Comparative analysis of transcriptomics based hypoxia signatures in head- and neck squamous cell carcinoma

Tawk, Bouchra; Schwager, Christian; Deffaa, Oliver Johannes; Dyckhoff, Gerhard; Warta, Rolf; Linge, Annett; Krause, Mechthild; Weichert, Wilko; Baumann, Michaël; Herold‐Mende, Christel; Debus, Jürgen; Abdollahi, Amir

doi:10.1016/j.radonc.2015.11.027

Cited by 48 publications

(51 citation statements)

References 34 publications

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“…and Toustrup et al . could be confirmed in subsequent publications (Keck et al ., ; Tawk et al ., ), many molecular signatures, some of them very complex, fail independent validation and therefore to change practice in a clinical setting. This might be explained by methodological aspects such as the selection and number of genes examined, differences in the analysis platforms used, restrictions due to small sample sizes, lack of independent validation, but also by demographic differences in the patient groups examined or the unavailability of detailed clinical information.…”

Section: Introductionmentioning

confidence: 99%

A prognostic mRNA expression signature of four 16q24.3 genes in radio(chemo)therapy‐treated head and neck squamous cell carcinoma (HNSCC)

et al. 2018

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Previously, we have shown that copy number gain of the chromosomal band 16q24.3 is associated with impaired clinical outcome of radiotherapy‐treated head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify a prognostic mRNA signature from genes located on 16q24.3 in radio(chemo)therapy‐treated HNSCC patients of the TCGA (The Cancer Genome Atlas, n = 99) cohort. We applied stepwise forward selection using expression data of 41 16q24.3 genes. The resulting optimal Cox‐proportional hazards regression model included the genes APRT, CENPBD1, CHMP1A, and GALNS. Afterward, the prognostic value of the classifier was confirmed in an independent cohort of HNSCC patients treated by adjuvant radio(chemo)therapy (LMU‐KKG cohort). The signature significantly differentiated high‐ and low‐risk patients with regard to overall survival (HR = 2.01, 95% CI 1.10–3.70; P = 0.02125), recurrence‐free survival (HR = 1.84, 95% CI 1.01–3.34; P = 0.04206), and locoregional recurrence‐free survival (HR = 1.87, 95% CI 1.03–3.40; P = 0.03641). The functional impact of the four signature genes was investigated after reconstruction of a gene association network from transcriptome data of the TCGA HNSCC cohort using a partial correlation approach. Subsequent pathway enrichment analysis of the network neighborhood (first and second) of the signature genes suggests involvement of HNSCC‐associated signaling pathways such as apoptosis, cell cycle, cell adhesion, EGFR, JAK‐STAT, and mTOR. Furthermore, a detailed analysis of the first neighborhood revealed a cluster of co‐expressed genes located on chromosome 16q, substantiating the impact of 16q24.3 alterations in poor clinical outcome of HNSCC. The reported gene expression signature represents a prognostic marker in HNSCC patients following postoperative radio(chemo)therapy.

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Section: Introductionmentioning

confidence: 99%

A prognostic mRNA expression signature of four 16q24.3 genes in radio(chemo)therapy‐treated head and neck squamous cell carcinoma (HNSCC)

et al. 2018

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“…Of our topmost novel prognostic marker genes for primary melanomas, P4HA1 seemed the most interesting as its expression was largely tumor cell‐specific and upregulated in melanoma cell lines compared to normal melanocytes. Its mRNA expression is also reported to associate with poor survival in breast cancer (Gilkes et al , ) and squamous cell carcinoma (Kappler et al , ; Tawk et al , ), and the P4HA1 protein expression correlates with poor prognosis in high‐grade gliomas (Hu et al , ). Our preliminary results from immunohistochemical staining of primary melanomas suggest that, in addition to P4HA1 mRNA levels, also high P4HA1 protein expression may be associated with increased metastasis and mortality and may serve as a prognostic factor (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

et al. 2020

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Melanoma is an unpredictable, highly metastatic malignancy, and treatment of advanced melanoma remains challenging. Novel molecular markers based on the alterations in gene expression and the molecular pathways activated or deactivated during melanoma progression are needed for predicting the course of the disease already in primary tumors and for providing new targets for therapy. Here, we sought to identify genes whose expression in primary melanomas correlate with patient disease‐specific survival using global gene expression profiling. Many of the identified potential markers of poor prognosis were associated with the epithelial–mesenchymal transition, extracellular matrix formation, and angiogenesis. We studied further the significance of one of the genes, prolyl 4‐hydroxylase subunit alpha 1 (P4HA1), in melanoma progression. P4HA1 depletion in melanoma cells reduced cell adhesion, invasion, and viability in vitro. In melanoma xenograft assays, we found that P4HA1 knockdown reduced melanoma tumor invasion as well as the deposition of collagens, particularly type IV collagen, in the interstitial extracellular matrix and in the basement membranes of tumor blood vessels, leading to vessel wall rupture and hemorrhages. Further, P4HA1 knockdown reduced the secretion of collagen triple helix repeat containing 1 (CTHRC1), an important mediator of melanoma cell migration and invasion, in vitro and its deposition around tumor blood vessels in vivo. Taken together, P4HA1 is an interesting potential prognostic marker and therapeutic target in primary melanomas, influencing many aspects of melanoma tumor progression.

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“…A hypoxic tumor microenvironment reduces cellular radiosensitivity and is a well-known negative prognosticator of radiation response. [24][25][26] Destruction of the vasculature network after radiation may activate hypoxia induced transcription factor alpha (HIF1A) signaling and consequently expression of genes involved in cell survival and angiogenesis such as VEGF and CXCL12. 27 Interestingly, a link between hypoxia and regulation of candidate miR identified in our study was previously reported.…”

Section: Discussionmentioning

confidence: 99%

Large scale in vivo micro‐RNA loss of function screen identified miR‐29a, miR‐100 and miR‐155 as modulators of radioresistance and tumor‐stroma communication

Golestaneh

Lecker

Schlegel

et al. 2019

Intl Journal of Cancer

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Micro RNAs (miR) are master regulators of cellular transcriptome. We aimed to investigate the role of miR regulation on tumor radiosensitivity and development of local tumor recurrence by a novel large‐scale in vivo loss of function screen. For stable miR silencing, human A431 tumor cells were transduced with lentiviral constructs against 170 validated human miR (miRzip library). Fractionated radiotherapy (5x6Gy) was applied to A431 miRzip library growing s.c. in NCr nude mice. Enrichment of miRZip and miR expression was assessed using multiplexed qRT‐PCR. The modulatory effect of miR on tumor and tumor microenvironment response to ionizing radiation was further evaluated by clonogenic survival, apoptosis (Caspase 3/7), DNA double‐strand breaks (DSB, nuclear γH2AX foci), tumor microvessel density (MVD), transcriptome and protein analysis. Fractionated irradiation of the A431 miRzip library led to regression of tumors. However, after a latency period, tumors ultimately progressed and formed local recurrences indicating the survival of a subpopulation of miRzip expressing tumor clones. Among the selected miR for subsequent validation studies, loss of miR‐29a, miR‐100 and miR‐155 was found to enhance clonogenic survival, reduce apoptosis and residual γH2AX foci of irradiated tumor cells. Moreover, knockdown of miR increased tumor angiogenesis correlating with elevated VEGF and TGFα expression levels. This phenomenon was most evident after tumor irradiation in vivo suggesting a critical role for tumor‐stroma communication in development of the radioresistant phenotype. Engineering radioresistant tumors in vivo by modulating miR expression may lead to identification of critical targets for conquering local therapy failure.

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Comparative analysis of transcriptomics based hypoxia signatures in head- and neck squamous cell carcinoma

Cited by 48 publications

References 34 publications

A prognostic mRNA expression signature of four 16q24.3 genes in radio(chemo)therapy‐treated head and neck squamous cell carcinoma (HNSCC)

A prognostic mRNA expression signature of four 16q24.3 genes in radio(chemo)therapy‐treated head and neck squamous cell carcinoma (HNSCC)

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

Large scale in vivo micro‐RNA loss of function screen identified miR‐29a, miR‐100 and miR‐155 as modulators of radioresistance and tumor‐stroma communication

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