Low SLC22A7 expression in noncancerous liver promotes hepatocellular carcinoma occurrence - a prospective study
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE40873 | GEO | 2013/04/01
SECONDARY ACCESSION(S): PRJNA175146
REPOSITORIES: GEO
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Project description:Background & Aims: The recurrence determines the postoperative prognosis of patients with hepatocellular carcinoma (HCC). It is unknown whether de novo HCCs derive from the liver with disability of an organic anion transport. This study was designed to elucidate the link between such transporters and the multicentric occurrence (MO) after radical hepatectomy. Results: SLC22A7 expression was the best predictor of metastasis-free survival (MFS) as judged by the GA (Fold, 0.726; P=0.001). High SLC22A7 gene expression in noncancerous tissue prevent HCC occurrence after hepatectomy (Odds Ratio (OR), 0.2; 95%CI, 0.1-0.6; P=0.004). Multivariate analyses of MFS revealed the independent risk factor to be SLC22A7 expression (OR, 0.3; 95%CI, 0.1-1.0, P=0.043). Low SLC22A7 expression caused MO of HCC significantly (log-rank, P=0.001). In the validation study, multivariate analyses of MFS revealed the independent risk factor to be SLC22A7 expression (OR, 0.5; 95%CI, 0.3-0.8; P=0.012). As judged by Gene set-enrichment analysis, SLC22A7 down-regulation associated with mitochondrion (P=0.008; false discovery rate (FDR)=0.199; normalized enrichment score (NES) =1.804), oxidoreductase activity (P=0.006; FDR=0.157; NES=1.854) and fatty acid metabolic process (P=0.021; FDR=0.177; NES=1.723). Sirtuin3 also determined MFS (P= 0.018). Conclusions: These pathways involving SLC22A7 dysfunction may promote the occurrence of HCC. The 49 noncancerous liver tissues of HCC patients within Milan criteria, treated at our institution between January 2004 and August 2008, were examined as a training set by genome-wide gene expression analysis (GA). Cox proportional hazards regression analyses for MO-free survival (MFS) were performed to estimate the risk factors. Using the independent two institutional cohorts of 134 patients between September 2008 and December 2009, a validation study was employed using tissue microarrays.
2013-04-01 | E-GEOD-40873 | biostudies-arrayexpress
Project description:Exosomal microRNAs have recently been studied as potential diagnostic marker for various malignancies, including hepatocellular carcinoma (HCC). The aim of this study was to investigate serum exosomal microRNA profiles as HCC diagnostic marker. Transmission electron microscopy and western blot were used to identify serum exosomes. Deep sequencing was performed to screen differentially expressed microRNAs between HCC (n=5) and liver cirrhosis (LC, n=5) group. Three upregulated and two downregulated microRNAs were selected for qPCR analysis. The levels of selected microRNAs were normalized to Caenorhabditis elegans miR-39 microRNA mimics. Serum exosomal level of miR-122, miR-148a, and miR-1246 were further analyzed and significantly higher in HCC than LC and normal control (NC) group (P<0.001), but not different from chronic hepatitis group(p>0.05). The receiver operating characteristic curve was used to evaluate diagnostic perfromance of candidate microRNAs. Area under the curve (AUC) of miR-148a was 0.891 [95 % confidence interval (CI), 0.809-0.947] in discriminating HCC from LC, remarkably higher than alpha fetoprotein (AFP) (AUC: 0.712, 95 % CI: 0.607-0.803). Binary logistic regression was adpoted to establish the diagnostic model for discriminating HCC from LC. And the combination of miR-122, miR-148a and AFP increased the AUC to 0.931 (95% CI, 0.857-0.973), which can also be applied for distinguishing early HCC from LC. miR-122 was the best for differentiating HCC from NC (AUC: 0.990, 95% CI, 0.945-1.000). These data suggests that serum exosomal microRNAs signature or their combination with traditional biomarker may be used as a suitable peripheral screening tool for HCC.
2018-10-01 | GSE104251 | GEO
Project description:Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) can be offered to patients beyond Milan criteria. However, there are currently no molecular markers that can be used on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to identify proteins on HCC explant predictive of recurrence post-transplant, thereby guiding surveillance strategies and identifying patients beyond Milan criteria who would fare well following LT. Methods: LT recipients who had been transplanted at the University Health Network for HCC beyond Milan criteria in the context of Hepatitis B cirrhosis were identified. Snap-frozen samples from the dominant tumors of recurrent (N=7) and non-recurrent (N=4) patients were analyzed using LC-MS/MS on a Q-Exactive Plus mass spectrometer to delineate a distinctive proteomic signature. These tumors were also profiled by a Human Gene 2.0 ST microarray platform to identify a transcriptomic signature predictive of recurrence and analyzed with R packages. STRING database was used to characterize the implicated pathways. Kaplan-Meier estimator was used to generate a combined proteomic/transcriptomic signature predictive of HCC recurrence in patients with HCC beyond Milan criteria at time of LT. Significantly predictive proteins were verified and internally validated by immunoblotting or immunohistochemistry. Results: A total of 79 proteins and 636 genes were significantly differentially expressed in recurrent HCC, compared to non-recurrent (p<0.05). Among these, LGALS3, LGALS3BP, HAL, THBS1, and BLMH, were significantly increased in recurrent HCC at the protein and gene expression level. In turn, ALDH1A1 protein and gene expression were significantly decreased in recurrent HCC. Univariate survival analysis depicted ALDH1A1 (HR=0.084, 95%CI 0.01-0.68, p=0.02), LGALS3BP (HR=7.14, 95%CI 1.20-42.96, p=0.03), and LGALS3 (HR=2.89, 95%CI 1.01-8.3, p=0.049) as the key dysregulated proteins and genes in the patients with HCC recurrence versus those with non-recurrence by both proteomic and transcriptomic analysis. Decreased ALDH1A1 and significantly increased LGALS3 protein expression in recurrent HCC was verified by immunoblotting. Increased LGALS3BP protein expression in recurrent HCC was orthogonally verified and validated by immunohistochemistry in 30 independent HCC samples. Conclusion: Protein and gene expression of the cancer stem cell marker ALDH1A1 was protective against cancer recurrence in patients transplanted for HCC beyond Milan criteria. Conversely, increased expression of LGALS3 and LGALS3BP on explant was significantly predictive of post-transplant recurrence. These findings were internally validated, suggesting potential utility in identifying patients with HCC beyond Milan who would clearly benefit from transplant with limited recurrence risk and guiding post-transplant surveillance.
2022-02-22 | PXD022881 | Pride
Project description:Rationale: Sepsis patients suffer from severe metabolic and immunologic dysfunction that may be amplified by standard carbohydrate-based nutritional regimes. We therefore hypothesize that a ketogenic diet improves sepsis treatment. Objectives: We investigated the safety and feasibility of a ketogenic diet in sepsis patients. Methods: We conducted a monocentric open-labeled randomized controlled trial (DRKS00017710) enrolling adult sepsis patients randomly assigned to either ketogenic or standard high-carbohydrate diet for 14 days with follow-up until day 30. The primary outcome measure was β-hydroxybutyrate serum concentration on day 14. Secondary outcomes included safety, clinical and immunological changes. Measurements and Main Results: 40 critically ill septic patients were assigned to the study groups. Increase in β-hydroxybutyrate concentrations from baseline to day 14 was markedly greater under ketogenic diet (1.2 ±0.9) compared to controls (-0.3 ±0.4); estimated mean difference 1.4 (95%-CI 1.0-1.8; p<0.0001). During ketogenic diet, no patient required insulin treatment beyond day 4, whereas 35% to 60% of control patients did (p=0.0095). Metabolic side effects were not observed under ketogenic diet. Ventilation-free (IRR 1.7; 95%-CI: 1.5 to 2.1; p<0.0001), vasopressor-free (IRR 1.7; 95%-CI: 1.5 to 2.0; p<0.0001), dialysis-free (IRR 1.5; 95%-CI: 1.3 to 1.8; p<0.0001), and ICU-free days (IRR 1.7; 95%-CI: 1.4 to 2.1; p<0.0001) significantly increased in patients under ketogenic diet. There was no difference in 30-day mortality. Analyses indicated favorable changes towards immune homeostasis. Conclusions: Ketogenic diet is a feasible and safe nutritional regimen in septic patients promoting recovery from sepsis-related organ dysfunction and could become a new tool in modern treatment concepts.
2024-06-13 | PXD046061 | Pride
Project description:Purpose: Black/African American (AA) women are twice as likely to be diagnosed with triple negative breast cancer (TNBC) compared to whites, an aggressive breast cancer subtype associated with poor prognosis. There are no routinely used targeted clinical therapies for TNBC; thus there is a clear need to identify prognostic markers and potential therapeutic targets. Methods: We evaluated expression of 27,016 genes in 155 treatment-naïve TN tumors from AA women in Detroit. Associations with survival were evaluated using Cox proportional hazards models adjusting for stage and age at diagnosis, and p-values were corrected using a false discovery rate. Our validation sample consisted of 158 TN tumors (54 AA) from The Cancer Genome Atlas (TCGA). Meta-analyses were performed to obtain summary estimates by combining TCGA and Detroit AA cohort results. Results: In the Detroit AA cohort, CLCA2 [Hazard ratio (HR)=1.56, 95% confidence interval (CI) 1.31-1.86, nominal p=5.1x10-7, FDR p=0.014], SPIC [HR=1.47, 95%CI 1.26-1.73, nominal p=1.8x10-6, FDR p=0.022], and MIR4311 [HR=1.57, 95% CI 1.31-1.92, nominal p=2.5x10-5, FDR p=0.022] expression were associated with overall survival. Further adjustment for treatment and breast cancer specific survival analysis did not substantially alter effect estimates. Meta-analysis with TCGA data showed that CLCA2 and SPIC were associated with overall survival for TNBC among AA women. Conclusions: We identified three potential prognostic markers for TNBC in AA women, for which SPIC may be an AA-specific prognostic marker.
2019-12-17 | GSE142102 | GEO
Project description:Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear. In this study, palliative hepatectomy was performed in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Using Human Tumor Metastasis Microarray, we screened the metastasis-related genes in tumor tissues following palliative resection, and found that Metastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC; MTSS1 was up-regulated in residual tumor after palliative resection. Further studies found that MTSS1 enhanced the metastasis of residual HCC. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by the activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1 level. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9% in vitro, and averted the deteriorated lung metastatic extent in vivo. In conclusion, the poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment.
2015-12-15 | GSE75965 | GEO
Project description:Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear. In this study, palliative hepatectomy was performed in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Using Human Tumor Metastasis Microarray, we screened the metastasis-related genes in tumor tissues following palliative resection, and found that Metastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC; MTSS1 was up-regulated in residual tumor after palliative resection. Further studies found that MTSS1 enhanced the metastasis of residual HCC. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by the activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1 level. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9% in vitro, and averted the deteriorated lung metastatic extent in vivo. In conclusion, the poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment. Eighteen nude mice bearing HCC xenografts were randomized into three groups 14 days after orthotopic implantation: palliative resection group (mice received partial HCC resection with preservation of 2 mm tumor pedicles), sham operation group (mice only undergone an exposure of liver but without resection), and blank control group (mice without further surgical intervention). All mice were sacrificed by cervical dislocation 14 days following palliative resection based on pre-experimental results. The first time surgically removed HCC tissues were named tumor tissues T1; the second time surgically removed HCC tissues from sham operation group were named tumor tissues T2; Tissues from blank control group were named tumor tissues T3; Tissues from palliative resection group were named tumor tissues T4 that was residual HCC. Randomly selected 5 tumor specimens from each group were used for the screen of genes related to metastasis by microarray techniques.
2015-12-15 | E-GEOD-75965 | biostudies-arrayexpress
Project description:Background: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. Methods: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2,554 Chinese subjects: 1,204 HCC patients, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC), and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularization for feature selection. Results: The 5hmC-Seal data from HCC patients showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer (BCLC) staging system from non-HCC (validation set: AUC = 88.4%; 95% CI, 85.8-91.1%), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumors (e.g., ≤ 2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC = 84.6%; 95% CI, 80.6-88.7%), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (e.g., smoking/alcohol intake history). Conclusions: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.
2019-08-07 | GSE112679 | GEO
Project description:The NSC differentiation of six validated iPSC lines were induced using commercially available PSC neural induction medium and following manufacturer method with minor modifications (Gibco). An extensive characterization of generated NSCs on day 14 (at passage P1) was performed using immunocytochemistry (ICC) analysis of the NSC specific markers and by genome wide mRNA sequencing. The iPSC differentiated NSCs expressed NSC specific markers Nestin, PAX6, SOX1 and SOX2 across all six samples. The average correlation coefficient at 95% CI between 6 NSC samples, calculated based on all expressed mRNAs, was 0.97 ± 0.008 suggesting a uniform differentiation of generated NSC lines. The generated NSC showed high expression of neuroepithelial genes/transcription factors (NES, SOX2, SOX1, PAX6, NOTCH1, MSI1,and CHD2) and genes/transcription factors of dorsal tube neuroepithelium (PAX3, GDF7, SOX9 and SNAI2) but lacked the expression of ventral tube neuroepithelial markers (NKX2-2, FOXA2 and SHH) suggesting a dorsal tube neuroepithelial transcriptomic and functional profile of the generated NSCs. A differential gene expression analysis of iPSC’s and NSC’s expressed transcription identified 4,033 mRNAs that were significantly differentially expressed (DE) between iPSCs and differentiated NSCs. The 2,006 DE mRNA were significantly upregulated in differentiated NSCs and were highly enriched in developmental functional categories such as embryonic development (572 mRNAs; FDR adjusted p-value range: 1.92x10-53 – 3.26x10-9), organism development (749 mRNAs; FDR adjusted p-value range: 1.92x10-53 – 4.30x10-9), nervous system development and function (629 mRNAs; FDR adjusted p-value range: 3.23x10-48 – 4.15x10-9), tissue development (655 mRNAs; FDR adjusted p-value range: 3.63x10-40 – 4.32x10-9) and organ development (406 mRNAs; FDR adjusted p-value range: 8.74x10-40 – 2.37x10-9).
2020-08-22 | GSE156617 | GEO
Project description:Background Currently, no gene-expression signature (GES) established from node-positive cohorts, able to predict breast cancer evolution after systemic adjuvant chemotherapy, exists. Methods Gene-expression profiles of 252 node-positive patients (median follow-up: 7.7 years), mostly included in a randomized clinical trial (PACS01), receiving systemic adjuvant regimen, were determined by means of cDNA custom array representing 5,776 distinct genes. Findings In the training cohort, we established a 38-GES for the purpose of predicting time to distant metastasis. The 38-GES yielded unadjusted hazard ratio of 4.86 (95% CI=2.76-8.56). Even when adjusted with the two best clinicopathological prognostic scoring: NPI and Adjuvant!, 38-GES HR were 3.30 (1.81-5.99) and 3.40 (1.85-6.24), respectively. Furthermore, 38-GES improved mostly NPI and Adjuvant! intermediate-risk classified patients. NPI intermediate-risk patients (7-year MFS=87.2%) were divided into 2/3 (7-year MFS=95.5%) close to NPI low-risk group and 1/3 (7-year MFS=69.3%) close to NPI high-risk group (HR=6.97 [2.51-19.36]). Adjuvant! intermediate-risk patients (7-year MFS=88.0%) were divided into 2/3 (7-year MFS=94.8%) close to Adjuvant! low-risk group and 1/3 (7-year MFS=71.7%) close to Adjuvant! high-risk group (HR=5.31 [5.38-11.87]). The 38-GES was validated on gene-expression datasets from three external node-positive breast cancer subcohorts (n=224) generated from different microarray platforms. The 38-GES yielded unadjusted HR=2.95 (1.74-5.01). Furthermore, 38-GES showed performance in supplementary cohorts with different lymph-node status and endpoint (1,031 new patients). Interpretation The 38-GES represents a robust tool able to type systemic adjuvant treated node-positive patients at high risk of metastatic relapse, and especially powerful to separate NPI or Adjuvant! intermediate-risk node-positive patients. Keywords: disease-state analysis 252 breast cancer patients at diagnosis examined with spotted cDNA nylon membrane. Patient details: PACS01x are 2 parts of a clinical trial : PACS01A : patients had received 6 cycles of FEC100 PACS01B : patients had received 3 cycles of FEC100 then 3 cycles of Docetaxel CCRG are patients from our local cancer center (Cancer Center René Gauducheau) included with the same criteria as PACS01A (6 cycles of FEC100).
2008-11-27 | E-GEOD-11264 | biostudies-arrayexpress