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Oncotarget Transcriptional regulation of HSPB1 by Friend leukemia integration-1 factor


FOR IMMEDIATE RELEASE
2020-04-06

Oncotarget Volume 11, Issue 13 RNAseq analysis identified HSPB1 as a prominent upregulated HSP in GBM and in radiation resistant/temozolomide resistant GBM. Overexpression of Fli-1 in GBM promotes resistance, whereas Fli-1 knockdown in radio/TMZR GBM cells suppresses resistance.

This study uncovers Fli-1 as a potential therapeutic target for combating radiation and temozolomide resistance in GBM.

Dr. Mahitosh Mandal from the School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India as well as the Department of Human and Molecular Genetics and the VCU Institute of Molecular Medicine at Virginia Commonwealth University, School of Medicine, Richmond, VA, USA and Dr. Paul B. Fisher from the Department of Human and Molecular Genetics, the VCU Institute of Molecular Medicine, and the VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA said, "GBM account for the majority of brain tumors with high proliferative potential, infiltrative (invasive) growth behavior, intratumoral heterogeneity and tumor recurrence."

"GBM account for the majority of brain tumors with high proliferative potential, infiltrative (invasive) growth behavior, intratumoral heterogeneity and tumor recurrence."

- Dr. Mahitosh Mandal, Indian Institute of Technology Kharagpur, Department of Human and Molecular Genetics, and the VCU Institute of Molecular Medicine at Virginia Commonwealth University, School of Medicine & Dr. Paul B. Fisher, Department of Human and Molecular Genetics, the VCU Institute of Molecular Medicine and the VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine

HSPs coordinate multiple components of the ECM remodeling system revealing a positive correlation between high expression of HSPs and invasive capacity of GBM cells.

HSPB1 was identified using RNA sequencing amplification as the most upregulated heat shock family protein in GBM and in radio/TMZR GBM. Fli-1 overexpression promotes radiation- and TMZ-resistance in GBM cells resulting in morphological and molecular characteristics in these cells that are similar to those of radio/TMZR GBM cells.

Conversely, Fli-1 knockdown in radio/TMZR GBM cells sensitizes these cells to radiation and TMZ concomitantly promotes morphological and molecular characteristics similar to those of parental GBM cells.

Figure 1: Comparative expression pattern of different HSPs and determination of radiation resistance and TMZ resistance (radio/TMZR) in GBM. (A) Graphical representation of absolute RNAseq quantification of different HSPs involved in GBM from TCGA cBioPortal (n = 155). (B) Relative expression (RT-qPCR; average ± S. E.) of MMP-2, MMP-9 and EMT markers of U87MG RR and T98G RR cells. (C) Relative expression (RT-qPCR; average ± S. E.) of MMP-2, MMP-9 and EMT markers of U87MG TMZR and T98G TMZR cells. Normalization of data was performed with 18S rRNA. Data representation is with respect to expression of respective genes in U87MG RR/TMZR and T98G RR/TMZR cells vs. expression in U87MG and T98G cells, respectively.

In total, these studies provide compelling evidence that Fli-1 can directly regulate radiation and temozolomide resistance in GBM and targeting Fli-1 has potential as an effective therapy for treating both primary GBM and radio/TMZR GBM.

The Mandal/Fisher Research Team concluded in their Oncotarget Priority Research Paper, "the current study documents the importance of HSPB1 and Fli-1 in the regulation of radiation- and TMZ-resistance of GBM cells. It illustrates that targeted inhibition of Fli-1/HSPB1-mediates EMT and ECM remodeling signaling axes by genetic (shRNAs/siRNAs) inhibitors can regulate GBM phenotype and might provide novel therapeutic reagents for radio/TMZR glioblastoma."

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DOI - https://doi.org/10.18632/oncotarget.27425

Full text - https://www.oncotarget.com/article/27425/text/

Correspondence to - Mahitosh Mandal - mahitosh@smst.iitkgp.ac.in and Paul B. Fisher - paul.fisher@vcuhealth.org

Keywords - HSPB1, RNAseq, Fli-1, radioresistant GBM, temozolomide resistant GBM

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