An integrated analysis of the SOX2 microRNA response program in human pluripotent and nullipotent stem cell lines

Vencken, Sebastian; Sethupathy, Praveen; Blackshields, Gordon; Spillane, Cathy; Elbaruni, Salah A; Sheils, Orla; Gallagher, Michael; O’Leary, John

doi:10.1186/1471-2164-15-711

Cited by 17 publications

(15 citation statements)

References 110 publications

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“…However, it is worth noting that in contrast to our cell lines, Hep‐2 lacks gain of 3q and is characterized by rather low basal SOX2 expression. In line with our findings, whole‐microRNAome and genome analysis of SOX2‐silenced human embryonal carcinoma cell (hECC) revealed a large miRNA network regulating the expression of crucial genes involved in EMT (Vencken et al., 2014). Hence, deregulation of genes involved in tumor cell motility can be at least in part due to SOX2‐related regulation of miRNAs.…”

Section: Discussionsupporting

confidence: 86%

Loss of SOX2 expression induces cell motility via vimentin up‐regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma

et al. 2015

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Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up-regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down-regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression-free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure.

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Section: Discussionsupporting

confidence: 86%

Loss of SOX2 expression induces cell motility via vimentin up‐regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma

et al. 2015

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“…Functional annotations from HaploReg indicated that rs763354 might increase the binding of Sox2 , which might bind to the promoter regions of miRNAs [34]. However, we did not observe significant association between rs763354 and miR-30a-3p or miR-30a-5p expression in 38 TCGA adjacent normal tissues.…”

Section: Discussioncontrasting

confidence: 66%

Genetic variants in regulatory regions of microRNAs are associated with lung cancer risk

et al. 2016

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Genetic variants in regulatory regions of some miRNAs might be associated with lung cancer risk and survival. We performed a case-control study including 1341 non-small cell lung cancer (NSCLC) cases and 1982 controls to evaluate the associations of 7 potentially functional polymorphisms in several differently expressed miRNAs with NSCLC risk. Each SNP was also tested for the association with overall survival of 1001 NSCLC patients. We identified that rs9660710 in miR-200b/200a/429 cluster and rs763354 in miR-30a were significantly associated with NSCLC risk [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.06–1.30, P = 0.002; OR = 0.88, 95% CI = 0.80–0.98, P = 0.017; respectively]. However, no significant association between variants and NSCLC death risk was observed in survival analysis. Functional annotation showed that both rs9660710 and rs763354 were located in regulatory elements in lung cancer cells. Compared to normal tissues, miR-200a-3p, miR-200a-5p, miR-200b-3p, miR-200b-5p and miR-429 were significantly increased in The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma (LUAD) tumors, whereas miR-30a-3p and miR-30a-5p were significantly decreased in tumors (all P < 0.05). Furthermore, we observed that rs9660710 is an expression quantitative trait locus (eQTL) or methylation eQTL for miR-429 expression in TCGA normal tissues. Our results indicated that rs9660710 in miR-200b/200a/429 cluster and rs763354 in miR-30a might modify the susceptibility to NSCLC.

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“…expression of ABC transporters, enhanced expression of aldehyde dehydrogenase, expression of pro-survival proteins altered DNA damage response and altered signaling pathways) [65, 66]. As a result of their ability to better tolerate drug exposure, CSCs are often refractory to drug treatment.…”

Section: Other Factorsmentioning

confidence: 99%

Molecular chess? Hallmarks of anti-cancer drug resistance

2017

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BackgroundThe development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years.ReviewResistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients.ConclusionThe oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

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An integrated analysis of the SOX2 microRNA response program in human pluripotent and nullipotent stem cell lines

Cited by 17 publications

References 110 publications

Loss of SOX2 expression induces cell motility via vimentin up‐regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma

Loss of SOX2 expression induces cell motility via vimentin up‐regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma

Genetic variants in regulatory regions of microRNAs are associated with lung cancer risk

Molecular chess? Hallmarks of anti-cancer drug resistance

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