miRNA Signaling
MicroRNAs (miRNA) physiological role is vital in controlling the cell cycle, cell proliferation, differentiation, and apoptosis in normal cells. Most tumor neoplasms such as, gastric, ovarian and uveal melanoma cancers showed high levels of aberrant miRNAs expression. MiRNAs can act as oncogenic miRNAs (onco-miRs) during tumor development and progression based on their level of expression and their main targets are oncogenes and tumor suppressor genes. As an example, in human glioblastoma (GBM) cells, an endogenous miR-7 target the epidermal growth factor receptor (EGFR) and independently inhibit this signalling pathway. High expression of miR-7 in the GBM cell can activate the Akt signalling pathway, thus enhance the invasiveness and viability of GBM cells [22].
Specific lncRNAs may act as competing endogenous RNAs (ceRNAs) to control miRNAs and subsequently affect the expression of their target genes by absorbing or sponging the miRNAs in the cytoplasm [23]. The ceRNAs are lncRNAs that bind to miRNAs and prevent miRNAs from interacting with their target by decoying or sponging [24]. For example, ZFAS1 has been shown to sponge miRNAs, and influence tumor growth in melanoma cancer by sponging miR-150-5p [25], microRNA-200b-3p in gastric cancer [26], miR-10a in clear cell renal cell carcinoma [27], miR-329 in bladder cancer [28], and miR-484 in colorectal cancer [29]. In glioma, studies show that ZFAS1 acts as a molecular sponge for miRNAs such as miR-1271-5p[17], miR-150-5p [30], and miR‐432‐5p [31]. ZFAS1 is found primarily in the cytoplasm of glioma cells, implying that it may play a role in the ceRNA network, where ZFAS1 regulates target gene expression via miRNA sponging [17].
Through three online bioinformatic databases prediction, starBase V3, DIANA and miR code; miR-150-5p was predicted as ZFAS1 ’s potential target, and following that, this prediction was confirmed by luciferase reporter and RNA pull-down analysis, where ZFAS1 was observed to act as a sponge for miR-150-5p [30]. Furthermore, results revealed that miR-150-5p’s expression level in glioma was lower than in Normal Human Astrocytes (NHA) [30]. Pearson’s correlation coefficient analysis showed a negative correlation between miR-150-5p’s expression and ZFAS1 ’s expression in glioma tissues. The glioma tissues originated from patients who endured tumor resection (ten grade IV, ten grade III, and seven grade II patients). [30]. Moreover, the expression of an endoplasmic reticulum 4-transmembrane protein, proteolipid protein 2 (PLP2), is found to be associated with glioma cell proliferation, migration and invasion [32].
PLP2 protein was discovered to be a functional target mRNA of miR-150-5p [30]. The expression level of PLP2 in glioma cell lines and tissues was higher than in normal brain tissue (NBT), and this protein is implicated in glioma progression regulated by miR-150-5p to inhibit tumor progression and decrease drug-resistance in glioma cells. The same study revealed that ZFAS1 functions as a miR-150-5p sponge to regulate PLP2 expression in promoting the proliferation, migration and invasion while increasing resistance to TMZ in glioma cells in vitro and in vivo , via immunodeficient male nude mice [30]. In other studies, miR-150-5p has been implicated in suppressing the progression of several human cancers, such as melanoma cancer and epithelial ovarian cancer (EOC) [33].
For instance, Liang et al.[25] found that miR-150-5p acts as a tumor suppressor in melanoma cells by negatively regulating the expression of Ras-related protein Rab9A (RAB9A ). The elevated expression of ZFAS1 in melanoma tissues and cells promoted melanogenesis, including proliferation, migration, and invasion, while suppressing apoptosis via the ZFAS1 /miR-150-5p/RAB9A axis [25]. Xia et al.[33] also reported that miR-150-5p is involved in EOC, where this miRNA suppressed the malignancy and reduced chemoresistance in EOC cells by targeting the expression of specificity protein 1 (Sp1 ) . They found that ZFAS1 ’s expression was overexpressed in EOC tissues and cell lines, and ZFAS1 directly regulated miR-150-5p to promote the progression and chemoresistance in EOC by regulating Sp1 [33].
ZFAS1 enhanced gliomagenesis through modulating the miR-1271-5p/HK2 axis, where miR-1271-5p was suggested to beZFAS1 ’s potential target and Hexokinase 2 (HK2) was miR-1271-5p’s target. ZFAS1 enhanced the expression level of HK2 in glioma cells through sponging activity of miR-1271-5p, and subsequently promoting the development of glioma. MiR-1271-5p was found to be downregulated in glioma tissues, and a dual-luciferase reporter assay confirmed the existence of an interaction between miR-1271-5p and ZFAS1. It was reported that their interactions were negatively proportional with each other [17]. Upregulation of miR-1271-5p suppressed gliomagenesis by increasing apoptosis and reducing glioma cell proliferation, migration, and invasion which is consistent with earlier research findings [34]. Additionally, the study reported that ZFAS1 and HK2 protein expression in glioma tissues exhibited a positive correlation, whereas HK2 and miR-1271-5p protein expression exhibited an inverse correlation [17]. HK2 was found to be the key enzyme that contributes significantly to the Warburg effect. Warburg effect is a term to indicate cancer cells’ preference to metabolise glucose anaerobically. High expression of HK2 can lead to chemo- or radiation resistance of glioma cells via the aberrant of the apoptosis pathway [35].
Apart from miR-150-5p and miR-1271-5p, ZFAS1 can also sponge miR-432-5p. A study has shown that ZFAS1 and miR‐432‐5p had a significant negative association where miR‐432‐5p was a direct target ofZFAS1 to modulate glioma cells viability and cisplatin resistance [31]. miR‐432‐5p expression was found to be downregulated in glioma tissues and cell lines, while overexpression of this miRNA lowered glioma cell viability and enhanced cisplatin-induced glioma cell death [36]. In breast cancer tissues, miR‐432‐5p expression level was found to be downregulated as compared to neighbouring healthy tissues [37].