An Analysis of G3BP2 in Non-Small Cell Lung Cancer

TL;DR

This study explores the role of G3BP2 in non-small cell lung cancer and finds it is linked to cancer-related pathways but not patient survival.

Contribution

The study reveals novel associations between G3BP2 and cancer pathways like immune cell infiltration and DNA damage response in non-small cell lung cancer.

Findings

G3BP2 expression was not upregulated in non-small cell lung cancer tissues.

G3BP2 correlated with immune cell infiltration and DNA damage response pathways.

Two CpG residues showed higher methylation linked to worse survival.

Abstract

Exposure to stress can make cells die, and cells develop coping strategies to prevent this. One of the things that can lead to this stress in a cancer cell is an overproduction of messages (called mRNA) which overwhelms the cells’ ability to turn these messages into protein. To stop this, cells respond by pulling these mRNAs into a complex called a stress granule, which stops the cells from making these messages into protein. In cancer, this stress granule response can, however, lead to cancer cell survival and poor outcomes for cancer patients. An essential molecule found in stress granules is a protein called G3BP2. This study examines G3BP2 in lung cancer, and the results provide a better understanding of how this protein affects lung cancer and how we may be able to target this protein for patient benefit.

Background/Objectives: Cancer cells are subjected to various stress conditions and have stress adaptability strategies to survive. Various types of stresses lead to the aggregation of cytoplasmic RNA granules known as stress granules (SGs), seen in normal and tumor cells, and aid in cell survival by avoiding cell apoptosis. G3BP stress granule assembly factor 2 (G3BP2) encodes a multifunctional protein with known roles as a critical component of SGs and is also associated with chemoresistance in cancer, but its known roles in non-small cell cancer (NSCLC) are limited. Methods: We evaluated the expression of G3BP2 via qPCR and immunohistochemistry on a retrospective cohort of NSCLC isolated at surgery in St James’s Hospital, Dublin, Ireland. Expression levels were correlated with clinicopathological parameters. Survival analyses, including Kaplan–Meier analyses, were used to determine the prognostic value. Additional correlations with other available NSCLC datasets were explored. Results: In contrast to other studies, we did not observe upregulated expression of G3BP2. Furthermore, Kaplan–Meier analyses did not identify any prognostic value associated with G3BP2 expression in patient tissues in contrast to other published data. Bioinformatic analyses on these other datasets found strong correlations between G3BP2 and core stress granule genes in NSCLC. Additional analyses also identified correlations between G3BP2 expression and immune cell infiltration, immune cell exhaustion, and DNA Damage Response pathways. An examination of the available datasets did not find any overall prognostic value for altered DNA methylation and survival. However, two individual CpG residues were identified for which higher methylation was associated with worse overall survival. Finally, the effects of a G3BP2 inhibitor on cellular proliferation were assessed. Conclusions: In our analysis, G3BP2 was not associated with survival benefit. However, clear associations were observed between altered expression of this gene and a number of important pathways linked to cancer pathogenesis, and further studies are warranted to assess this gene (and/or) stress granules in cancer.

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