Non-coding RNAs as Genetic Biomarkers for the Diagnosis, Prognosis, Radiosensitivity, and Histopathologic Grade of Meningioma

Meningioma is considered the most common primary benign brain tumor. It originates from the arachnoid cells of the leptomeninges surrounding the brain. The mainstay treatment of meningiomas is microsurgical resection. Meningioma prognosis depends on tumor grade, location, and patient age. Recently, using non-coding RNA as a prognostic and diagnostic biomarker for many tumors became a trend. Herein, we demonstrate the importance of non-coding RNAs, including microRNAs and lncRNAs in meningioma and their potential role in meningioma's early diagnosis, prognosis, histological grade, and radiosensitivity. In this review, many microRNAs were found to be upregulated in radioresistant meningioma cells such as microRNA-221, microRNA-222, microRNA-4286, microRNA-4695-5p, microRNA-6732-5p, microRNA-6855-5p, microRNA-7977, microRNA-6765-3p, and microRNA-6787-5p. Moreover, there are many microRNAs downregulated in radioresistant meningioma cells such as microRNA-1275, microRNA-30c-1-3p, microRNA-4449, microRNA-4539, microRNA-4684-3p, microRNA-6129, and microRNA-6891-5p. Also, we highlight the possible use of non-coding RNAs as serum non-invasive biomarkers and their potential role as therapeutic targets to treat high-grade meningiomas. Recent studies show that microRNA-497, microRNA-195, microRNA-18a, microRNA-197, and microRNA-224 are downregulated in the serum of patients with meningiomas. Additionally, microRNA-106a-5p, microRNA-219-5p, microRNA-375, and microRNA-409-3p are found to be upregulated in the serum of patients with meningioma. We also found that there are many deregulated microRNAs in meningioma cells that can be used as potential biomarkers for meningioma diagnosis, prognosis, and histopathologic grade, such as microRNA-17-5p, microRNA-199a, microRNA-190a, microRNA-186-5p, microRNA155-5p, microRNA-22-3p, microRNA-24-3p, microRNA-26-5p, microRNA-27a-3p, microRNA-27b-3p, microRNA-96-5p, microRNA-146a-5p, microRNA-29c-3p, microRNA-219-5p, microRNA-335, microRNA-200a, microRNA-21, microRNA-107, microRNA-224, microRNA-195, microRNA-34a-3p, and microRNA-let-7d. Of interest, we found fewer studies discussing deregulated long non-coding RNAs (lncRNAs) in meningioma cells. LncRNAs work as competitive endogenous RNA (ceRNA) by binding to oncogenic or anti-oncogenic microRNAs. We found that lncRNA- NUP210, lncRNA-SPIRE2, lncRNA-SLC7A1, lncRNA-DMTN, lncRNA-LINC00702, and lncRNA-LINC00460 are upregulated in meningioma cells. In contrast, lncRNA-MALAT1 was found to be downregulated in meningioma cells.


Introduction And Background
Meningioma is considered the most common primary benign brain tumor. It originates from the arachnoid cells of the leptomeninges surrounding the brain [1]. The mainstay treatment of meningiomas is microsurgical resection. The meningioma prognosis depends on tumor grade, location, and patient's age [1][2][3][4]. Chemotherapy and hormonal treatment have bad results in treating meningioma, despite meningiomas' expression of hormonal receptors; subsequently, patients having recurrence after surgical resection and radiotherapy have very limited options for treatment [2,[5][6][7][8]. As a result, searching for other potential therapies for meningioma should be encouraged by studying the role of non-coding RNAs on tumor differentiation, growth, and proliferation.
coding RNAs (ncRNA) that are not translated into proteins. Also, ncRNAs were considered to have unknown and less important roles than the protein-encoding genes [12]. Despite this, ncRNAs have been shown to have an important role in regulating gene expression, and cell differentiation [13]. NcRNAs having greater than 200 nucleotides (nt) are called long non-coding RNA (lncRNA) while those having 200 nt or less are considered small ncRNAs [12].
LncRNAs can suppress or induce tumor growth and proliferation through many mechanisms. First, it can attach to the promoters of many tumor suppressor genes, enabling lncRNAs to silence those genes through its epigenetic modifications [12,17]. Second, it can bind to microRNAs and act as a competing endogenous RNA (ceRNA); as a result, it can alter microRNAs' binding to protein-coding mRNAs [18]. Herein, we discuss dysregulated microRNAs and lncRNAs associated with meningioma growth, proliferation, and malignancy transformation.

MicroRNA-335 as a potential therapeutic target in meningioma and a possible biomarker of meningioma diagnosis
MicroRNA-335 is found to have a protective role in some tumors such as breast cancer metastasis, and malignant astrocytoma [19,20]. In contrast to the anti-oncogenic role of microRNA-335 in these tumors, Shi et al. found that microRNA-335 has an oncogenic effect in meningioma [11]. They showed that the inhibition of microRNA-335 induces cell arrest and suppresses cell proliferation. They suggested that this happened due to microRNA-335 ability to decrease the expression of the tumor-suppressing human retinoblastoma 1 (Rb1) protein. Moreover, they found that overexpression of microRNA-335 induces cell growth and proliferation [11]. This suggests the possibility of using microRNA-335 as a therapeutic target in meningioma treatment.

MicroRNA-200a as a potential therapeutic target in meningioma and a possible biomarker of meningioma prognosis
Senol et al. found that microRNA-200a inhibits meningioma cells' growth and migration by decreasing the expression of the non-muscle heavy chain IIB (NMHCIIB) protein by targeting its mRNA [21]. They also found that on microRNA-200a overexpression, cells from malignant meningiomas (WHO-III) showed a significant decrease in migration [21]. Of interest, overexpression of microRNA-200a has been found to decrease the migration of tumor cells such as breast epithelial cells, and nasopharyngeal carcinoma [22,23]. This shows the potential role of microRNA-200a as a therapeutic target to decrease the aggressiveness of malignant meningiomas. Further, it shows the possibility of using microRNA-200a as a biomarker for meningioma's aggressiveness. Katar et al. found that increased expression of microRNA-21 and decreased expression of microRNA-107 are significantly associated with higher histopathologic grades [24]. Of interest, overexpression of microRNA-21 is associated with grade 3 and 4 gliomas, compared to grade 1 gliomas and normal brain tissues [25][26][27]. Barnabo et al. and Shi et al. found that there is a positive correlation between glioma grade and microRNA-21 expression [25,27]. Furthermore, Teplyuk et al. found that increased expression of microRNA-21 is associated with more advanced disease in glioblastoma multiforme (GBM) and metastatic brain tumors [26]. Regarding microRNA-107, Song et al. found that microRNA-107 expression is negatively correlated with renal cell carcinoma's stage and size [28]. They also showed that decreased expression of microRNA-107 is associated with the incidence of metastasis [28]. Li et al. suggested that by targeting CKD8 in meningioma cells, microRNA-107 inhibits migration and proliferation [29].

MicroRNA-21 and microRNA-107 as potential biomarkers associated with changes in the histopathologic grades
MicroRNA-224 as a potential biomarker associated with changes in the histopathologic grades and a possible biomarker for meningioma diagnosis Wang et al. found that there is a higher microRNA-224 expression in meningioma cells compared to normal cells [30]. They also found that microRNA-224 expression is positively correlated with the histopathologic grade [30]. They suggested that microRNA-224 induces meningioma's growth and proliferation by targeting the early growth response 2 (ERG2) protein's expression, which is a contributor to the apoptosis process [30]. Interestingly, microRNA-224 has been reported to be positively correlated to poor prognosis and aggressive behavior in many tumors such as liver, gastric, lung, and prostate cancers [31][32][33].

MicroRNAs as potential therapies inducing radiosensitivity of meningioma cells and possible biomarkers for radioresistance
Ionizing radiation's therapeutic effect is achieved by its ability to cause DNA damage, which induces several repair signaling cascades [34]. Subsequently, it leads to P53 protein phosphorylation [34,35]. Phosphorylated P53 induces the expression of various genes including the Phosphatase and Tensin Homolog (PTEN) gene. As a result, it induces cell arrest and apoptosis [34][35][36]. This shows that the PTEN protein has an antioncogenic effect, and its expression can be induced by ionizing radiation.
In contrast to the previously discussed antioncogenic effect of ionizing radiation, ionizing radiation can induce epithelial-mesenchymal transition (EMT) and cancer cells' invasive and migratory properties [37][38][39][40]. As a result, ionizing radiation can induce meningioma cells' invasiveness, recurrence, or malignant transformation. This paradoxical effect of ionizing radiation encourages more research to find potential radiosensitive-inducing agents. In meningioma cells, Zhang et al. found that decreasing microRNA-221 and microRNA-222 expression can enhance the apoptosis-inducing effect of ionizing radiation by increasing PTEN levels [41].
Regarding other tumors, recent studies show the effect of co-suppression of both microRNA-221 and microRNA-222 expression on inducing radiosensitivity [42,43]. Zhang et al. found that decreased expression of microRNA-221 and microRNA-222 induces radiosensitivity in gastric cancer and GBM cells by increasing the expression of the PTEN gene [42,43]. Furthermore, Khoshinani et al. showed that microRNA-222 regulates radiosensitivity by targeting PTEN in colorectal cancer cells [44]. Similarly, Xue et al. found that anti-microRNA-221 induces radiosensitivity in colorectal cancer cells by regulating the expression of the PTEN protein [45].

MicroRNA-195 as a malignant meningioma suppressor and a potential biomarker for meningioma histopathologic grade
Song et al. found that increased expression of microRNA-195 significantly decreased meningioma cells' proliferation, invasion, and migration by targeting fatty acid synthase (FASN), which is found to be upregulated in high-grade meningioma compared to grade 1 meningioma cells [47]. This shows the possibility of using microRNA-195 as a biomarker for meningioma's histopathologic grade. Of interest, microRNA-195 is found to be downregulated in many tumors such as non-small-cell lung cancer, and hepatocellular carcinoma [48,49]. Also, Mao et al. reported that osteosarcoma cell migration and invasion are suppressed by microRNA-195 [50].
Song et al. also found that there are many lncRNAs, such as NUP210, SPIRE2, SLC7A1, and DMTN, act as ceRNAs by sponging microRNA-195 and preventing it from binding to mRNA [47]. As a result, these lncRNAs are considered oncogenic by increasing FASN expression by targeting microRNA-195 [47].

MicroRNAs as serum non-invasive biomarkers for meningiomas
Tang et al. examined the levels of serum microRNA-185 in patients with meningiomas, gliomas, acoustic neuroma, and pituitary adenoma [51]. They found that the plasma level of microRNA-185 is only significantly changed in gliomas [51]. Another failed trial to find serum biomarkers for meningioma is reported by Wang et al. [52]. They found that serum microRNA-21, microRNA-128, and microRNA-342-3p are insignificantly altered in meningiomas [52]. Fortunately, Negroni et al. found that in patients with highgrade meningiomas, serum levels of microRNA-497 and microRNA-195 are lower than in those who do not have meningiomas [53]. This demonstrates the potential use of microRNA-497 and microRNA-195 as serum biomarkers for high-grade meningioma. Furthermore, Li et al. found that serum and cerebrospinal fluid (CSF) levels of microRNA-18a are significantly lower in patients with invasive meningioma than in healthy subjects [54]. They also found that only CSF levels of microRNA-18a are significantly lower in invasive meningioma than in patients with non-invasive meningioma [54].
In another study, Zhi et al. found that in patients with meningioma, microRNA-106a-5p, microRNA-219-5p, microRNA-375, and microRNA-409-3p are increased in the serum [55]. In contrast to this, they found that serum levels of microRNA-197 and microRNA-224 decreased in those patients [55]. This highlights the possibility of microRNAs as serum biomarkers for meningiomas. Of interest, the effect of inhibition of one of the microRNAs reported by Zhi et al. is studied by Hu et al. [56]. They found that inhibition of microRNA-197 in meningioma cells by Quercetin induces apoptosis and inhibits proliferation [56]. Quercetin's effect on meningioma cells' proliferation was reported in a previous study by Piantelli et al. [57]. However, the molecular mechanism was unknown. MicroRNAs that are considered potential serum non-invasive biomarkers for meningioma are summarized in Table 2. More clinical studies are encouraged to study the correlation between the serum levels of different ncRNAs and menenigeoma's diagnosis, prognosis, histopathologic grade, and radiosensitivity.
BCL2 has an antiapoptotic role. High levels of BCL2 are associated with increased recurrence in patients with benign meningioma. Moreover, in patients with atypical meningioma, BCL2 is found to be associated with a shorter time to recurrence [61,62]. Lower levels of microRNA-34a-3p increase BCL2 expression and induce meningiomas' growth, invasiveness, and proliferation. Similarly, lower levels of microRNA-34a-3p increase FRAT1 expression and induce meningioma proliferation and invasiveness [59].

Conclusions
Non-coding RNAs, including microRNAs and lncRNAs, are potential biomarkers for meningioma diagnosis, prognosis, aggressiveness, histopathologic grade, and radiosensitivity. More clinical studies with large samples are encouraged to examine serum, biopsy, and CSF levels of these non-coding RNAs' sensitivity and specificity.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.