SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types

Richtig, Georg; Aigelsreiter, Ariane; Schwarzenbacher, Daniela; Ress, Anna Lena; Adiprasito, Jan Basri; Stiegelbauer, Verena; Höefler, Gerald; Schauer, Silvia; Kiesslich, Tobias; Kornprat, Peter; Winder, Thomas; Eisner, Florian; Gerger, Armin; Stoeger, Herbert; Stauber, Rudolf; Lackner, Carolin; Pichler, Martin

doi:10.1371/journal.pone.0187814

Cited by 52 publications

(53 citation statements)

References 43 publications

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“…We found that transcriptional factor Sox9 was a potential NBAT1-interacting candidate. As we know, Sox9 plays critical roles to drive cancer development including proliferation, migration, invasion, and angiogenesis [ 13–15 ]. RIP assay was used to confirm the interaction of between NBAT1 and Sox9 ( Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

A negative feedback loop between long noncoding RNA NBAT1 and Sox9 inhibits the malignant progression of gastric cancer cells

Yan¹,

Huang²,

Huang³

et al. 2018

Bioscience Reports

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Long noncoding RNAs (lncRNAs) play critical roles in carcinogenesis and progression, and act as important gene expression modulators. Recent evidence indicates that lncRNA neuroblastoma associated transcript 1 (NBAT1) functions as a tumor suppressor in some types of human cancers. However, its functional role in the development of gastric cancer (GC) remains unknown. The aim of this research was to investigate the clinical significance and biological functions of NBAT1 in GC. NBAT1 was found to be significantly down-regulated in GC tissue. Decreased NBAT1 expression was correlated with poor differentiation, higher tumor stage and lymph node metastasis, and poor prognosis. Functional assays showed that NBAT1 inhibited GC proliferation, migration, and invasion. NBAT1 also suppressed proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, NBAT1 interacted with Sox9, and reduced its protein stability by promoting it from polyubiquitination and proteasome-dependent degradation. Moreover, we revealed that Sox9 could occupy the NBAT1 promoter to inactivate its transcription. The negative feedback loop of NBAT1 and Sox9 continuously enhanced the suppressive effects. In conclusion, these findings suggest that feedback regulation of NBAT1 and Sox9 served as a critical effector in GC progression.

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Section: Resultsmentioning

confidence: 99%

A negative feedback loop between long noncoding RNA NBAT1 and Sox9 inhibits the malignant progression of gastric cancer cells

Yan¹,

Huang²,

Huang³

et al. 2018

Bioscience Reports

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“…33 Importantly, extended analysis in additional cohorts showed that those genes that were epigenetically changed by HCV infection and that persisted after DAA cure predicted HCC risk in cohorts of patients with HCV cirrhosis and SVR ( Figure 6C). Although we do not have experimental evidence that HCV-mediated modulation of SPHK1 or SOX9 gene expression is sufficient to promote cancer, our data combined with published knowledge on the role of these proteins in cancer biology 31,32 nevertheless suggest that SPHK1 and SOX9, among additional tumor-associated proteins, participate in HCV-induced HCC. This strongly supports the hypothesis that H3K27ac alterations of the identified genes precede HCC onset.…”

Section: Discussionmentioning

confidence: 54%

HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response

et al. 2019

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infection is an important risk factor for hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the risk for HCC is decreased but not eliminated after a sustained virologic response (SVR) to direct-acting antiviral (DAA) agents, and the risk is higher in patients with advanced fibrosis. We investigated HCV-induced epigenetic alterations that might affect risk for HCC after DAA treatment in patients and mice Gastroenterology 2019;156:2313-2329 BASIC AND TRANSLATIONAL LIVER with humanized livers. METHODS: We performed genomewide ChIPmentation-based ChIP-Seq and RNA-seq analyses of liver tissues from 6 patients without HCV infection (controls), 18 patients with chronic HCV infection, 8 patients with chronic HCV infection cured by DAA treatment, 13 patients with chronic HCV infection cured by interferon therapy, 4 patients with chronic hepatitis B virus infection, and 7 patients with nonalcoholic steatohepatitis in Europe and Japan. HCV-induced epigenetic modifications were mapped by comparative analyses with modifications associated with other liver disease etiologies. uPA/SCID mice were engrafted with human hepatocytes to create mice with humanized livers and given injections of HCV-infected serum samples from patients; mice were given DAAs to eradicate the virus. Pathways associated with HCC risk were identified by integrative pathway analyses and validated in analyses of paired HCC tissues from 8 patients with an SVR to DAA treatment of HCV infection. RESULTS:We found chronic HCV infection to induce specific genome-wide changes in H3K27ac, which correlated with changes in expression of mRNAs and proteins. These changes persisted after an SVR to DAAs or interferon-based therapies. Integrative pathway analyses of liver tissues from patients and mice with humanized livers demonstrated that HCV-induced epigenetic alterations were associated with liver cancer risk. Computational analyses associated increased expression of SPHK1 with HCC risk. We validated these findings in an independent cohort of patients with HCV-related cirrhosis (n ¼ 216), a subset of which (n ¼ 21) achieved viral clearance. CONCLUSIONS: In an analysis of liver tissues from patients with and without an SVR to DAA therapy, we identified epigenetic and gene expression alterations associated with risk for HCC. These alterations might be targeted to prevent liver cancer in patients treated for HCV infection.

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“…Results showed highly significant correlations in CA1a/AT for tumorigenic processes such as angiogenesis, cytokine-mediated signaling, cell migration, apoptosis and epithelial cell differentiation. Specific proteins in this group which have known roles in breast cancer include fibroblast growth factor receptor 2 (FGFR2) [ 11 ], filamin A (FLNA) [ 12 , 13 ], forkhead box A1 (FOXA1) [ 14 ], integrin subunit α5 (ITGA5) [ 15 ], intercellular adhesion molecule 1 (ICAM1) [ 16 ], interleukin 1β (IL1B) [ 17 ], interleukin 8 (CXCL8) [ 18 ], protein tyrosine kinase 6 (PTK6) [ 19 ], transcription factor SOX-9 [ 20 ], transforming growth factor β1 (TGFB1) [ 21 ], and Wnt-5a [ 22 ]. Please note that all three comparisons have significant associations for epithelial cell differentiation, but only the malignant CA1a cells within the CA1a/AT comparison is significantly associated with angiogenesis.…”

Section: Resultsmentioning

confidence: 99%

Global Signaling Profiling in a Human Model of Tumorigenic Progression Indicates a Role for Alternative RNA Splicing in Cellular Reprogramming

Caruso

Carruthers

Thibodeau³

et al. 2018

IJMS

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Intracellular signaling is controlled to a large extent by the phosphorylation status of proteins. To determine how human breast cells can be reprogrammed during tumorigenic progression, we profiled cell lines in the MCF10A lineage by phosphoproteomic analyses. A large cluster of proteins involved in RNA splicing were hypophosphorylated as cells progressed to a hyperplastic state, and then hyperphosphorylated after progression to a fully metastatic phenotype. A comprehensive transcriptomic approach was used to determine whether alterations in splicing factor phosphorylation status would be reflected in changes in mRNA splicing. Results indicated that the degree of mRNA splicing trended with the degree of tumorigenicity of the 4 cell lines tested. That is, highly metastatic cell cultures had the greatest number of genes with splice variants, and these genes had greater fluctuations in expression intensities. Genes with high splicing indices were mapped against gene ontology terms to determine whether they have known roles in cancer. This group showed highly significant associations for angiogenesis, cytokine-mediated signaling, cell migration, programmed cell death and epithelial cell differentiation. In summary, data from global profiling of a human model of breast cancer development suggest that therapeutics should be developed which target signaling pathways that regulate RNA splicing.

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SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types

Cited by 52 publications

References 43 publications

A negative feedback loop between long noncoding RNA NBAT1 and Sox9 inhibits the malignant progression of gastric cancer cells

A negative feedback loop between long noncoding RNA NBAT1 and Sox9 inhibits the malignant progression of gastric cancer cells

HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response

Global Signaling Profiling in a Human Model of Tumorigenic Progression Indicates a Role for Alternative RNA Splicing in Cellular Reprogramming

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