Abstract
Dysregulation in calcium signalling is implicated in several cancer-associated processes, including cell proliferation, migration, invasion and therapy resistance. Modulators of specific calcium-regulating proteins have been proposed as promising future therapeutic agents for some cancers. Alterations in calcium signalling have been extensively studied in some cancers; however, this area of research is highly underexplored in medulloblastoma (MB), the most common paediatric malignant brain tumour. Current MB treatment modalities are not completely effective and can result in several long-lasting mental complications. Hence, new treatment strategies are needed. In this study, we sought to probe the landscape of calcium signalling regulators to uncover those most likely to be involved in MB tumours. We investigated the expression of calcium signalling regulator genes in MB patients using publicly available datasets. We stratified the expression level of these genes with MB molecular subgroups, tumour metastasis and patient survival to uncover correlations with clinical features. Of particular interest was CACNA1 genes, in which we were able to show a developmentally-driven change in expression within the cerebellum, MB’s tissue of origin, highlighting a potential influence on tumour incidence. This study lays a platform for future investigations into molecular regulators of calcium signalling in MB formation and progression.
Highlights
Calcium ions (Ca2+) are the most abundant second messengers in the human body, where they play vital roles in various physiological processes
This study showed that the level of STIM1 expression is directly associated with metastasis and reduced survival among breast cancer patients, and blocking store-operated calcium entry reduces the migration of breast cancer cells [8]
We used three independent patient datasets, including Pomeroy [17], Donson [18] and Zhao [19] datasets. These studies demonstrated that out of the 92 genes, 14 genes were significantly downregulated, and two were significantly upregulated in MB tissues compared to normal brain tissues in all the three datasets (Table 2 and Figure 1)
Summary
Calcium ions (Ca2+) are the most abundant second messengers in the human body, where they play vital roles in various physiological processes. Ca2+ plays an integral role in cell cycle progression where it controls the induction of immediate response genes such as FOS, JUN and MYC. Dysregulated expression of calcium influencing cell cycle proteins has been implicated in several cancers [2,3,4]. In many instances, migrated cancer cells show aberrant expression of calcium controlling genes leading to a higher activity of key invasion markers such as matrix metalloproteinases, MMP2 and MMP9 [6]. Calcium is a key player in the phosphorylation of contractile proteins required for maintaining the morphological changes for efficient cell migration [7]. This study showed that the level of STIM1 expression is directly associated with metastasis and reduced survival among breast cancer patients, and blocking store-operated calcium entry reduces the migration of breast cancer cells [8]. TRPM7, for example, has been shown to regulate cell migration, through myosin II-dependent contractility, in human breast cancer cells [10], and TRPV1 is linked to the modulation of migration and invasion of several cancer types [11]
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