Copper chaperone for superoxide dismutase expression is down-regulated and correlated with more malignant tumoral features and poor prognosis in human hepatocellular carcinoma
Authors: Wen Chun-yong , Shan Chang-liang , Sun Wen-jing , Wan Yuan , Lin Run , Chen Bin , Li Nan , Dai Hai-tao , Tang Ke-yu , Xiang Xian-hong , Yang Jian-yong , Yonghui Huang 
Published: November 2020

Abstract
Background: Up-regulated expression of copper chaperone for superoxide dismutase (CCS) is identified in a multitude of tumors and is closely related to more malignant tumoral biological behaviors. However, little is known about the role of CCS in hepatocellular carcinoma (HCC). This study aims to explore the expression pattern and the significance of CCS in human HCC.Methods Fresh samples of HCC with paired adjacent tissues, as well as the clinicopathological features and prognosis data were obtained from 32 patients who underwent hepatectomy from January 2018 to December 2018. The expression levels of CCS and a series of representative malignant biomarkers in HCC and adjacent tissues were investigated by western blotting and immunohistochemistry staining, respectively. The correlation between the expression status of CCS and the activities of selected malignant biomarkers and important drive genes of HCC oncogenesis, patient’s clinicopathological features and prognosis, were analyzed. Additional bioinformatics investigation of dataset retrieved from TCGA, the GEPIA, HPA, and Kaplan-Meier plotter (KM plotter) database were performed to further explore the role of CCS in human HCC and to validate the aforementioned findings. Results A unique express pattern was found that the majority of the HCC tumor (78.1%, 25/32) presented a lower expression of CCS as compared with that in adjacent tissues, whereas in the minority of the tumor (22.9%, 7/32) the expression of CCS was determined as higher. The distinctive CCS express status in HCC was further validated by the analysis of the data from TCGA and the GEPIA database. Furthermore, it was found that the expression level of CCS was significantly correlated with the those of the selected biomarkers including Ki67, vimentin, GPC3, and E-cadherin, which were also confirmed by the bioinformatic study. On the clinicopathological features, the expression of CCS was reversely correlated with ES grade and TNM stage to some extent, whereas there were no apparent correlations were proved with the remaining parameters included. Additional explorations revealed that there is a significant correlation between the CCS gene and a series of the driving/high-frequency mutation genes of various signal pathways in the development and progression of HCC. Despite statistic significant was not achieved, patients with higher CCS expression lever were prone to have a better prognosis. And a robust prognostic value of CCS was further proven in bioinformatic study. Conclusion HCC presented a unique lower expression pattern of CCS which reversely correlated with the more malignant tumoral features and poor prognosis as demonstrated by both experimental and bioinformatic studies. These findings improved our knowledge for understanding of the unique biological behavior of human HCC.