Stanniocalcin-1 promotes temozolomide resistance of glioblastoma through regulation of MGMT.

in Scientific reports by Chao Duan, Bincan He, Yiqi Wang, Wanying Liu, Wendai Bao, Li Yu, Jinxin Xin, Hui Gui, Junrong Lei, Zehao Yang, Jun Liu, Weiwei Tao, Jun Qin, Jie Luo, Zhiqiang Dong

TLDR

  • The study found that a protein called stanniocalcin-1 (STC) is made by tumour reproductive cells (TRCs) in glioblastoma (GBM). The study also found that overexpression of STC1 promotes and knockdown of STC1 inhibits TMZ-induced DNA damage. The study also showed that high expression of STC1 is closely associated with poor prognosis, glioma grade and resistance to TMZ treatment.

Abstract

Temozolomide (TMZ) resistance is a major challenge in the treatment of glioblastoma (GBM). Tumour reproductive cells (TRCs) have been implicated in the development of chemotherapy resistance. By culturing DBTRG cells in three-dimensional soft fibrin gels to enrich GBM TRCs and performing RNA-seq analysis, the expression of stanniocalcin-1 (STC), a gene encoding a secreted glycoprotein, was found to be upregulated in TRCs. Meanwhile, the viability of TMZ-treated TRC cells was significantly higher than that of TMZ-treated 2D cells. Analysis of clinical data from CGGA (Chinese Glioma Genome Atlas) database showed that high expression of STC1 was closely associated with poor prognosis, glioma grade and resistance to TMZ treatment, suggesting that STC1 may be involved in TMZ drug resistance. The expression of STC1 in tissues and cells was examined, as well as the effect of STC1 on GBM cell proliferation and TMZ-induced DNA damage. The results showed that overexpression of STC1 promoted and knockdown of STC1 inhibited TMZ-induced DNA damage. These results were validated in an intracranial tumour model. These data revealed that STC1 exerts regulatory functions on MGMT expression in GBM, and provides a rationale for targeting STC1 to overcome TMZ resistance.

Overview

  • The study investigates the role of tumour reproductive cells (TRCs) in temozolomide (TMZ) resistance in glioblastoma (GBM).
  • The study uses three-dimensional soft fibrin gels to enrich GBM TRCs and performs RNA-seq analysis to identify stanniocalcin-1 (STC) as a gene encoding a secreted glycoprotein upregulated in TRCs. The study also examines the viability of TMZ-treated TRC cells and the effect of STC1 on GBM cell proliferation and TMZ-induced DNA damage. The results are validated in an intracranial tumour model. The primary objective of the study is to understand the mechanisms underlying TMZ resistance in GBM and identify potential therapeutic targets.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, including the use of three-dimensional soft fibrin gels to enrich GBM TRCs and RNA-seq analysis to identify STC1 as a gene encoding a secreted glycoprotein upregulated in TRCs. The study also compares the viability of TMZ-treated TRC cells and the effect of STC1 on GBM cell proliferation and TMZ-induced DNA damage. The results show that overexpression of STC1 promotes and knockdown of STC1 inhibits TMZ-induced DNA damage. The study also shows that high expression of STC1 is closely associated with poor prognosis, glioma grade and resistance to TMZ treatment.

Implications and Future Directions

  • The study's findings suggest that STC1 may be involved in TMZ drug resistance in GBM. The study also provides a rationale for targeting STC1 to overcome TMZ resistance. Future research directions could include further investigation of the regulatory functions of STC1 on MGMT expression in GBM and the development of targeted therapies against STC1.
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