32P - Expression of STAT3 and hypoxia markers in repeatedly resected glioma patients

Background

Hypoxia is characterized by low oxygen levels in tissues and plays a significant role in the development and progression of gliomas. Hypoxia induces activation of several signals including STAT3 which has been implicated in the cancer progression and development of drug resistance including in gliomas used temozolomide (TMZ) via modulation of O6-methylguanin-DNA-methyltransferase (MGMT) mediated repair of TMZ-induced DNA damage.

Methods

Our study was focused on the expression of STAT3 and hypoxia related factors in a set of repeatedly resected glioma patients (one patient without treatment, seven patients with chemoradiotherapy) and glioma cell lines with normal and knockout STAT3 using IHC, mutational and RT-PCR analyses correlated with clinical data.

Results

In patients' samples, IHC analysis showed that in all but one repeated glioma resections from individual patients pSTAT3 levels were elevated. Higher pSTAT3 levels as well as MGMT methylation status corresponded with a shortened survival of these patients. Further analyses carried out in cryopreserved glioma samples revealed upregulation of STAT3 in an untreated patient corresponding with upregulation of hypoxia factors (HIF1α, HIF1β), proangiogenic factor VEGFA and EGFR. STAT3 knockout in glioma cells produced a similar trend - downregulation of hypoxia and proangiogenic factors.

Conclusions

Our results demonstrated a biological relationship between the expression of pSTAT3, hypoxia and proangiogenic factors and MGMT methylation in both cultivated glioma cells and glioma resected samples. Moreover, we discovered that pSTAT3 levels tend to increase in repeated resections. MGMT methylation status and increased pSTAT3 levels in these samples correlate with shorter survival of investiagted glioma bearing patients.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

This study was supported by Ministry of Health, Czech Republic, project No. NU20-03-00360.

Disclosure

All authors have declared no conflicts of interest.