New targets for cancer promotion and therapy in gliomas: Scinderin

Abstract

Glioma is one of the most common primary intracranial tumors, characterized by invasive growth and poor prognosis. Actin cytoskeletal rearrangement is an essential event in tumor cell migration. Scinderin (SCIN), an actin severing and capping protein that regulates the actin cytoskeleton, is involved in the proliferation and migration of certain cancer cells. However, its biological role and molecular mechanism in glioma remain unclear. Lin et al explored the role and mechanism of SCIN in gliomas. The results showed that SCIN mechanically affected cytoskeleton remodeling and inhibited the formation of lamellipodia via RhoA/FAK signaling pathway. This study identifies the cancer-promoting role of SCIN and provides a potential therapeutic target for SCIN in glioma treatment.

Key Words: Glioma, Scinderin, Actin cytoskeleton, RhoA/FAK signaling, 1p/19q co-deletion

Core Tip: The role of scinderin (SCIN) in cancer progression has been studied, but its role in glioma remains unknown. Lin et al found that the expression level of SCIN mRNA was positively correlated with the tumor grade of glioma. SCIN affected cytoskeletal remodeling and inhibited lamellipodia formation through RhoA/FAK signaling pathway, thereby facilitating the migration and invasion of glioma cells.

INTRODUCTION

Gliomas, tumors arising from glial cells or precursor cells, are the most common primary intracranial tumors, accounting for 26% of all primary brain and other central nervous system tumors and 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity[1]. Though they are most common in the brain and glial tissue, they can arise anywhere in the central nervous system[2]. Gliomas can be categorized as Grades 1-4 based on malignant behavior, according to the fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System, where Grades 1 and 2 are low-grade gliomas (LGG) and Grades 3 and 4 are high-grade gliomas[3]. 3 to 6 out of 100000 people suffer from glioma in China, the majority of which are Grades 3 and 4 gliomas [glioblastoma multiforme (GBM)]. For patients with intact brain function, surgical excision is still the preferred course of treatment. For high-grade gliomas, chemotherapy and radiation therapy come next. Glioma sufferers still have a dismal outlook, nonetheless. Thus, research into the molecular mechanisms underlying the growth of gliomas as well as the creation of novel prognostic markers and therapeutic targets are becoming increasingly important.

SCIN’S PRO-ONCOGENIC FUNCTION

An initial and fundamental step in the process of tumor metastasis is the active migration of tumor cells, which depends critically on the reorganization of the actin cytoskeleton, which drives the cellular motor signaling cascade downstream of the complex. Factors that regulate actin assembly begin to emerge as potential targets to prevent the spread and invasion of tumor cells[4]. Scinderin (SCIN), a member of the calcium-dependent gelatin superfamily, controls the tissue of actin by cutting off and capping actin. The SCIN protein consists of six homologous structural domains (i.e., A1-A6). The analysis of the X-ray crystal structure indicates that calcium binding at the N-terminal end of SCIN inhibits the activation process, thereby exposing the F actin binding site on A2[5]. Prior research has documented that SCIN impacts several cellular functions, such as cancer differentiation, migration, and proliferation. For example, SCIN promotes the survival of prostate cancer cells by stabilizing epidermal growth factor receptor and MEK/ERK signaling[6]. Furthermore, filopodia formation, Cdc42 expression, and the proliferation and migration of gastric cancer cells are all inhibited by SCIN knockdown[7]. Lung cancer’s progression and dissemination are likewise encouraged by SCIN[8]. Uncertainty persists regarding the molecular mechanism and biological function of SCIN in gliomas. Lin et al[9] were the first to investigate how SCIN works in gliomas and to search for new targets for the treatment of gliomas. Based on the GEPIA database, Lin et al[9] found that there was a notable increase in SCIN abundance in both LGG and GBM compared to normal tissues, and there was also an increase in SCIN expression in different types of gliomas. Recent studies have identified three particularly noteworthy molecular changes that occur early in glioma formation are prevalent in gliomas, and are tumor markers[10]. The first molecular alteration identified in gliomas is codeletion of chromosome arms 1p and 19q (1p/19q codeletion), which is believed to be associated with the diagnosis of oligodendrogliomas, greater sensitivity to chemotherapy, and better prognosis[11]. In addition, the other two are telomerase reverse transcriptase promoter mutations and indole dehydrogenase (IDH) mutations[12,13]. Mutant IDH genes have been shown to generate the proteins that change α-ketoglutarate into 2-hydroxyglutarate (2HG), a possible tumor metabolite[14]. One of the earliest known processes in the creation of gliomas has been shown to involve IDH mutations; nevertheless, the ensuing 2HG appears to promote broad epigenetic alterations, changing cellular differentiation and perhaps stimulating tumorigenesis[15]. According to Lin et al[9], the expression of SCIN was found to be significantly reduced in gliomas with both IDH mutations and 1p/19q chromosome co-deletion. They also observed a positive correlation between the expression level of SCIN mRNA and the tumour grade of gliomas. Lin et al[9] experimentally demonstrated decreased cell proliferation after silencing endogenous SCIN. Wound healing experiments demonstrated that SCIN-deficient cells migrated significantly more slowly to the scratch area than to the sh-NC group. In addition, SCIN knockdown inhibited the invasive ability of cells. The findings indicate that SCIN exerts a stimulatory influence on the migration and invasion of glioma cells. To explore this even further, Lin et al[9] experimentally demonstrated that SCIN prevented the RhoA/FAK signaling pathway from being activated. Interestingly, it is commonly recognized that F-actin polymerization is correlated with the inhibition of the RhoA/FAK signaling pathway, which indicates weak F-actin polymerization[16], which implies that SCIN regulates F-actin polymerization through RhoA/FAK signaling pathway. Moreover, cell motility was inhibited after the selective FAK inhibitor pf573228 and the RhoA inhibitor CCG1423SCIN were employed, indicating that SCIN promotes the malignant behavior of glioma cells through RhoA/FAK signaling pathway. In summary, lack of SCIN prevented glioma cells from proliferating, invading, and migrating. Mechanistically, SCIN blocked the RhoA/FAK signaling pathway to prevent plate foot formation and altered cytoskeletal remodeling[9]. This work establishes SCIN’s pro-oncogenic function and offers a possible therapeutic target for the management of gliomas.

CONCLUSION

A correlation has been identified between the presence of wild-type IDH and an advanced tumour grade, and an elevated expression of SCIN. The absence of SCIN has been demonstrated to inhibit the development, invasion, and migration of glioma cells. Mechanistically, SCIN influences the RhoA/FAK signaling pathway, which in turn influences cytoskeletal remodeling and plate foot formation. As a possible therapeutic target for the treatment of gliomas, this study highlights the pro-oncogenic activity of SCIN.