Prognostic significance of cytoskeleton‐associated membrane protein 4 and its palmitoyl acyltransferase DHHC2 in hepatocellular carcinoma

Abstract

BACKGROUND:The functions of cytoskeleton-associated membrane protein 4 (CKAP4), one kind of type II transmembrane protein, are associated with the palmitoyl acyltransferase DHHC2. The objective of the current study was to investigate CKAP4=DHHC2 expression and its prognostic significance in patients with hepatocellular carcinoma (HCC). METHODS: Two independent cohorts of 416 patients with HCC were enrolled. All the patients included had defined clinicopathologic and follow-up data. Using real-time polymerase chain reaction and immunohistochemical assay, CKAP4 and DHHC2 expression were evaluated. The association between CKAP4=DHHC2 expression and HCC-specific disease-free survival and overall survival was analyzed by Kaplan-Meier curves, the logrank test, and Multivariate Cox regression analyses. RESULTS: The data documented that CKAP4 expression was much higher in HCC tumor tissues compared with adjacent normal tissues and its expression was significantly correlated with tumor size, intrahepatic metastases, portal venous invasion, and Barcelona Clinic Liver Cancer stage of disease in 2 cohorts of patients. On survival analysis, patients with high CKAP4 expression appeared to have a favorable overall survival and a longer disease-free survival compared with those with low expression. DHHC2 expression was also examined in tissue microarray analysis by immunohistochemistry and the results demonstrated that 87.6% of the cases had low expression of DHHC2. Kaplan-Meier analysis indicated that a high level of DHHC2 expression predicted favorable overall survival and disease-free survival rates in both the training cohort and validation set. Furthermore, the combination of CKAP4 and DHHC2 was found to have a more powerful efficiency in prognosis prediction than either one alone. CONCLUSIONS: To the best of our knowledge, the current study is the first to demonstrate that the expression of CKAP4 and its palmitoyl acyltransferase DHHC2 correlates with disease progression and metastasis in patients with HCC and may provide prognostic and therapeutic value. Cancer 2014;120:1520-31.

Cytoskeleton-associated membrane protein�4 is upregulated in tumor tissues and is associated with clinicopathological characteristics and prognosis in hepatocellular carcinoma

“…All four datasets showed consistent results, indicating that CKAP4 mRNA levels were significantly higher in tumor tissues compared with adjacent liver tissues. These results confirm the upregulation of CKAP4 in tumor tissues in accordance with previous results found in HCC (19) and other types of cancer, including cervical cancer, bladder cancer, lung cancer, pancreatic cancer, ESCC, CLL, PDAC and intrahepatic cholangiocellular carcinoma (12)(13)(14)(15)(16)(17)(18)27).…”

“…Recently, exosomal CKAP4 was reported to be a promising biomarker for pancreatic ductal adenocarcinoma (PDAC) (18). In 2013, Li et al (19) first revealed that CKAP4 was associated with progression and metastasis in patients with HCC. CKAP4 expression was demonstrated to be significantly higher in HCC tissues compared with adjacent normal tissues, and was associated with tumor size, intrahepatic metastasis, portal venous invasion and tumor stage; furthermore, upregulated CKAP4 expression increased overall survival (OS) and disease-free survival (DFS) times in patients with HCC.…”

CKAP4 is a Dickkopf1 receptor and is involved in tumor progression

“…transition from the precancerous state to the cancerous state. However, it was reported that high expression of CKAP4 is correlated with longer overall survival in cholangiocarcinoma and hepatocellular carcinoma patients (48,49), although the expression levels of DKK1 were not examined in these cases. CKAP4 might function in a positive or negative role for cellular proliferation in cancer contexts.…”

The Dickkopf1‐cytoskeleton‐associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy

“…There are opposing reports for intrahepatic cholangiocarcinoma (ICC) and HCC (Li et al, ; Li et al, ). CKAP4 expression is associated with tumour size and lymph node metastasis of ICC, but CKAP4 is expressed less in lymph node metastatic lesions rather than in primary lesions.…”