The importance of miRNA‐630 in human diseases with an especial focus on cancers

miR‐630 is encoded by MIR630 gene (NC_000015.10) on 15q24.1. This miRNA is mostly associated with cytokine sign‐ aling in immune system. Several neoplastic as well as non‐neoplastic conditions have been linked with dysregulation of miR‐630. It is an oncogenic miRNA in renal cell carcinoma, multiple myeloma, colorectal cancer, acute lymphoblas‐ tic leukemia, ovarian cancer and prostate cancer. On the other hand, it is a putative tumor suppressor miRNA in lung, cervical, breast, thyroid and esophageal tissues. In a number of other tissues, data regarding the role of miR‐630 in the carcinogenesis is conflicting. Expression levels of miR‐630 can be used as markers for prediction of cancer course. Moreover, miR‐630 can influence response to chemoradiotherapy. This miRNA is also involved in the pathoetiology of IgA nephropathy, obstructive sleep apnea, age‐related nuclear cataract and vitiligo. In the present review, we discuss the role of miR‐630 in these conditions.


Introduction
MicroRNAs (miRNAs) are small sized transcripts with no capacity of protein coding [1]. miRNAs can bind to coding sequences and miRNA seeds in coding regions are coordinated with regulation/influencing the targets [2][3][4]. Moreover, various molecular techniques like reporter assays confirms that miRNA seeds in coding region can be functional and influence the protein synthesis [5,6]. Mature miRNAs have sizes about 22 nucleotides and are made from their precursors in a multistep process being catalyzed by Drosha and Dicer RNase III proteins. These transcripts serve as guide molecules for suppression of expression of target RNAs. Since they can target the majority of protein-coding RNAs, miRNAs partake in virtually total physiological and pathological events. miRNA synthesis is tightly controlled in terms of time and location. Not surprisingly, dysregulation of expression of miRNAs is linked with the pathoetiology of several human diseases, above all being cancer [7]. miR-630 is an example of these transcripts which is encoded by MIR630 gene (NC_000015.10) on 15q24.1. This miRNA is mostly associated with cytokine signaling in immune system. Moreover, this miRNA has functional interactions with other non-coding RNAs such as long non-coding RNAs and circular RNAs. Thus, it contributes in the construction of a complex interactive network that is implicated in the pathogenesis of human disorders. Several neoplastic as well as non-neoplastic conditions such as IgA nephropathy, obstructive sleep apnea, cataract, vitiligo and heterotopic ossification have been linked with dysregulation of miR-630. In malignant conditions, both high throughput sequencing methods and candidate gene expression analyses have confirmed association between dysregulation of miR-630 and disease progression. Although there are several miRNAs that play important roles in the pathogenesis of disorders, we have selected miR-630 with respect to being targeted by important upstream factors such as long non-coding RNA H19 and also targeting several important genes and participation in key signaling pathway such as AKT, P53, TGFβ-ERK/SP1, JNK/c-Jun, PI3K/AKT and JAK2/ STAT3 which contribute in the development of various malignant and non-malignant diseases. Thus, in the present review, we discuss the role of miR-630 in these conditions.

miR-630 in malignancies
miR-630 has been found to be over-expressed in renal cancer cell lines compared with HK-2 normal renal cells. Inhibition of miR-630 has resulted in suppression of proliferation, migratory aptitude, and invasiveness of 786-O renal cancer cells. Moreover, apoptosis has been induced following miR-630 inhibition, indicating potential of this method for treatment of renal cancer [8]. miR-630 has also been shown to promote proliferation of HCT116 colorectal cancer cells and inhibit their apoptosis. The impact of miR-630 on apoptosis of HCT116 cells has also been verified through the observed reduction of expressions of p27, BAX (BCL2 Associated X), procaspase-3 and active caspase-3. Moreover, miR-630 has enhanced levels of phosphorylated-AKT and BCL2 (B-Cell CLL/ Lymphoma 2). Thus, miR-630 has an oncogenic role in colorectal cancer through modulation of p27 and AKT pathway [9]. In Jurkat cell line, miR-630 has induced cell proliferation and reduced cell apoptosis through affecting expressions of p53, p21 and BCL2 [10]. Expression of miR-630 has been reported to be increased in epithelial ovarian cancer tissues as compared with normal ovarian tissues. In SKOV3 cells, miR-630 up-regulation has shown pro-proliferative and pro-migratory effects, at least partly through targeting KLF6 (Krüppel-like Factor 6) [11]. Moreover, miR-630 has been shown to affect cell apoptosis and sensitivity of ovarian cancer cells to cisplatin through targeting PTEN (Phosphatase and Tensin Homolog) [12]. In a high throughput study using PCR array and NanoString techniques, miR-630 has been found to be among up-regulated miRNAs in tumoral tissues of young patients compared to normal tissues [13]. In hepatocellular carcinoma (HCC), two different studies have reported contradictory results regarding the role of miR-630. Zhang et al. have shown over-expression of miR-630 in HCC samples and cell lines compared with corresponding controls [14]. miR-630 expression has been found to be significantly elevated at advanced TNM stages [14]. Furthermore, up-regulation of miR-630 in tissue samples of HCC has been associated with elevation in serum levels of AFP (Alpha Fetoprotein), indicating its association with HCC progression [14]. On the other hand, Chen et al. have reported that downregulation of miR-630 in HCC patients is associated with higher chance of tumor recurrence and shorter survival of patients [15]. Functionally, miR-630 has been shown to attenuate epithelial-mesenchymal transition (EMT) in HCC through targeting Slug [15]. Moreover, TGF-β (Transforming Growth Factor Beta 1)-Erk (Extracellular Signal-Regulated Kinase)/SP1 (Specificity Protein 1) and JNK (Jun N-Terminal Kinase)/c-Jun cascades have been demonstrated to repress transcription of miR-630 via taking the position of transcription factors on promoters. Forced over-expression of miR-630 has reinstated the TGF-β-associated EMT [15]. In non-small cell lung cancer (NSCLC), circMTDH.4 has been shown to regulate expression of AEG-1 (Astrocyte Elevated Gene-1) oncogene through sequestering miR-630 [16]. CircMTDH.4 silencing or miR-630 up-regulation has suppressed resistance of NSCLC cells to chemo/radiotherapy, indicating the importance of circMTDH.4/miR-630/AEG-1 axis in modulation of response of NSCLC cells to these therapeutic options [16]. According to colony formation assays, suppression of circ-MTDH.4 with sh-circ-MTDH.4 or/and miR-630 up-regulation by miR-630 mimic significantly increased 5-FU or cisplatin-induced cell death in A549 cells [16]. Consistent with this study, miR-630 has been found to be down-regulated in NSCLC tissues and cells [17]. Forced up-regulation of miR-630 could suppress proliferation, migration, and invasiveness of NSCLC cells through targeting LMO3 (LIM Domain Only 3), a gene that encodes a nuclear LIM-only protein [17]. miR-630 acts as up-stream regulator for LMO3 [17]. Restoration of LMO3 significantly reversed the anti-cancerous effects of miR-630 on cell proliferation, migration, and invasion in malignant cells. So, miR-630 inhibited the proliferation, migration, and invasion of NSCLC cells by down-regulation of LMO3 level [17]. Expression of miR-630 has been shown to be decreased in serum of gastric cancer patients compared with controls [18]. Notably, levels of miR-630 have been much lower in those having aggressive tumors [18]. Down-regulation of miR-630 has been correlated with poor prognosis of these patients [18]. The tumor suppressor role of miR-630 in gastric cancer has been further verified through the observed reduction in proliferation ability of SGC-7901 cells following over-expression of this miRNA [18]. Functionally, miR-630 exerts these effects through down-regulating expression of SOX4 (SRY-Box 4) [18]. Conversely, in a study conducted by Zhang et al., expression of miR-630 has been reported to be higher in gastric cancer tissues (intestinal, mixed, and diffuse types) compared to corresponding nearby tissues [19]. The tumor suppressor circular RNA circRNA_100269 has been shown to suppress growth of gastric cancer cells through targeting miR-630 ( Fig. 1) [19]. Finally, Feng et al. have reported that miR-630 suppresses EMT, migration and invasive features of gastric cancer cells through regulating FoxM1 (Forkhead Box M1) and decreasing expressions of GTP-Rac1, p-PI3K (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha), and p-AKT [20]. In the cells treated with TGF-β, miR-630 via blocking of vimentin, slug, snail, and N-cadherin and also by induction of β-catenin, E-cadherin, wnt3a, and wnt5a inhibited cell viability, migration, invasion, and EMT ( Fig. 1) [21]. Thus, this miRNA has a role in modulation of canonical Wnt signaling [21]. In nasopharyngeal carcinoma (NPC), miR-630 has been up-regulated in serum samples of patients compared with controls, indicating a biomarker role for this miRNA [22]. On the other hand, its expression has been shown to be down-regulated in NPC samples compared with chronic inflammatory nasopharyngeal epithelium. Functionally, H19 through sponging miR-630 could regulate invasiveness of these cells [23]. Table 1 summarizes the role and expression pattern of miR-630 in cancers.
Expression levels of miR-630 could affect patients' prognosis. In renal cell carcinoma, its expression has been correlated with tumor grade, lymph node metastasis, as well as distant metastasis [33]. In NSCLC, low level of miR-630 and high level of BCL2 have predicted poor outcomes in the patients [34]. In HCC, miR-630 up-regulation has been correlated with advanced stage, micro and macro-vascular invasion in a single study [14], while in another study its down-regulation has been associated with high metastasis probability, incomplete encapsulation, high tumor number, and vascular invasion possibility [15]. In gastric cancer, Zhou et al. [18] and Chu et al. [35] have reported totally contradicted results. Table 2 summarizes the impact of miR-630 expression on patients' survival in different types of cancers.
miR-630 has also been found to affect response of cancer cells to chemo/radiotherapy. Pre-miR-630 has been shown to decrease cisplatin (CDDP)-induced cell death in NSCLC cells. Pre-miR-630 could modulate In gastric cancer, circRNA-100269 had a negative correlation with miR-630 and inhibited its expression (blue axis) [19]. In the cells treated with TGF-β, miR-630 via blocking of vimentin, slug, snail, and N-cadherin and also by induction of β-catenin, E-cadherin, wnt3a, and wnt5a inhibited cell viability, migration, invasion, and EMT (red axis) [21]. Moreover, miR-630 through inhibition of SOX4 could suppress invasion and proliferation of gastric cancer cells (purple axis) [18]   Tumor tissue from 118 gastric cancer (GC) patients Low level of miR-630 was associated with the poor prognosis There was correlation between miR-630 expression with tumor size, lymph node metastasis, depth of invasion, and stage [18] 236 GC tumors (intestinal and diffuse type) miR-630 up-regulation was associated with poor overall survival miR-630 over-expression correlated with invasion, lymph node and distant metastasis, and TNM stage [35] 147 osteosarcoma tissues Low level of miR-630 was associated with the worse prognosis There was a correlation between low miR-630 expression with higher stage and distant metastasis [29] Peripheral blood from 58 esophageal cancer patients Low level of miR-630 was associated with poor prognosis The levels of miR-630 were associated with disease course, stage, differentiation degree, and metastasis [31] 44 esophageal squamous cell carcinoma (ESCC) tumors Low level of miR-630 was associated with the unfavorable prognosis The levels of miR-630 were associated with tumor range, lymphatic metastasis, and stage [32] 116 pairs of bladder urothelial carcinoma and ANCTs, 42 normal tissue High level of miR-630 was associated with the worse prognosis There was a correlation between high miR-630 level with advanced TNM stage, higher grade and, lymph node metastasis [38] 206 colorectal cancer (CRC) High miR-630 expression was associated with poor overall survival High expression of miR-630 correlated with tumor invasion (T3+T4), lymph node metastasis, distant metastasis, and advanced TNM stage [39] Page 8 of 16 Kadkhoda and Ghafouri-Fard Cancer Cell International (2022) 22:105 several phase of the intrinsic pathway of apoptosis, such as oligomerization of BAX, dissipation of transmembrane potential in the mitochondria, and processing of caspases-9 and 3. Furthermore, pre-miR-630 has been found to obstruct early signs of the DNA damage responses, such as ATM (Ataxia Telangiectasia Mutated) phosphorylation (Fig. 2) [40].
In renal cancer cells, miR-630 up-regulation has been found to inhibit uptake of oxaliplatin by cancer cells through targeting organic cation transporter OCT2 (Organic Cation Transporter 2) [36]. On the other hand, expression of miR-630 has been demonstrated to be associated with higher response of colon cancer cells to radiotherapy. miR-630 has been shown to induce apoptosis Fig. 2 In non-small cell lung cancer (NSCLC) cells were treated with cisplatin (CDDP), miR-181a promoted cell death via BAX oligomerization and enhancement of procaspase-3 and procaspase-9 maturation, but miR-630 had an opposite effect. Also, miR-630 via blocking phosphorylation of ATM, H2AX, and P53 inhibited apoptosis. Moreover, miR-630 through enhancement of p27 expression, promoted cell cycle arrest in G0/G1 resulting in significant decrease in sensitivity to CDDP [40] Page 9 of 16 Kadkhoda and Ghafouri-Fard Cancer Cell International (2022) 22:105 in these cells following ionic radiation through targeting BCL2L2 (BCL2 Like 2) and TP53RK (TP53 Regulating Kinase). Moreover, CREB (CAMP Responsive Element Binding Protein 1) could regulate expression of miR-630, and demethylation could enhance expression of miR-630 [41]. In ovarian cancer cells, miR-630 inhibition could increase sensitivity to cisplatin [12], decline cell proliferation, invasion, and motility and improves apoptosis and sensitivity to paclitaxel [42]. miR-630 has also been shown to target IGF1R (Insulin Like Growth Factor 1 Receptor) to influence response of breast cancer cells to HER2-targeting agents [43]. Finally, in 4-aminobiphenyl-treated HCC cells, the level of miR-630 has been increased, leading to suppression of genes involved in DNA repair [44]. Table 3 shows the effect of miR-630 in the response of tumor cells to chemotherapy, radiotherapy and carcinogens.
In lung cancer cells after DNA damage, miR-630 could inhibit proliferation and promote apoptosis by CDC7 (Cell Division Cycle 7) targeting, but so it could suppress apoptosis via other targets. In other words, miR-630 could have dual effect on apoptosis process and this issue goes back to its downstream targets [45].
According to Rupaimoole et al. study, in ovarian and breast cancer cell lines, hypoxia condition led to miR-630 enhancement and targeting of Dicer by this miRNA [49]. This approach caused more tumor growth and metastasis. Moreover, the level of miR-630 expression affected the overall survival of patients, so that in patients who had a higher level of this miRNA, overall survival was more unfavorable [49]. The participation of miR-630 in various signaling pathways in different malignancies was shown in Fig. 3.

miR-630 in non-malignant conditions
Expression of miR-630 has also been appraised in the context of non-neoplastic conditions (Table 4). For instance, this miRNA has been found to be up-regulated in human milk exosomes of HIV (Human Immunodeficiency Virus)-1 infected mothers compared with uninfected controls [50]. Differentially expressed miR-NAs between these two groups have been enriched in pathways related with cell cycle transition, cancer, TGF-β pathway, FoxO pathway, fatty acid biosynthesis, p53 pathway and apoptosis [50]. Besides, the area under receiver operating characteristics curve of miR-630 has been measured to be 0.82, indicating its potential to detect HIV-1 infection in mothers [50]. In another study, miR-630 has been identified as a putative biomarker for prediction of AIDS (Acquired Immunodeficiency Syndrome) progression [51]. A high throughput method has shown down-regulation of miR-630 levels in palatal tonsils from IgA nephropathy patients compared with chronic tonsillitis. miR-630 has been shown to decrease expression of TLR4 (Toll-like Receptor 4), thus reducing levels of secreted IgA1 and increasing galactosylation of the IgA1 hinge region. Furthermore, TLR4 can influence expression levels of IL (Interleukin 1)-1β and IL-8 via NF-κB signaling to control both IgA1 levels and its glycosylation [52]. miR-630 has also been among miRNAs whose expressions have been correlated with the severity of nuclear opacity in age-related nuclear cataract [53]. This miRNA has been found to regulate expression of MAPK14 (Mitogen-Activated Protein Kinase 14) and a number of other genes [53].

Discussion
miR-630 has different gene targets among them are those associated with cancer phenotype such as BCL2 [50], YAP-1 [27] and Slug [15]. Expression of this miRNA has been best assessed in the context of malignant conditions. However, the results of conducted studies in this field are contradictory. It is an oncogenic miRNA in renal cell carcinoma [8], multiple myeloma [24], colorectal cancer [9], acute lymphoblastic leukemia [10], ovarian cancer [11] and prostate cancer [13]. On the other hand, it is a putative tumor suppressor miRNA in lung [17], cervical [26], breast [28], thyroid [30] and esophageal tissues [31]. In a number of other tissues, data regarding the role of miR-630 in the carcinogenesis is conflicting [18,19].
Circulating levels of miR-630 can be used as marker for separation of cancer patients from controls [22]. Moreover, expression profile of this miRNA has the potential to predict course of malignancy in several types of cancers (summarized in Table 2).
In addition, miR-630 can affect response of cancer cells to ionizing radiation, oxaliplatin and cisplatin. Thus, prior identification of miR-630 levels in tumoral tissues or circulation of patients might help in choosing the best efficient anticancer regimen in a personalized manner.
miR-630 is functionally linked with AKT, P53, TGFβ-ERK/SP1, JNK/c-Jun, PI3K/AKT and JAK2/STAT3 pathways which are among the mostly dysregulated pathways in cancers. Similar to other miRNAs, miR-630 has functional interactions with other classes of non-coding RNAs including long non-coding RNAs and circRNAs. H19, circMTDH.4 and circRNA_100269 are among transcripts whose interactions with miR-630 have been verified so far. High throughput evaluation of expression profiles of different classes of RNAs and additional functional analyses are needed for identification of other interacting molecules with miR-630.

Conclusion
Cumulatively, miR-630 is involved in the pathoetiology of several malignant and non-malignant conditions. Yet, its role in the carcinogenesis is so complicated that it is not possible to assign a tumor suppressor or oncogene role for it in all tissue contexts. In spite of the presence of vast body of literature on the role of this miRNA in malignant conditions, few studies have addressed its contribution in non-malignant conditions. Among non-malignant conditions, the pathogenesis of IgA nephropathy, obstructive sleep apnea, age-related nuclear cataract, vitiligo and heterotopic ossification is related with levels of miR-630. Moreover, this miRNA has been found in exosome secreted in the human milk, possibly reflecting the disease status of the mother. This miRNA can be used as a potential biomarker for cancerous conditions. However, since its levels are different in diverse malignancies, it can be better used for patients' follow-up rather than initial diagnosis. The presence of this miRNA in exosomes potentiates its applications in non-invasive diagnostic methods. However, future studies are necessary for validation of this hypothesis. A major limitation of studies that assessed the diagnostic or prognostic impact of miR-630 in human disorders is lack of validation in independent cohorts.    [57]