Paraoxonase 3 inhibits cell proliferation and serves as a prognostic predictor in hepatocellular carcinoma

Abstract

Paraoxonase 3 (PON3) exerts prominent anti-inflammation and anti-oxidation properties mainly at the cellular level, and is primarily expressed in the liver. However, its role in HCC remains unexplored. Here, we investigated the expression pattern, clinical significance, and function of PON3 in HCC. PON3 mRNA and protein levels were respectively determined in two large cohorts using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) of tissue microarray. We found that PON3 was downregulated in most HCCs. Kaplan-Meier and log-rank test showed that PON3 downregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in all HCC patients, especially early-stage HCC patients. Cox regression analysis revealed that the PON3 downregulation was an independent risk factor for RFS and OS. Gain- and loss-of-function experiments revealed that PON3 suppressed cell proliferation in vivo and in vitro, which was attributed to its cell-cycle arrest effect. In addition, microarray analysis showed that some pro-proliferative genes were elevated when PON3 was knockdown, and these genes possibly involved in the underlying mechanisms. In conclusion, our studies reveal the cell proliferation inhibitory function of PON3 and offer a potential prognostic predictor and therapeutic target for HCC.

Identification of potential core genes in hepatoblastoma via bioinformatics analysis

“…SNP in enriched genes such as ADH1B [Shih et al 2018], NAT2 [Farker et al 2003], CYP1A1 [Abo-Hashem et al 2016], CYP2D6 [Agundez et al 1996], GSTA1 [Akhdar et al 2016], MBL2 [Wang et al 2016] C6 [Wang et al 2016] and SERPINE1 [Divella et al 2015] were linked with advancement of hepatocellular carcinoma, but these polymorphic genes may be responsible for progression of hepatoblastoma. Enriched genes such as KMO (kynurenine 3-monooxygenase) [Jin et al 2015], HMGCS2 [Wang et al 2019], LIPG (lipase G, endothelial type) [Cadenas et al 2019], PON3 [Cai et al 2016], AASS (aminoadipate-semialdehyde synthase) [Xue et al 2019], PCK2 [Liu et al 2012], PPARGC1A [Wang et al 2018] and JUNB (JunB proto-oncogene, AP-1 transcription factor subunit) [Kim et al 2001] were associated with proliferation of hepatocellular carcinoma cells, but these genes may be associated with proliferation of hepatoblastoma cells. Enriched genes such as CYP1A2 [Biazi et al 2017], ADH4 [Wei et al 2012], ACSL1 [Cui et al 2014], UGT2B4 [Wijayakumara et al 2017], ALDH1A1 [Yan et al 2016], PON1 [Shu et al 2017], ASS1 [Frulio et al 2019], AKR1D1 [Nikolaou et al 2019], PTGS2 [Chen et al 2019], NNMT (nicotinamide N-methyltransferase) [Kim et al 2009], GPT (glutamic--pyruvic transaminase) [Shimokawa et al 1977], NNT (nicotinamide nucleotide transhydrogenase) [Lu et al 2017] and PCK1 [Xiang et al 2020] were linked with metabolic activity in hepatocellular carcinoma, but these genes may be involved in metabolic activity in hepatoblastoma.…”

KRT8 upregulation promotes tumor metastasis and is predictive of a poor prognosis in clear cell renal cell carcinoma

“…Density of KRT8 positive staining was quantifed using Leica DFC420 CCD camera connected to Leica DM IRE2 microscope (Leica Microsystems Imaging Solutions Ltd, Cambridge, United Kingdom). With the same setting for the background of the photographs, the integrated optical density of KRT8 was counted with the ImagePro Plus v6.0 software (Media Cybernetics Inc, MD, USA) as previously described [ 48 ]. KRT8 protein density of each photograph was calculated as the ratio of integrated optical density to total tissue area.…”

Integrated Proteomics and Bioinformatics to Identify Potential Prognostic Biomarkers in Hepatocellular Carcinoma

“… 39 PON3 is a member of Paraoxonase (PON) proteins primarily expressed in the liver, its expression and specific activities were found to negatively correlate with several inflammatory disorders and served as a prognostic predictor in HCC. 40 Song et al identified AMDHD1 was as a novel tissue-specific gene in human and mouse liver tissues. 41 CYP2C8, CYP4A11 and CYP2E1 are members of cytochrome P450 family which related iron ion binding and oxidoreductase activity and functioned in drug metabolism in the liver.…”