Downregulation of CYP39A1 Serves as a Novel Biomarker in Hepatocellular Carcinoma with Worse Clinical Outcome

Abstract

Background. CYP39A1 is a poorly characterized metabolic enzyme that has been investigated in a few tumors. However, the role of CYP39A1 in hepatocellular carcinoma (HCC) has not yet been clarified. In this study, the expression and clinical significance of CYP39A1 in HCC were explored. Methods. CYP39A1 protein expression was detected in Akt/c-Met-induced HCC mice and 14 paired fresh HCC samples as well as another 159 HCC and matched noncancerous tissues. Meanwhile, the mRNA expression was analyzed by GEO and TCGA analysis and validated in 14 paired fresh HCC tissues. Furthermore, the relationships between CYP39A1 expression and clinicopathologic features as well as prognosis were analyzed. HCC cell growth changes were analyzed by cell viability assays after CYP39A1 overexpression and then validated after CYP39A1 knockout by DepMap database analysis. Results. CYP39A1 protein expression was lower expressed in HCC mouse models, and its mRNA and protein expression were also downregulated in HCC compared with noncancerous liver tissues. Higher CYP39A1 expression was associated with well differentiation. Moreover, survival analysis indicated that lower CYP39A1 expression was associated with poorer overall survival. In addition, HepG2 and SMMC-7721 cell viability were inhibited after CYP39A1 overexpression. Genome-wide CRISPR/Cas9 proliferation screening indicated that knockout of CYP39A1 could promote HCC cell growth. Likewise, p-NF-κB and Nrf2 were suppressed after CYP39A1 overexpression. It is worth mentioning that total bile acid, total bilirubin, and direct bilirubin were significantly increased in the patients with low CYP39A1 expression. Conclusions. Downregulation of CYP39A1 is associated with HCC carcinogenesis, tumor differentiation, and poor overall survival, suggesting that CYP39A1 may serve as a tumor suppressor gene and novel biomarker for HCC patients.

Distinctive Metabolism-Associated Gene Clusters That Are Also Prognostic in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma

“…This superfamily contains enzymes that are important for the clearance of various compounds including drugs, as well as for the synthesis and breakdown of hormones. Specific mutations of certain members within this family affect the efficacy of chemotherapeutical treatment [ 36 ], and dysregulations have been linked with the carcinogenesis of HCC and ICC [ 37 ]. The transcriptomic information of the cytochrome P450 system can provide insights into both the identification and prognosis of HCC [ 38 ].…”

Machine Learning to Identify Molecular Markers for Metabolic Disease Development Using Mouse Models

“…Among the diet predictors, downregulation of Cyp39a1 (24-hydroxycholesterol 7-alpha-hydroxylase) by WD has been proposed as a novel biomarker for poor overall survival of HCC patients [28]. In contrast, Gramd1b (GRAM domain containing 1B), a cholesterol transporter, was upregulated in WD-fed mouse livers suggesting cholesterol overload.…”

INSC Is Down-Regulated in Colon Cancer and Correlated to Immune Infiltration

“…In order to further confirm the expression of INSC in the colon and COAD tissues, 82 paired normal and COAD tissues (49 men and 33 women, average age of 63 ± 13 years old) were enrolled and determined by IHC staining ( Li et al, 2021a ). Briefly, deparaffinized and rehydrated sections were subjected to 3% H 2 O 2 and then antigen retrieval by citric acid buffer (pH 6.0).…”