Loss of Tid1/DNAJA3 Co-Chaperone Promotes Progression and Recurrence of Hepatocellular Carcinoma after Surgical Resection: A Novel Model to Stratify Risk of Recurrence

SIMPLE SUMMARY: Tid1 acts as a tumor suppressor in various cancer types, however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we observed a low protein level of Tid1 in poorly differentiated HCC cell lines. The expression of Tid1 affected the malignancy in human HCC cell lines; meanwhile the protein level of Nrf2 was negatively regulated by Tid1. In multivariate analysis, using immunohistochemical (IHC) assay in 210 HCC cases, we found the tumor size > 5 cm, multiple tumors, presence of vascular invasion, low Tid1 expression in the non-tumor part, and high Nrf2 expression in the non-tumor part, were independently associated with worse recurrence-free survival (RFS). A scoring system by integrating the five clinical and pathological factors predicts the RFS among HCC patients after surgical resection. In summary, Tid1 plays a prognostic role for surgically resected HCC. ABSTRACT: Tid1, a mitochondrial co-chaperone protein, acts as a tumor suppressor in various cancer types. However, the role of Tid1 in hepatocellular carcinoma (HCC) remains unclear. First, we found that a low endogenous Tid1 protein level was observed in poorly differentiated HCC cell lines. Further, upregulation/downregulation of Tid1 abrogated/promoted the malignancy of human HCC cell lines, respectively. Interestingly, Tid1 negatively modulated the protein level of Nrf2. Tissue assays from 210 surgically resected HCC patients were examined by immunohistochemistry (IHC) analyses. The protein levels of Tid1 in the normal and tumor part of liver tissues were correlated with the clinical outcome of the 210 HCC cases. In multivariate analysis, we discovered that tumor size > 5 cm, multiple tumors, presence of vascular invasion, low Tid1 expression in the non-tumor part, and high Nrf2 expression in the non-tumor part were significant factors associated with worse recurrence-free survival (RFS). A scoring system by integrating the five clinical and pathological factors predicts the RFS among HCC patients after surgical resection. Together, Tid1, serving as a tumor suppressor, has a prognostic role for surgically resected HCC to predict RFS.