Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X-C motif chemokine 1 and C-C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients.  Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis.

From this case, we suggest that long-term traction could be another treatment method for chronic AARF, especially in children.

Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6) in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence.

PurposeHomeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.Materials and MethodsThe full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis.ResultsThe underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified.ConclusionThe treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

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