Notch Signaling Pathway
The Notch signalling pathway is an evolutionary conserved intercellular pathway that governs various physiological and developmental processes such as tissue homeostasis, stem cell maintenance, proliferation, apoptosis, and cell fate decision [47]. Several studies have shown a positive correlation between Notch signaling pathway and lncRNA involved in various tumor progressions whereby the lncRNA regulates this pathway by acting as an oncogene or tumor suppressor [48]. For instance, Wu et al. (2021) discovered that the lncRNA, HOXA cluster antisense RNA 2 (HOXA-AS2 ) plays a tumour-promoting role in cell proliferation and migration of cervical cancer by activating Notch pathway [49]. LncRNA, FAM83H antisense RNA 1 (FAM83H-AS1 ) promotes cell proliferation of colorectal carcinoma and is linked to poor prognosis by regulating the Notch pathway [50]. In a study by Liu et al.[37] they found that the lncRNA, small nucleolar RNA host gene 1 (SNHG1 ), enhances progression of laryngeal cancer in cell proliferation by modulating Notch1 pathway [35].
In glioma, overexpression of Notch receptors occurred, and activation of the Notch pathway plays a critical oncogenic role by contributing to brain tumours’ growth, survival, invasion and recurrence [51]. The most frequent somatically mutated gene in more than 2900 tumors; Endometrial cancer (n = 248), prostate cancer (n = 112), large intestine (n = 224), esophageal cancer (n = 146), lung cancer (n = 230), glioblastoma (n = 291), ovarian cancer (n = 316), skin cancer (n = 121), liver cancer (n = 231), pancreatic cancer (n = 99), breast cancer (n = 507) and renal cancer (n = 424) are as follows; Notch-1 (7.3%), Notch-2 (7.0%), Notch-3 (5.9%) and Notch-4 (5.6%) [52]. Research by Wang et al. (2018) reported that upregulation of prostate cancer-up-regulated long non-coding RNA 1 (PlncRNA-1) might promote glioma development and progression by activating the Notch pathway through modulation of several Notch signal-related protein expressions, including Notch-1, Jagged 1 and HES family bHLH transcription factor 1 (Hes-1) [48]. As for the correlation between lncRNA ZFAS1 and Notch pathway in glioma, Gao et al. [18] discovered the inhibition of ZFAS1 significantly reduced the expression of two Notch signal-relate proteins, Hes-1 and notch intracellular domain (NICD) [18], where both proteins have crucial roles in Notch pathway [53]. This result suggested that ZFAS1 could be another key activator for the Notch pathway, facilitating glioma progression. However, the exact mechanism by which ZFAS1 activates the Notch pathway is still unknown, whether directly or indirectly [13].
The general outcome of ZFAS1 upregulation in glioma cells is depicted in Figure 2. Figure 3 shows how high ZFAS1 expression in gliomas can affect the activities of glioma cells, with miRNA sponging inhibiting cell apoptosis and cisplastin cytotoxicity, and decreasing patient survival. Additionally, it summarises the impact of ZFAS1 expression on glioma cell metabolisms. For instance, it increases glucose uptake by glioma cells, increases cell migration, invasion, and proliferation, and increases resistance to chemotherapy drugs like TMZ. Furthermore, by regulating the expression of a protein that’s essential to the development of gliomas, high ZFAS1 expression can promote the development of gliomas through the EMT and Notch signalling pathways.