Is 26S proteasome non-ATPase regulatory subunit 6 a potential molecular target for intrahepatic cholangiocarcinoma?

Abstract

In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology. Drug therapy of intrahepatic cholangiocarcinoma (iCCA) poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic agents. Thus, there has been a sustained search for novel molecular targets for iCCA. The study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6 (PSMD6), a 19S regulatory subunit of the proteasome, in human iCCA cells and specimens. The authors employed clustered regularly interspaced short palindromic repeat (CRISPR) knockout screening technology integrated with the computational CERES algorithm, and analyzed the human protein atlas (THPA) database and tissue microarrays. The results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines, and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological parameters. The authors conclude that PSMD6 may play a promoting role in iCCA. The major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening, in vivo experiments, and a discussion of plausible mechanistic cues, which, therefore, dampen the significance of the results. Further studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for iCCA. In addition, the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA, development of proteasome inhibitors for cancer therapy, and advantages of CRISPR screening technology, computational methods, and THPA database as experimental tools for fighting cancer. We hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.

Keywords: Cholangiocarcinoma; 26S proteasome non-ATPase regulatory subunit 6; Molecular targeted therapies; Proteasome inhibitors; Clustered regularly interspaced short palindromic repeat

Core Tip: Drug therapy of intrahepatic cholangiocarcinoma (iCCA) poses a big challenge and seeking potential molecular targets is being actively pursued. The study published by Tang et al indicated that 26S proteasome non-ATPase regulatory subunit 6 (PSMD6) gene is essential for cell proliferation and PSMD6 protein was overexpressed in iCCA tissues, indicating that PSMD6 may play a promoting role in iCCA. However, this study has several limitations and defects, such as the lack of detailed information of CRISPR knockout screening, in vivo experiments, and exploration of plausible mechanisms, reducing the significance of the results. Further studies are required to verify the role of PSMD6 as a molecular target for iCCA.