Research progress on microRNA-1258 in the development of human cancer

microRNAs (miRNAs) are small endogenous RNAs composed of 20-22 nucleotides that do not encode proteins, which regulate the expression of downstream genes by targeting the 3’ untranslated region of mRNA. Plentiful research has demonstrated that miRNAs participate in the initiation and development of diverse diseases and malignant tumors. miR-1258 exerts great influence on tumors, including tumor growth, distant metastasis, migration, invasion, chemosensitivity, cell glycolysis, apoptosis, and stemness. Interestingly, miR-1258 is a miRNA with explicit functions and has been investigated to act as a tumor suppressor in studies on various types of tumors. With accumulating research on miR-1258, it has been found to be used as a biomarker in the early diagnosis and prognosis prediction of tumor patients. In this review, we outline the development of miR-1258 research, describe its regulatory network, and discuss its roles in cancer. Additionally, we generalize the potential clinical applications of miR-1258. This review offers emerging perspectives and orientations for further comprehending the function of miR-1258 as a diagnostic and prognostic biomarker and potent therapeutic target in cancer.


Introduction
MicroRNAs (miRNAs) are non-coding RNAs composed of about 21-25 nucleotides, which are widely distributed from viruses to numerous cells (1). These miRNAs generally target one or more messenger RNAs (mRNAs), split them directly, or block their translation by binding to mRNAs, thereby blocking their protein production (2). miRNAs are produced by endogenous transcription of primary transcripts, first cut in the nucleus by Drosha, generating stem-loop precursor miRNAs (about 70 nucleotides). Subsequently, Exportin5 transports precursor miRNA from the nucleus to the cytoplasm. Finally, mature miRNAs about 22 nucleotides in length are processed by Dicer (3).
Heretofore, most of the miRNAs found and reported are highly conserved among species, which are closely related to the significance of their functions (4). miRNAs play an essential role in the regulation of cell differentiation, tissue development, metabolism, and tumorigenesis (5,6). Extensive studies have shown that miRNAs are dysregulated in tumors, and they widely participate in the whole process of tumor development as tumor suppressors or carcinogens (7)(8)(9)(10)(11). Moreover, miRNAs also act key roles in early diagnosis, treatment response predictors, and prognostic biomarkers of cancer (12)(13)(14)(15)(16).
miR-1258 is located in the first intron of its host gene ZNF385B (Zinc Finger Protein 385B) on chromosome 2q31. 3 and plays a key regulatory role in intestinal barrier function, herpesvirus Lytic replication, bronchopulmonary dysplasia, brown adipose differentiation, and other diseases (17)(18)(19)(20). miR-1258 is a miRNA with explicit functions and has been reported to act as a tumor suppressor in studies on diverse types of tumors. So far, there is no review on the research progress of miR-1258 in the development of human cancer. Hence, we first comprehensively and systematically reviewed the research progress of miR-1258 in the inhibitory role of human cancer and its detailed mechanism, to better translate the key role of miR-1258 into diagnostic and prognostic biomarkers and potential targets of cancer.
The regulatory network of miR-1258 in cancer As shown in Figure 1 and Table 1, miR-1258 was regulated by Nef, c-Myb, and Kindlin-2 at the transcriptional stage. Yan et al. reported that negative factor (Nef), a secreted HIV-1 protein, elevated the expression of has-miR-1258 in primary effusion lymphoma cells (18). Kindlin-2 inhibited the transcription of miR-1258 by increasing methylation of the CpG island in the miR-1258 promoter (23). Moreover, c-Myb, a transcriptional factor, is directly bound to the promoter of has-miR-1258 to repress the transcription of miR-1258 (30). Furthermore, the hypermethylation of the CpG island of the miR-1258 promoter was demonstrated in the tissues of ovarian cancer, myeloma, prostate cancer, and BC, inhibiting the transcription of miR-1258 (38, 42,[46][47][48][49]. Accumulative studies indicated that the mature miRNAs were inactivated by lncRNAs or circRNAs through competing endogenous RNAs (ceRNAs) (50)(51)(52). miR-1258 was inactivated by LncRNA Zeb1 in the intestinal barrier (19). In addition, miR-1258 was targeted by circ_0046599, circ_0046600, and lncRNA LINC01278 in HCC (21,22,25). Besides, extracellular vesicles also acted key roles in the regulation of miR-1258 by transferring circ_0000519 as ceRNA in NSCLC (34). Zhang et al. noted that upregulated circ_SMAD2 suppressed the expression of miR-1258 through the ceRNAs mechanism in CRC (27). LncRNA ASB16-AS1, as sponge molecules, regulated the EC progression by absorbing miR-1258 (31). Li et al. reported that miR-1258 was directly regulated by circ_002178 via using luciferase reporter assay (35). Therefore, it is necessary to provide a theoretical basis for using miR-1258 as a potential therapeutic target by in-depth excavating of the regulatory mechanisms of miR-1258 in cancer.

The biological functions of miR-1258 in cancer
MiR-1258 profoundly inhibited tumor progression by binding to the mRNA of downstream genes ( Figure 1). As shown in Figure 2, miR-1258 was involved in the biological processes of the cell cycle transition, cell apoptosis, cell stemness, cell migration and invasion, and EMT to restrain the progression of tumors. Also, miR-1258 repressed glycolysis metabolisms by targeting the mRNA of RPN2 to suppress the cell growth of HCC (21). The stemness of cancer cells plays a crucial role in the survival, proliferation, recurrence, and drug resistance of cancer (53). miR-1258 significantly suppressed the cell stemness and tumor progression of HCC by binding to the mRNA of cyclindependent kinase regulatory subunit 1B (CKS1B) (24). In the following parts, we comprehensively revealed the biological functions of miR-1258 as tumor suppressors.

Inhibition of the cancerogenic process in human cancer
MiR-1258 was extensively investigated in digestive systemrelated tumors as a tumor suppressor, including HCC (21-25),  (42)(43)(44)(45). Abovementioned facts indicated that miR-1258 was extensively involved in the development of human cancer (Figure 3).  Mechanism and function of miR-1258 downregulation in human cancer.

Promotion of cell apoptosis and chemosensitivity
Currently, numerous small-molecule anti-cancer drugs are targeting molecules involved in cell apoptosis (56). Growth factor receptor binding protein 2 (GRB2) is a key adapter protein that activates the RAS/ERK signaling pathway, and its dysregulation can profoundly affect the process of cell apoptosis in cancer (57). miR-1258 inhibited the NSCLC progression via inducing cell apoptosis and senescence by directly targeting GRB2 (32). Tumor cells evade immune clearance by increasing the expression of PD-L1 on the surface and inhibiting T cell function via binding to PD-1 on the surface of T cells (58). Wang et al. reported that overexpressed miR-1258 inhibited cell proliferation and increased cell apoptosis by restraining the expression of PD-L1 in completely methylated myeloma cells (42). In addition, miR-1258 strengthened the cell apoptosis to repress cell proliferation by binding to mRNA of SERBP1, CKS1B, and E2F1 in HCC (22, 24) and BC (37). Furthermore, the sensitivity of chemotherapy was increased by enhancing cell apoptosis (59). Hu et al. indicated that upregulated miR-1258 greatly reinforced the sensitivity of HCC cells to chemotherapy drugs in vivo by restraining the expression of CKS1B (24).

Suppression of cell migration and invasion
The migratory and invasive ability of cells largely determines whether distant metastasis occurs in tumors, which is the main reason for the poor prognosis of patients with cancer (60). TGFb (transforming growth factor-b)/Smad signaling pathway significantly regulates the biological behaviors of cell migration and invasion in cancer (61). Huang et al. found that miR-1258 inhibited the metastasis of cells by impairing the migratory and invasive ability of cells via targeting the mRNA of Smad2 and Smad3 in HCC (25). Besides, the translation of RPN2, TCF4, KDM7A, HPSE, TMPRSS4, and E2F1 was also suppressed by miR-1258 overexpression, according to recent research, which prevented cell invasion and migration in HCC (21,23), CRC (27), BC (35,40), and TC (43). It is impossible to disregard the roles of the matrix metalloproteinase (MMP) family in regulating cell migration and invasion (62). Qin et al. The biological functions of miR-1258 in human cancer.

Inhibition of cell cycle transition
The cell cycle includes four consecutive phases of G0/G1, S, G2, and M, which is a set of organized and monitored events that are responsible for dividing cells into two daughter cells. The aberrant regulation of cell cycle transition has played a critical role in the growth and development of tumors (63). E2F family performs crucial functions in controlling cell cycle, maintaining genomic integrity, and coping with replication stress and DNA damage as transcriptional factors (64). miR-1258 arrested the cell cycle in G0/G1 phase by targeting E2F1 and E2F8 in CRC, BC, CC, and glioblastoma (28,37,41,44). CKS1B is engaged in the transcription regulation of a series of genes involved in the cell cycle process, which is closely related to the abnormal cell proliferation of tumors (65). Overexpressed miR-1258 greatly inhibited cell cycle arrest in G0/G1 phase by directly repressing the expression of CKS1B in HCC (24). Additionally, miR-1258 inhibited the cell cycle transition by binding to mRNA of SERBP1, GRB2, and AKT3 in HCC (22), NSCLC (32), and osteosarcoma (45), respectively. These data proved that miR-1258, a potential therapeutic target, performed key roles in cell cycle arrest in cancer.

Role in EMT
Epithelial-mesenchymal transition (EMT) refers to the transformation of epithelial cells into invasive mesenchymal cells, which plays a crucial function in the invasion and metastasis of various types of cancer (66,67). SP1, as a transcription factor, directly modulates the EMT and metastasis of cancer at transcriptional levels (68,69). Overexpressed miR-1258 significantly repressed the EMT and metastasis in OSCC cells by targeting the mRNA of SP1 (30). In addition, Lin et al. demonstrated that miR-1258 suppressed the EMT and metastasis of HCC cells through targeting TCF4, a key member of the Wnt/ b-catenin signaling pathway (23). Heparanase (HPSE) is a potent enzyme that fosters tumor growth, angiogenesis, and metastasis (70). Its dysregulation can produce a wide range of effects that significantly alter the microenvironment, stimulating cell growth and metastasis of tumors (71). Zhang et al. first revealed that upregulated miR-1258 inhibited breast cancer brain metastasis MiR-1258 functions as a tumor suppressor in diverse cancer.

Clinical application
It has been reported that it is promising to manipulate these miRNAs for cancer treatment by combining effective applications of miRNA delivery systems, such as chemical modification of miRNAs, lipid-based miRNA delivery systems, and organic/ inorganic composite nanoparticles (72). Besides, abundant studies have found that the differential profiles of miRNAs in circulation or tissues were closely correlated to the early diagnosis, clinical stage, response to therapy, and pathological characteristics of tumors (11). In addition, the abnormal expression of miRNAs can also be used to predict the long-term survival of tumor patients (73). The probability of distant metastasis and the clinical stage of OC can be predicted by the frequency of methylation in the promoter of the miR-1258 host gene. Metastatic patients had a twofold higher rate of miR-1258 methylation than non-metastatic OC patients did (46, 47). In addition, the methylation level of miR-1258 was positively correlated to the advanced clinical stage and pathological characteristics of OC, BC, and myeloma (38, 42,48). Besides, the level of miR-1258 promoter methylation can accurately diagnose prostate cancer in clinical samples with 97.8% sensitivity and 100% specificity (49). Due to the important role of miR-1258 as a tumor suppressor, the level of its expression profoundly affected the prognosis and clinicopathological characteristics of tumor patients. As shown in Table 2, a lower level of miR-1258 meant an inferior progression-free survival (PFS) and a higher probability of recurrence in 63 patients of myeloma (42). Low expression of miR-1258 was not only associated with the advanced clinical stage but also meant worse overall survival (OS) and relapse-free survival (RFS) in BC patients (36,39). In addition, the level of miR-1258 was negatively correlated with the probability of tumor recurrence and metastasis and poor disease-free survival (DFS), OS, and RFS in HCC (24,25). Shi et al. demonstrated that miR-1258 was negatively correlated to advanced clinical stage and lymphatic vessel invasion by analyzing the postoperative pathological data of 116 GC patients (26). Furthermore, a lower expression of miR-1258 in ESCC patients meant a shorter OS and DFS (30). Qin et al. discovered that the level of miR-1258 expression was decreased with the elevation of pathological grade by analyzing the postoperative pathological results of 33 glioblastoma patients (44). In addition, patients with low miR-1258 were greatly related to bigger tumor size in CRC (28). The OS would be greatly shortened in osteosarcoma patients with a low level of miR-1258 expression. Meanwhile, decreased miR-1258 was strongly correlated to the malignant clinicopathological characteristics of patients with osteosarcoma (45). These results verified the significant role and prospective clinical relevance of miR-1258 as diagnostic and prognostic biomarkers in cancer.

Conclusions and prospects
At present, malignant tumors with high morbidity and mortality imposed a heavy burden on patients worldwide. Accumulative studies have been trying to reveal the etiology of tumor initiation and explore significant therapies. However, the mechanisms of tumorigenesis, recurrence, metastasis, and drug resistance remained unclear. Researchers reported that the expression of miR-1258 was considerably downregulated in tumor tissues and cell lines. To date, miR-1258 has been shown to act as a tumor suppressor in the development and progression of tumors, suppressing cell cycle transition, metastasis, stemness, migration, invasion, EMT, and glycolysis while boosting cell apoptosis and chemosensitivity. Furthermore, studies revealed that miR-1258 can be employed as a biomarker for early diagnosis and prognosis prediction in tumor patients. In summary, with the deepening related research of miR-1258, the mechanism of miR-1258 in tumorigenesis and progression would be gradually disclosed. miR-1258 can be exploited as an indicator for early tumor diagnosis and prognosis as well as a potential target for tumor treatment, providing novel perspectives and orientations for precision therapy.