Background & AimsCurrently, using biopsy specimens to confirm suspicious liver lesions of early hepatocellular carcinoma are not entirely reliable because of insufficient sampling amount and inaccurate sampling location. It is necessary to develop a signature to aid early hepatocellular carcinoma diagnosis using biopsy specimens even when the sampling location is inaccurate.MethodsBased on the within‐sample relative expression orderings of gene pairs, we identified a simple qualitative signature to distinguish both hepatocellular carcinoma and adjacent non‐tumour tissues from cirrhosis tissues of non‐hepatocellular carcinoma patients.ResultsA signature consisting of 19 gene pairs was identified in the training data sets and validated in 2 large collections of samples from biopsy and surgical resection specimens. For biopsy specimens, 95.7% of 141 hepatocellular carcinoma tissues and all (100%) of 108 cirrhosis tissues of non‐hepatocellular carcinoma patients were correctly classified. Especially, all (100%) of 60 hepatocellular carcinoma adjacent normal tissues and 77.5% of 80 hepatocellular carcinoma adjacent cirrhosis tissues were classified to hepatocellular carcinoma. For surgical resection specimens, 99.7% of 733 hepatocellular carcinoma specimens were correctly classified to hepatocellular carcinoma, while 96.1% of 254 hepatocellular carcinoma adjacent cirrhosis tissues and 95.9% of 538 hepatocellular carcinoma adjacent normal tissues were classified to hepatocellular carcinoma. In contrast, 17.0% of 47 cirrhosis from non‐hepatocellular carcinoma patients waiting for liver transplantation were classified to hepatocellular carcinoma, indicating that some patients with long‐lasting cirrhosis could have already gained hepatocellular carcinoma characteristics.ConclusionsThe signature can distinguish both hepatocellular carcinoma tissues and tumour‐adjacent tissues from cirrhosis tissues of non‐hepatocellular carcinoma patients even using inaccurately sampled biopsy specimens, which can aid early diagnosis of hepatocellular carcinoma.
Cholestasis has limited therapeutic options and is associated with high morbidity and mortality. The A(1) adenosine receptor (A(1)AR) was postulated to participate in the pathogenesis of hepatic fibrosis induced by experimental extrahepatic cholestasis; however, the contribution of A(1)AR to intrahepatic cholestatic liver injury remains unknown. Here, we found that mice lacking A(1)AR were resistant to alpha-naphthyl isothiocyanate (ANIT)-induced liver injury, as evidenced by lower serum liver enzyme levels and reduced extent of histological necrosis. Bile acid accumulation in liver and serum was markedly diminished in A(1)AR(-/-) mice compared with wild-type (WT) mice. However, biliary and urinary outputs of bile acids were significantly enhanced in A(1)AR(-/-) mice. In the liver, mRNA expression of genes related to bile acid transport (Bsep and Mdr2) and hydroxylation (Cyp3a11) was increased in A(1)AR(-/-) mice. In the kidney, A(1)AR deficiency prevented the decrease of glomerular filtration rate caused by ANIT. Treatment of WT mice with A(1)AR antagonist DPCPX also protected against ANIT hepatotoxicity. Our results indicated that lack of A(1)AR gene protects mice from ANIT-induced cholestasis by enhancing toxic biliary constituents efflux through biliary excretory route and renal elimination system and suggested a potential role of A(1)AR as therapeutic target for the treatment of intrahepatic cholestasis.
Integrative analyses identified ion channel genes GJB2 and SCNN1B as prognostic biomarkers and therapeutic targets for lung adenocarcinoma
Upregulated de novo lipogenesis (DNL) plays a pivotal role in the progress of the nonalcoholic fatty liver disease (NAFLD). Cytoplasmic citrate flux, mediated by plasma membrane citrate transporter (SLC13A5), mitochondrial citrate carrier (SLC25A1), and ATP-dependent citrate lyase (ACLY), determines the central carbon source for acetyl-CoA required in DNL. Curcumin, a widely accepted dietary polyphenol, can attenuate lipid accumulation in NAFLD. Here, we first investigated the lipidlowering effect of curcumin against NAFLD in oleic and palmitic acid (OPA)-induced primary mouse hepatocytes and high-fat plus high-fructose diet (HFHFD)-induced mice. Curcumin profoundly attenuated OPA-or HFHFD-induced hyperlipidemia and aberrant hepatic lipid deposition via modulating the expression and function of SLC13A5 and ACLY. The possible mechanism of curcumin on the citrate pathway was investigated using HepG2 cells, HEK293T cells transfected with human SLC13A5, and recombinant human ACLY. In OPA-stimulated HepG2 cells, curcumin rectified the dysregulated expression of SLC13A5/ACLY possibly via the AMPK−mTOR signaling pathway. Besides, curcumin also functionally inhibited both citrate transport and metabolism mediated by SLC13A5 and ACLY, respectively. These findings confirm that curcumin improves the lipid accumulation in the liver by blocking citrate disposition and hence may be used to prevent NAFLD.
Background The qualitative transcriptional characteristics, the within‐sample relative expression orderings (REOs) of genes, are highly robust against batch effects and sample quality variations. Hence, we develop a qualitative transcriptional signature based on REOs to predict the biochemical recurrence risk of prostate cancer (PCa) patients after radical prostatectomy. Methods Gene pairs with REOs significantly correlated with the biochemical recurrence‐free survival (BFS) were identified from 131 PCa samples in the training data set. From these gene pairs, we selected a qualitative transcriptional signature based on the within‐sample REOs of gene pairs which could predict the recurrence risk of PCa patients after radical prostatectomy. Results A signature consisting of 74 gene pairs, named 74‐GPS, was developed for predicting the recurrence risk of PCa patients after radical prostatectomy based on the majority voting rule that a sample was assigned as high risk when at least 37 gene pairs of the 74‐GPS voted for high risk; otherwise, low risk. The signature was validated in six independent datasets produced by different platforms. In each of the validation datasets, the Kaplan‐Meier survival analysis showed that the average BFS of the low‐risk group was significantly better than that of the high‐risk group. Analyses of multiomics data of PCa samples from TCGA suggested that both the epigenomic and genomic alternations could cause the reproducible transcriptional differences between the two different prognostic groups. Conclusions The proposed qualitative transcriptional signature can robustly stratify PCa patients after radical prostatectomy into two groups with different recurrence risk and distinct multiomics characteristics. Hence, 74‐GPS may serve as a helpful tool for guiding the management of PCa patients with radical prostatectomy at the individual level.
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