Elevated nuclear expression of ZHX1 correlates with poor prognosis in hepatocellular carcinoma (HCC): Comparison of nuclear and cytoplasmic distribution of the ZHX family in HCC cells.

Aim: The role of the zinc fingers and homeoboxes family (ZHX1-3), transcriptional repressors, through their subcellular localization in hepatocellular carcinoma (HCC), is not fully understood. The present study aimed to examine the differential nuclear and cytoplasmic expression of ZHXs in HCC tissues.

Methods: Immunohistochemistry was utilized to detect the expression of ZHXs in 54 liver tissues from HCC (n = 33), hepatitis C (n = 16), and the normal liver tissue surrounding hepatic metastasis of colorectal cancer (n = 5). Next-generation sequencing and digital polymerase chain reaction identified gene mutations associated with HCC. Kaplan-Meier curves were constructed to evaluate the relationship between ZHX expression and survival. The results were validated using data from The Cancer Genome Atlas. Univariate and multivariate Cox regression analyses were undertaken to identify independent prognostic factors.

Results: High nuclear expression of ZHX1 was associated with poor overall survival (OS), while high nuclear expression of ZHX2 correlated with higher recurrence. Conversely, patients with high cytoplasmic expression of ZHX3 had lower recurrence and better OS. Hepatitis B virus-associated HCC was related to high cytoplasmic expression of ZHX1, which was marginally related to telomerase reverse transcriptase (TERT) promoter mutation-negative HCC. In contrast, low nuclear expression of ZHX3 was associated with TERT promoter mutation-positive HCC and HCC patients over 70 years old.

Conclusions: These results suggest that the expression and localization of different ZHXs may be related to HCC progression, potentially inferring genetic backgrounds such as TERT promoter mutation. Further studies on the relationship between HCC and ZHXs will enhance our understanding and control of HCC.