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SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma.

ABSTRACT: Reliable biomarkers are required to predict the response to sorafenib. We investigated genomic variations associated with responsiveness to sorafenib for patients with unresectable hepatocellular carcinoma (HCC). Blood samples from 2 extreme, 2 strong and 3 poor responders to sorafenib were subjected to whole-genome analysis. Then, we validated candidate genomic variations with another 174 HCC patients, and performed in vitro functional analysis and in silico analyses. Genomic data of >96 gigabases/sample was generated at average of ~34X sequencing depth. In total, 1813 genomic variations were matched to sorafenib responses in clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes. From them, 36 variants were within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2). Validation genotyping confirmed sequencing results and revealed patients genotype for rs2257212 in SLC15A2 showed longer progression-free survival (HR = 2.18). In vitro study displayed different response to sorafenib depending on the genotype of SLC15A2. Structural prediction analysis revealed changes of the phosphorylation levels in protein, potentially affecting sorafenib-associated enzymatic activity. Our finding using extreme responder seems to generate robust biomarker to predict the response of sorafenib treatment for HCC.

SUBMITTER: Lee YS

PROVIDER: S-EPMC4599281 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma.

Lee Yeon-Su YS Kim Bo Hyun BH Kim Byung Chul BC Shin Aesun A Kim Jin Sook JS Hong Seung-Hyun SH Hwang Jung-Ah JA Lee Jung Ahn JA Nam Seungyoon S Lee Sung Hoon SH Bhak Jong J Park Joong-Won JW

Oncotarget 20150601 18

Reliable biomarkers are required to predict the response to sorafenib. We investigated genomic variations associated with responsiveness to sorafenib for patients with unresectable hepatocellular carcinoma (HCC). Blood samples from 2 extreme, 2 strong and 3 poor responders to sorafenib were subjected to whole-genome analysis. Then, we validated candidate genomic variations with another 174 HCC patients, and performed in vitro functional analysis and in silico analyses. Genomic data of >96 gigaba ...[more]

PMID: 25965825

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Project description:BackgroundSeveral studies suggest the role of circulating microRNAs (miRNAs) as biomarkers of hepatocellular carcinoma (HCC). However, the serum miRNA profile associated with the response to sorafenib remains to be elucidated. The aim of this study was to clarify the specific miRNAs in serum that could predict the early response of HCC to sorafenib treatment.SummaryAnalyzing the sera from 16 HCC patients, we selected five miRNAs that showed differences in serum levels between patients with and without tumor responses among 179 known secretory miRNAs by using locked nucleic acid probe-based quantitative PCR. Through further analysis using a validation cohort that included 53 HCC patients who underwent sorafenib treatment and 8 healthy control subjects, we found that miR-181a-5p and miR-339-5p showed significant differences in serum levels among patients with partial response (PR), stable disease (SD), and progressive disease (PD), where PR patients showed the highest and PD the lowest levels. We also analyzed the factors associated with disease control (DC; PR or SD) 3 months after the initiation of sorafenib treatment; patients with DC showed a significantly higher level of serum miR-181a-5p than non-DC patients or healthy control subjects (p = 0.0349 and 0.0180 for DC vs. non-DC and control vs. non-DC by Tukey-Kramer test, respectively). We further conducted multivariate analysis among HCC patients with Barcelona Clinic Liver Cancer stage C using extrahepatic metastasis, serum decarboxyprothrombin, and miR-181a-5p levels as covariables; serum miR-181a-5p was the only independent factor for achieving DC (p = 0.0092, odds ratio 0.139, and 95% confidence interval 0.011-0.658). In addition, miR-181a-5p level was also the only independent factor affecting overall survival (p = 0.0194, hazard ratio 0.267, and 95% confidence interval 0.070-0.818).Key messagesA high serum level of miR-181a-5p before treatment is associated with DC after the initiation of sorafenib.

Project description:Rationale: Glycogen synthase kinase-3? (GSK-3?) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3? can confer tumor growth. However, the expression and function of GSK-3? in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3? in HCC. Methods: We firstly clarified the expression of GSK-3? in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3? could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3? in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments. Results: We demonstrated that GSK-3? is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3? confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3? is correlated with reduced expression of retinoic acid receptor-? (RAR?), which is caused by GSK-3?-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXR?) with RAR? on RAR? promoter. Overexpression of functional GSK-3? impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3? by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RAR? by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RAR?. Conclusions: Our findings demonstrate that GSK-3? is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3? may be a promising strategy for HCC treatment in clinic.

Dataset Information

SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma.

Publications

SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma.

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