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Oncolytic HSV-1 suppresses cell invasion through downregulating Sp1 in experimental glioblastoma
Junwen Zhang1, Jialin Wang1, Mingxin Li1
1Brain Tumor Research Center, Beijing Neurosurgical Institute, Department of Neurosurgery, Beijing Tiantan Hospital affiliated to Capital Medical University, Beijing Laboratory of Biomedical Materials, Beijing, China.
Abstract:
Gliomas are highly aggressive intracranial tumors that are difficult to resect and have high lethality and recurrence rates. According to WHO grading criteria, glioblastoma with wild-type IDH1 has a poorer prognosis than WHO grade 4 IDH-mutant astrocytomas. To date, no effective therapeutic strategies have been developed to treat glioblastoma. Clinical trials have shown that herpes simplex virus (HSV)-1 is the safest and most efficacious oncolytic virus against glioblastoma, but the molecular antitumor mechanism of action of HSV-1 has not yet been determined. Deletion of the γ34.5 and ICP47 genes from a strain of HSV-1 yielded the oncolytic virus, oHSV-1, which reduced glioma cell viability, migration, and invasive capacity, as well as the growth of microvilli. Infected cell polypeptide 4 (ICP4) expressed by oHSV-1 was found to suppress the expression of the transcription factor Sp1, reducing the expression of host invasion-related genes. In vivo, oHSV-1 showed significant antitumor effects by suppressing the expression of Sp1 and invasion-associated genes, highly expressed in high-grade glioblastoma tissue specimens. These findings indicate that Sp1 may be a molecular marker predicting the antitumor effects of oHSV-1 in the treatment of glioma and that oHSV-1 suppresses host cell invasion through the ICP4-mediated downregulation of Sp1.
Insights
Herpes simplex virus-1 (HSV-1) effectively targets glioblastoma by reducing tumor cell invasion. The oncolytic virus oHSV-1 suppresses Sp1, a key factor in glioma invasion, offering a potential new therapeutic strategy.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Gliomas are aggressive brain tumors with poor prognoses.
- Glioblastoma, particularly wild-type IDH1, presents significant therapeutic challenges.
- The precise antitumor mechanisms of oncolytic viruses like herpes simplex virus-1 (HSV-1) remain unclear.
Purpose of the Study:
- To investigate the molecular antitumor mechanism of the oncolytic virus oHSV-1 against glioma.
- To determine if oHSV-1 affects glioma cell viability, migration, and invasion.
- To explore the role of Sp1 transcription factor in oHSV-1's antitumor activity.
Main Methods:
- Engineered an oncolytic virus, oHSV-1, by deleting specific genes (γ34.5 and ICP47) from HSV-1.
- Assessed the effects of oHSV-1 on glioma cell viability, migration, and invasive capacity in vitro.
- Investigated the expression of Infected cell polypeptide 4 (ICP4) and its effect on Sp1 and host invasion-related genes.
- Evaluated oHSV-1's antitumor effects in vivo and correlated Sp1 expression with treatment outcomes.
Main Results:
- oHSV-1 significantly reduced glioma cell viability, migration, and invasive capacity.
- ICP4 expressed by oHSV-1 suppressed the transcription factor Sp1.
- Sp1 downregulation led to reduced expression of host invasion-related genes.
- In vivo studies confirmed oHSV-1's antitumor effects by suppressing Sp1 and invasion-associated genes in high-grade glioblastoma.
Conclusions:
- oHSV-1 demonstrates significant antitumor activity against glioma by targeting Sp1.
- ICP4-mediated downregulation of Sp1 is a key mechanism by which oHSV-1 suppresses host cell invasion.
- Sp1 may serve as a predictive molecular marker for oHSV-1 treatment efficacy in glioma.
