Serum PKCS is a useful biomarker to distinguish hepatocellular carcinoma from other gastrointestinal cancers

Protein kinase C delta (PKCS) is a leaderless protein generally localized in the cytoplasm and nucleus; however, its extracellular unconventional protein secretion occurs exclusively in hepatocellular carcinoma (HCC) cells (but not in normal and non-cancerous hepatocytes or other gastrointestinal cancer cells) via an autophagy mechanism, despite the lack of a secretory signal. Therefore, PKCS is detectable in the peripheral blood of HCC patients. Serum PKCS indicates cancer-related unconventional protein secretion of an inactive form of cytosolic PKCS and can be a unique biomarker independent of conventional markers. To examine the specificity of serum PKCS for HCC, its levels and positivity rates were compared between 226 HCC and 108 gastrointestinal cancer patients. Furthermore, we focused on patients with malignant or benign intrahepatic tumors (17 intrahepatic cholangiocarcinoma, 42 liver metastases, and 6 focal nodular hyperplasia). A sandwich enzyme-linked immunosorbent assay was used to measure serum PKCS levels; the optimal cutoff value was set to 57.7 ng/mL. HCC patients had significantly higher PKCS levels and positivity rates than gastrointestinal cancer patients (median, 51.1 vs. 34.6 ng/mL; 39.8 % vs. 4.6 %; P < 0.001 for both). Thus, the specificity was 95.4 %. Focusing on intrahepatic tumors, 2 (4.8 %) of 42 gastrointestinal cancer patients with liver metastasis were positive for PKCS. Notably, all patients with intrahepatic cholangiocarcinoma and focal nodular hyperplasia were negative for PKCS, irrespective of their intrahepatic tumors being malignant or benign. Serum PKCS is an extracellularly secreted protein specific for HCC that can be a novel diagnostic biomarker because it distinguishes HCC from other gastrointestinal cancers and intrahepatic non-HCC tumors.