in an independent validation cohort with 102 patients. RESULTS: In distinguishing all HCC patients from those with cirrhosis and chronic HBV/HCV, LC-SPIK had an AUC of 0.87, with 80% sensitivity and 90% specificity using a cutoff of 21.5 ng/mL. This is significantly higher than AFP, which had an AUC of 0.70 and 52% sensitivity and 86% specificity using a standard cutoff value of 20.0 ng/mL. For early-stage HCC (Barcelona Clinic Liver Cancer stage 0 and A), LC-SPIK had an AUC of 0.85, with 72% sensitivity and 90% specificity, compared with AFP, which had an AUC of 0.61, with 42% sensitivity and 86% specificity. In addition, LC-SPIK accurately detected the presence of HCC in more than 70% of HCC patients with false-negative AFP results. DISCUSSION: The study provided strong evidence that LC-SPIK detects HCC, including early-stage HCC, with high sensitivity and specificity, and might be useful for surveillance in cirrhotic and chronic HBV/HCV patients, who are at an elevated risk of developing HCC.

Liver Cancer-Specific Isoform of Serine Protease Inhibitor Kazal for the Detection of Hepatocellular Carcinoma: Results from a Pilot Study in Patients with Dysmetabolic Liver Disease

“…To partially overcome this issue, we performed specific sub-analyses to investigate the accuracy of the biomarkers for the detection of early-stage HCC and AFP-negative HCC; in both cases, LC-SPIK still exhibited a good discriminatory ability. Despite our preliminary results, our results are in agreement with those published by Lu and colleagues in a cohort of patients with viral-related chronic liver disease [ 10 ]. Furthermore, we included in our study only patients with cirrhosis, who are at higher risk of HCC development; despite setting more stringent conditions for the evaluation of the biomarkers’ performance, the results still showed high accuracy for LC-SPIK in discriminating patients with HCC from those without tumor.…”

“…Furthermore, the combined use of serum LC-SPIK and PIVKA-II further increased the accuracy of HCC detection. These results provide additional evidence regarding the diagnostic value of LC-SPIK not only in patients with cirrhosis and HCC of viral etiology [ 10 ] but also in patients with dysmetabolic liver disease.…”

“…Serum LC-SPIK values were determined by enzyme-linked immunosorbent assay (ImCare Biotech, Doylestown, PA, USA) as described in detail by Lu and colleagues [ 10 ].…”

“…The liver-cancer-specific isoform of serine protease inhibitor Kazal (LC-SPIK) is a specific SPIK isoform exclusively secreted by liver cancer cells, able to inhibit serine protease-dependent cell apoptosis induced by cytotoxic T lymphocytes and natural killer cells [ 9 ]. In a recent study including patients with chronic liver disease of viral etiology, LC-SPIK showed remarkable diagnostic accuracy for the identification of patients with HCC [ 10 ].…”

Identification and Validation of DEPDC1B as an Independent Early Diagnostic and Prognostic Biomarker in Liver Hepatocellular Carcinoma

“…In addition, chromatin remodeling (ARID1A and ARID2) may also account for approximately 10 and 5% of LIHC patients, respectively ( Villanueva, 2019 ). Though the molecular mechanisms of LIHC remain far from being fully understood, the survival rate of LIHC patients could be improved by more than 50% with early detection of hepatocellular carcinoma ( Kim et al, 2016 ; Lu et al, 2020 ). Conversely, the early diagnosis of LIHC is far from satisfactory, hence the exploration of novel molecular markers for early diagnosis and therapies is of great value for LIHC patients.…”