Press release

August 4thThe Jikei University School of Medicine

Serum PKCδ is a novel biomarker for early-stage of Liver Cancer
The Jikei University School of Medicine (Location: Tokyo, Japan) discovered that serum
protein kinase C delta (PKCδ) Is a novel biomarker for early-stage of Hepatocellular
carcinoma (HCC).
Recently, Dr. Kohji Yamada and his team reported for the first time that (1) PKCδ is
specifically secreted into extracellular space in HCC cells, which was previously thought toexist in only cytoplasm, and autophagy is involved in this secretion mechanism, (2) PKCδcontributes to cell proliferation by activating Erk1/2 and STAT3 signaling via IGF-1R andEGFR, and (3) administration of anti-PKCδ antibody inhibits tumor growth (Cancer Res,
2021 81(2):414-425., Cancer Sci, 2022 113(7):2378-2385., PNAS in press).
The clinical usefulness of serum PKCδ as a biomarker for HCC diagnosis was confirmed bycollaboration with Division of Gastroenterology and Hepatology (Dr. Tsunekazu Oikawa, Dr.
Masayuki Saruta) and Core Research Facilities, Research Center for Medical Science (Dr.
Akihito Tsubota) at Jikei.
PKCδ levels in HCC patients were significantly higher than those in healthy subjects andchronic liver disease (CLD, chronic hepatitis and liver cirrhosis), and approximately 40% ofconventional tumor markers (AFP and DCP) double-negative HCC patients were positive
for PKCδ.
The diagnostic performance of serum PKCδ to discriminate HCC patients from patientswith chronic liver disease was comparable to that of AFP and DCP. Interestingly, PKCδyielded better diagnostic performance for detecting solitary small-sized (≤20 mm, BCLC
stage 0: very early-stage) HCC, compared to AFP and DCP.
Publication of this study
These findings were published in “Gastro Hep Advances” on the 4th August
https://www.ghadvances.org/article/S2772-5723(22)00134-0/fulltext. This study was
supported by the Japan Agency for Medical Research and Development (AMED).

Findings of this study
Liver cancer is the fourth leading cause of cancer-related death worldwide, and is known to
be a common cancer with a poor prognosis. The only curative treatments for liver cancer
are surgical resection and liver transplantation for early-stage patients. However, mostpatients are diagnosed at advanced stage by which time extant therapies are notineffective. AFP and DCP are commonly used as conventional biomarkers for HCC, andtheir serum levels are elevated along with advanced HCC stages. Identification of analternative biomarker that can detect early-stage and conventional tumor marker-negative
HCC is urgently needed. This study aimed to assess the practical usefulness of serum
PKCδ for detecting HCC in CLD patients. Serum PKCδ was measured in 9 healthy
subjects, 126 patients with CLD, and 187 HCC patients by a sandwich ELISA to analyze
the diagnostic performance for HCC and compare it with conventional markers.
Serum PKCδ in the HCC patients (median, 46.9 ng/mL) was significantly higher than that inhealthy subjects (median, 27.0 ng/mL) and patients with CLD patients (median, 37.9ng/mL) [P < 0.001]. ROC analysis of the diagnostic performance of serum PKCδ for HCC
showed a cutoff value of 57.7 ng/mL, AUC 0.686, sensitivity 38.0%, specificity 97.3%, AFP>20 (AUC 0.641, sensitivity 29.6%, specificity 98.6%), DCP >40 (AUC 0.716, sensitivity
50.0%, specificity 93.2%), indicating that the diagnostic performance for HCC iscomparable to that of conventional tumor markers. PKCδ, AFP, and DCP were independentof and complementary to each other, and the PKCδ-positive rate in the AFP(-) DCP (-) HCC
was 42.5%, suggesting that PKCδ has unique characteristics differed from conventionalmarkers. (Figure 1).

Figure 1. Serum PKCδ levels in HCC patients, non-HCC patients, and healthy subjects.
There were significant differences in serum PKCδ levels among the three groups (P <0.001 by the Kruskal–Wallis test) (right panel). The proportion of PKCδ-positive and negative patients in the AFP/DCP double-negative group (left panel).

It is noteworthy that that PKCδ had the highest sensitivity, with a positive rate of 45.0% in
HCC patients with a single and solitary small-sized (≤20 mm, BCLC stage 0: very earlystage). On the other hand, the positive rates of AFP and DCP were only 15% each, andeven when AFP and DCP were used in combination, the diagnostic performance of PKCδwas not exceeded (Figure 2).

Figure 2. The positive rates of PKCδ, AFP, and DCP according to the BCLC stages. ThePKCδ-positive rates were similar across all stages, whereas the AFP- and DCP-positive
rates were significantly increased stepwise along with advanced HCC stages.

Furthermore, PKCδ had the highest AUC of 0.762 among the three markers. Therefore,serum PKCδ is a novel HCC biomarker, which is independent of and complementary toconventional markers. Specifically, PKCδ may be useful for detecting very early-stage or
AFP/DCP double-negative HCC.

Future development
The sandwich ELISA kit used for the measurement of serum PKCδ is a research reagent.
The team has been aiming at the development of diagnosis kit for measurement in clinicalpractice. Currently, the research with a title of "Establishment of novel biomarker targeting
PKCδ in liver cancer” (principal investigator: Dr. Kohji Yamada) has been ongoing as
Practical Research for Innovative Cancer Control Program by Japan Agency for Medical
Research and Development (AMED).
Journal Name: Gastro Hep Advances
Title: Protein Kinase C delta Is a Novel Biomarker for Hepatocellular Carcinoma
Authors: Tsunekazu Oikawa1,5,(corresponding author), Kohji Yamada2,5, Akihito
Tsubota3,5, Chisato Saeki1, Naoko Tago2, Chika Nakagawa1, Kaoru Ueda1, Hiroshi
Kamioka1,2, Tomohiko Taniai4, Koichiro Haruki4, Masanori Nakano1, Yuichi Torisu1, Toru
Ikegami4, Kiyotsugu Yoshida2, and Masayuki Saruta1
1

Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei

University School of Medicine, Tokyo, Japan2

Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan

3

Core Research Facilities, Research Center for Medical Science, The Jikei University

School of Medicine, Tokyo, Japan
4

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei

University School of Medicine, Tokyo Japan5

contributed equally to this work with: Tsunekazu Oikawa, Kohji Yamada, and Akihito

Tsubota
DOI: https://doi.org/10.1016/j.gastha.2022.07.020
Support Grants
This work was supported by Grants from: AMED under Grant Number B326TS in part by
the Japan Society for the Promotion of Science and JP21ck0106712 to K.Yamada., theJapan Society for the Promotion of Science (KAKENHI Grant Numbers JP22K08063 toT.Oikawa., JP18K15253 and JP20K07621 to K.Yamada., JP18K19484 and JP20H03519 toK.Yoshida.). The Jikei University Graduate Research Fund to K.Yamada., T.Oikawa.,

Takeda Science Foundation to K.Yamada., and The Science Research promotion Fund toK.Yoshida.

Contact
Dr. Tsunekazu Oikawa
Assistant Professor
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei
University School of Medicine
3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan
Tel: +81-3-3433-1111; Fax: +81-3-3435-0569;
E-mail: oitsune[at]jikei.ac.jp (Please replace [at] to @)Media Contact
The Jikei University School of Medicine
3-25-8, Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan
Tel: +81-3-5400-1280;
E-mail: koho[at]jikei.ac.jp (Please replace [at] to @)