A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

Xu, Ye; Li, Cunyan; Zu, Xuyu; Lin, Minglin; Liu, Qiang; Liu, Jianghua; Xu, Guo-Guo; Chen, Zhiyong; Xu, Yuping; Liu, Long; Luo, Diteng; Cao, Zhe; Shi, Guiyuan; Feng, Zi-Rui; Deng, Hongyu; Liao, Qianjin; Cai, Chuan; Liao, Duan‐Fang; Wang, Jing; Jin, Junfei; Cao, Deliang

doi:10.1002/hep.30519

Cited by 69 publications

(70 citation statements)

References 46 publications

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“…Furthermore, consistent with our results, COL1A1,39 40 42 AKR1B1039 41 and ubiquitin D (UBD)41 42 were among the most upregulated genes in severe disease. While COL1A1 encodes for a major constituent of fibrous tissue during hepatic fibrogenesis (collagen type 1), AKR1B10 is implicated in intracellular metabolism and regulation of intracellular signalling, and it has robustly been implicated in hepatic carcinogenesis 43. UBD encodes for ubiquitin D, which is implicated in the formation of Mallory-Denk bodies during steatohepatitis and is also upregulated in liver cancer 44.…”

Section: Discussionmentioning

confidence: 99%

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker

Baselli¹,

Dongiovanni

Rametta

et al. 2020

Gut

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ObjectiveEfforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant.DesignWe sequenced the hepatic transcriptome of 125 obese individuals. ‘Severe NAFLD’ was defined as the presence of steatohepatitis, NAFLD activity score ≥4 or fibrosis stage ≥2. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA.ResultsCarriage of the PNPLA3 I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1×10−6), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p<0.01 for both). A linear combination of IL32-ALT-AST showed a better performance than ALT-AST alone in NAFLD diagnosis (area under the curve=0.92 vs 0.81, p=5×10−5).ConclusionHepatic IL32 is overexpressed in NAFLD, correlates with hepatic fat and liver damage, and is detectable in the circulation, where it is independently associated with the presence and severity of NAFLD.

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Section: Discussionmentioning

confidence: 99%

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker

Baselli¹,

Dongiovanni

Rametta

et al. 2020

Gut

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“…The N-glycosylated isoform of AFP (AFP-L3), which contains core fucosylation on its N-linked glycans, only exists in HCC but is absent in other liver diseases and therefore can further enhance the specificity of HCC diagnosis. Unfortunately, a quite large proportion of HCC patients have an AFP negative until the laterstage (5,6). In addition, the AFP level has also been associated with pathological grade, progression, and survival HCC patients.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, the concentration of serum AFP varies dramatically with patients. It is known that 30-40% of HCC patients have a AFP level below the detection level of 20 ng/mL in serum, and remain AFP negative until the later-stage (5)(6)(7). Meanwhile, many other studies have also revealed that the high concentration of AFP in patients' serum was associated with high risk of tumor recurrence/progression and reduced survival at different stages of the diseases (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneities of Site-Specific N-Glycosylation in HCC Tumors With Low and High AFP Concentrations

Zhao

et al. 2020

Front. Oncol.

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Hepatocellular carcinoma (HCC) is still one of the malignant tumors with high morbidity and mortality in China and worldwide. Although alpha-fetoprotein (AFP) as well as core fucosylated AFP-L3 have been widely used as important biomarkers for HCC diagnosis and evaluation, the AFP level shows a huge variation among HCC patient populations. In addition, the AFP level has also been proved to be associated with pathological grade, progression, and survival of HCC patients. Understanding the intrinsic heterogeneities of HCC associated with AFP levels is essential for the molecular mechanism studies of HCC with different AFP levels as well as for the potential early diagnosis and personalized treatment of HCC with AFP negative. In this study, an integrated N-glycoproteomic and proteomic analysis of low and high AFP levels of HCC tumors was performed to investigate the intrinsic heterogeneities of site-specific glycosylation associated with different AFP levels of HCC. By large-scale profiling and quantifying more than 4,700 intact N-glycopeptides from 20 HCC and 20 paired paracancer samples, we identified many commonly altered site-specific N-glycans from HCC tumors regardless of AFP levels, including decreased modifications by oligo-mannose and sialylated bi-antennary glycans, and increased modifications by bisecting glycans. By relative quantifying the intact N-glycopeptides between low and high AFP tumor groups, the great heterogeneities of site-specific N-glycans between two groups of HCC tumors were also uncovered. We found that several sialylated but not core fucosylated tri-antennary glycans were uniquely increased in low AFP level of HCC tumors, while many core fucosylated bi-antennary or hybrid glycans as well as bisecting glycans were uniquely increased in high AFP tumors. The data provide a valuable resource for future HCC studies regarding the mechanism, heterogeneities and new biomarker discovery.

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“…In oral squamous cell carcinoma [9,19], non-small cell lung carcinoma [20] and liver carcinoma [7], high expression levels of AKR1B10 in patients is correlated with poor prognosis. Large-scale and multicenter studies have shown that AKR1B10 may serve as a serological markers for HCC in humans [10]. AKR1B10 plays a critical role in invasion and chemoresistance in BC cells [11].…”

Section: Discussionmentioning

confidence: 99%

“…In recent studies, mRNA levels of AKR1B10 were detected in several types of tumors [7][8][9]. In hepatocellular carcinoma (HCC) patients, the high expression of AKR1B10 positively correlated with poor prognosis [10]. In patients with BC, high expression of AKR1B10 is associated with drug resistance [11].…”

mentioning

confidence: 99%

AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-κB signaling pathway

et al. 2020

Preprint

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BackgroudAberrant expression of Aldo-Keto reductase family 1 member B10 (AKR1B10) has been observed during the progression of some human carcinomas. However, the expression pattern and clinical relevance of AKR1B10 in breast cancer (BC) need clarification.MethodsThe relationship between the high expression of AKR1B10 and the overall prognosis and disease-free survival of breast cancer patients was analyzed by Kaplan-Meier Plotter database. Breast cancer cell lines MCF-7/AKR1B10 stably overexpressing AKR1B10 and breast cancer cell lines BT-20/shAKR1B10 that knock down AKR1B10 were constructed, respectively. RT-qPCR, Western blot and immunohistochemistry were used to detect the expression of AKR1B10 in breast cancer and its normal tissues. CCK8 cell proliferation assay and cell scratch test were used to detect the proliferation and migration of breast cancer cells. Western blot was used to detect the expression of proliferation-related proteins cyclinD1, c-myc, survivin and EMT-related proteins twist, snail, slug, ZEB1, E-cadherin, PI3K, p-PI3K, AKT, p-AKT, IKBα, p-IKBα, NF-κB p65, and p-NF-κB p65 proteins in breast cancer cells. The PI3K inhibitor LY94002 was used to treat MCF-7 cells to detect PI3K/AKT/NF-κB signal cascade protein Expression, and expression of NF-κB p65 in nucleoproteins and plasma proteins.ResultsIn this study, we found that AKR1B10 expression was higher in BC tissue compared to paired non-cancerous tissue. The expression of AKR1B10 positively correlated with lymph node metastasis, tumor size, Ki67 expression, and p53 expression, but inversely correlated with overall and disease-free survival rates. Gene Ontology (GO) analysis showed that AKR1B10 was closely related to cell proliferation. Overexpression of AKR1B10 facilitated proliferation and migration of BC cells in vitro in association with induction of epithelial-mesenchymal transition. Conversely, knockdown of AKR1B10 inhibited these effects. Mechanistically, silencing AKR1B10 reduced the phosphorylation of PI3K, AKT, and NF-κB p65, whereas AKR1B10 overexpression activated these signaling molecules. Indeed, PI3K inhibition attenuated NF-κB p65 nuclear localization.ConclusionsOur results demonstrate that AKR1B10 promotes proliferation and migration of BC cells and represents a novel prognostic indicator as well as a potential therapeutic target in BC.

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A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

Cited by 69 publications

References 46 publications

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker

Heterogeneities of Site-Specific N-Glycosylation in HCC Tumors With Low and High AFP Concentrations

AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-κB signaling pathway

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