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Oncogenic roles of the lncRNA LINC00460 in human cancers

Long noncoding RNAs (lncRNAs) represent an important group of endogenous RNAs with limit protein-encoding capability, with a length of more than 200 nucleotides. Emerging evidence have demonstrated that lncRNAs are greatly involved in multiple cancers by playing critical roles in tumor initiation and progression. Long intergenic non-protein coding RNA 460 (LINC00460), a novel cancer-related lncRNA, exhibits abnormal expression and oncogenic function in multiple cancers, and positively correlates with poor clinical characteristics of cancer patients. LINC00460 has also been shown to be a promising biomarker for diagnosis as well as prognostic evaluation in cancer patients. In this review, we briefly summarized recent knowledge on the expression, functional roles, molecular mechanisms, and diagnostic and prognostic values of LINC00460 in human malignancies.


Introduction
Deep sequencing of mammalian transcriptomes has revealed that approximately 98% of RNA sequences are noncoding RNAs (ncRNAs) that comprise two groups based on length, including small (< 200 nucleotides) and long (lncRNAs; >200 nucleotides) ncRNAs [1,2]. Over the past two decades, an increasing number of studies have assessed lncRNAs because of their potential involvement in many pathologies, including malignancies [3]. LncRNAs contribute to multiple biological functions in cancer, ranging from cell proliferation, invasion, stemness, angiogenesis, to chemotherapy resistance [4,5]. LncRNAs were demonstrated to mediate diverse molecular cellular events such as genetic transcription, nuclear compartment formation, alternative splicing and epigenetic modification [6,7]. For example, lncRNA metastasis-associated lung adenocarcinoma transcript1 (MALAT1) has high expression in non-small cell lung cancer (NSCLC), and promotes proliferation progression of NSCLC cells through stabilizing FOXP3 by inhibited its ubiquitination induced by STUB1 [8]. Glucose transporter 1 (GLUT1) associated lncRNA (GAL) was upregulated in colorectal cancer liver metastasis (CRLM) tissues and associated with the overall survival (OS) rates of CRLM patients. GAL promoted colorectal cancer cell migration and invasion. GAL served as an oncogene through interacting with the GLUT1 protein to increase GLUT1 SUMOylation, inhibiting the effect of the ubiquitin-proteasome system on the GLUT1 protein [9]. critical role in tumor progression [10]. LINC00460 (on chromosome 13q33.2), is a novel cancer-related lncRNA with a transcript length of 935 nucleotides that contains 3 exons [11,12]. In the present review, we summarize current research on the expression, functions, underlying mechanism and clinical significance of LINC00460 in human malignancies. Moreover, these provide support for the potential of LINC00460 as a novel biomarker and as a therapeutic target for cancers.

Regulation of LINC00460 in cancer
The expression of LINC00460 has been reported to be regulated by genetic and epigenetic methods. A study performed by Zhang and colleagues [50] revealed LINC00460 is increased in colorectal cancer HCT116 cells following irradiation at 2 or 4 Gy. The critical region controlling LINC00460 transcription after irradiation was shown to be between − 240 and − 44 bp upstream of the LINC0460 transcription initiating site. In addition, C-jun was identified as a positive regulator of LINC00460 expression post-irradiation.
Nakano et al. [51] demonstrated that cells transfected with active EGFR mutations have elevated LINC00460 amounts. Furthermore, EGFR activation induced by EGF treatment also caused LINC00460 upregulation, the EGFR-induced increase in LINC00460 expression could be significantly attenuated by gefitinib pre-treatment induced EGFR inactivation. These results suggested that overexpression of LINC00460 was associated with the the abnormal activation of EGFR.
In a report by Zhang et al. [18], LINC00460 showed significant hypomethylation in colorectal cancer tissue samples in comparison with adjacent noncancerous tissue specimens, which had a negative correlation with its expression. In addition, treatment with 5-aza-2'-deoxycytidine resulted in LINC00460 overexpression and demethylation in LOVO and SW620 cells, demonstrating that LINC00460 could be activated by DNA methylation.

LINC00460 in cell death
Apoptotic, autophagic and necrotic cell deaths are the main mechanisms of cell death [55]. Cell apoptosis is the common process of programmed cell death [56]. LINC00460 has been reported to inhibit apoptosis in various cancers. The anti-apoptotic function of LINC00460 might be related to the regulation of the apoptotic proteins caspase-3 [21,36], caspase-9 [10], PARP [17], Bcl-2 and Bax [10,44]. LINC00460 could also regulate autophagy in cancer cells [42]. Knockdown of LINC00460 resulted in increased amounts of autophagosomes in HNSCC cells, along with increased LC3 II/LC3 I ratio and Beclin 1 amounts. Meanwhile, overexpression of LINC00460 restrains autophagy, with reduced number of autophagosomes and decreased LC3 II/LC3 I ratio and Beclin 1 amounts.

LINC00460 in cancer metastasis
Metastasis is the major cause results in the high mortality rate of diverse types of cancer, and high rates of metastasis are characteristic of advanced malignancies [57,58]. LINC00460 has been reported to be positively associated with lymph node and distant metastases as well as TNM stage in diverse malignancies, including bladder [59], colorectal [21,22,24], esophageal [25], gastric [27], head and neck [39,41,42], liver [45] and papillary thyroid [34] cancers, as well as osteosarcoma [49]. In vitro experiments demonstrated LINC00460 could regulate migratory and invasive pathways in malignant cells. A role for LINC00460 in metastasis has  Papillary thyroid cancer TPC1 BALB/c nude mice Promote [33] also been documented, primarily involving the regulation of epithelial-to-mesenchymal transition (EMT), in which epithelial cells undergo diverse modifications to acquire a mesenchymal phenotype. Several studies have demonstrated that LINC00460 knockdown inhibits EMT development and regulates the expression of proteins relevant to EMT (upregulate E-cadherin, downregulate N-cadherin and vimentin) [19,22,29,38,39,41,50,54,[60][61][62].

LINC00460 in chemotherapeutic or radiation resistance
At present, intrinsic or acquired resistance is the main cause of chemotherapy failure in many cancers [63]. LINC00460 has been demonstrated to be involved in chemoresistance. Zhang et al. [18] investigated the associations of lncRNAs and antitumor drug response, and demonstrated that LINC00460 could distinguish responses to AZD6244 and PD-0325901 in colon cancer samples. Meng and colleagues [64] demonstrated that LINC00460 is upregulated in colorectal cancer cells with oxaliplatin resistance and p53 mutations, compared with parental oxaliplatin-sensitive cells. LINC00460 silencing sensitized oxaliplatin-resistant colorectal cancer cells to this drug via p53 regulation. The expression of LINC00460 was shown to be elevated in gefitinib-resistant NSCLC and cells [30]. Gainand loss of function assays showed LINC00460 induces gefitinib resistance by increasing the expression of EGFR and the multidrug-resistance-associated proteins P-gp, MRP1, and BCRP. In another study, Nakano and collaborators [51] demonstrated that LINC00460 amounts are markedly elevated in cancer with wildtype or mutated (exon 19 deletion and L858R) EGFR in comparison with noncancerous tissues. It was also upregulated in NSCLC cells with gefitinib resistance in comparison with gefitinibsensitive cells. EGFR activation, induced by transfection with active EGFR mutations or treatment with EGF, resulted in higher LINC00460 expression, suggesting LINC00460 contributes to resistance against EGFR-TKIs.
Radiation therapy is broadly utilized for treatment of some solid tumors, and recent advances enable direct tumor targeting, without harming adjacent noncancerous tissues [65]. Radiation treatment is mostly hampered by tumor resistance, and decreasing recurrence post-radiotherapy represents an important challenge [66]. LINC00460 was shown to be markedly upregulated following irradiation at 2 or 4 Gy in HCT116 cells [50]. Transient LINC00460 silencing remarkably reduced HCT116 cell proliferation and EMT induced by irradiation. Thus, LINC00460 was considered to mediate the sensitization of HCT116 cells to ionizing radiation.

Mechanisms underlying LINC00460's effects in malignancies
Mounting evidence suggests the regulatory mechanisms of lncRNAs include modulating epigenetic alterations, regulating transcription or splicing, interacting with RNA binding proteins, and acting as miRNA sponges [4]. LncRNAs are involved in the regulation of various biological functions in the nucleus and cytoplasm [67]. LINC00460 was shown to be subcellular distributed in both cytoplasm and nucleus, thus playing important modulatory roles at the transcriptional and post-transcriptional levels [10,11,25,48,60] (Fig. 1). The following sections mainly focus on the molecular mechanisms of LINC00460 in regulating biological functions of malignancies.

LINC00460 interacts with RNA binding proteins
LncRNAs has been shown to control gene expression by interacting with RNA binding proteins (RBPs) [68]. RNA pull-down assays and mass spectroscopy are generally performed in sequence for identifying RBPs for lncRNAs. Utilizing this method, Jiang et al. revealed PRDX1 as an RBP that binds LINC00460 [41]. The interaction between PRDX1 and LINC00460 was confirmed by RIP assays. In a further report, Li and co-workers [31] showed hnRNP K is a RBP that binds to LINC00460, and confirmed LINC00460 interacts with hnRNP K by immunoblot.
Apart from mass spectrometry, bioinformatics is also generally carried out for predicting the odds of LINC00460 interacting with RBPs, followed by confirmation by the RIP assay. Using this method, Yang and collaborators [26] showed LINC00460 interacts with EZH2 and LSD1, inducing H3K27 trimethylation and H3K4 demethylation of target gene promoters, thereby suppressing transcription. In addition, LINC00460 interactions with EZH2 and LSD1 were also confirmed by the ChIP assay. In another report, Lian et al. [10] predicted LINC00460 could potentially bind to EZH2, SUZ12, DNMT1, and AGO2, by using bioinformatics analysis. They further confirmed that LINC00460 interacts with EZH2 through RIP assays, and further regulates the expression of KLF2.

LINC00460 as a molecular marker for cancer diagnosis
It is now widely accepted that the early diagnosis is crucial for achieving a lower mortality rate of tumors [69]. The detection and identification of lncRNAs in body fluids, including serum and plasma, may provide a novel tool for early noninvasive diagnosis of cancer [70]. Serum LINC00460 amounts were markedly elevated in 80 AML or CN-AML cases compared with 67 healthy control cases [36]. Receiver operating characteristic (ROC) curve analysis revealed serum LINC00460 amounts provided a clear separation of AML and healthy controls, with an area under the curve (AUC) of 0.8488 (95% CI, 0.7697-0.9279). Additionally, serum LINC00460 reliably differentiated CN-AML cases from healthy control cases (AUC = 0.7591). Serum LINC00460 amounts were also markedly reduced in patients after complete remission. These findings suggested that LINC00460 might be a potential diagnostic biomarker for patients with AML.
However, LINC00460 is expressed in a broad range of cancer types, making it less specific in distinguishing the origin of tumors. Further studies for the expression, sensitivity and stability of LINC00460 in non-invasive body fluids should be further investigated for are required to make LINC00460 an ideal tool for disease diagnosis. In addition, LINC00460 in body fluids are required to investigate for its diagnostic value alongside other specific molecular markers, and further investigations with larger clinical sample sizes are still required.
Zhang et al. [74] conducted a lncRNA prognostic model with another lncRNA trio, comprising LINC00460, MIAT and LINC00443, which could independently distinguish kidney renal clear cell carcinoma cases at low-and high-risk of poor OS, with AUCs for 1-, 5-and 10-year OS of 0.723, 0.714 and 0.826, respectively. The model had independent and great prognostic value in these patients.
In another study, Huang et al. [72] identified another lncRNA trio, comprised of RP11-366H4.1.1, LINC00460 and AC093850.2, as an efficient predictive factor of OS and DFS in patients with ESCC. The authors utilized multivariable Cox regression analysis to generate a risk score as (0.882 × AC0 938 50. 2)+ (1.219 × LINC00460)+(0.921 × RP11-366H4.1.1), whose cutoff was 48.48. Median OS was markedly reduced in high-risk cases compared with the low-risk group in the training set (23.1 months vs. 39.1 months, P < 0.001), the test set (23 months vs. 59 months, P < 0.001) and an independent esophageal squamous cell carcinoma dataset (GSE53624) (22.4 months vs. 60.4 months, P < 0.001). In addition, the three-lncRNA signature could also be used for predicting DFS, with median DFS times of 15.2 and 33.3 months in highand low-risk cases of the training set, respectively (P < 0.001), versus 16.4 and 50.8 months in the test set, respectively (P < 0.001). The above findings demonstrated the prognostic capability of the three-lncRNA signature to predict survival and recurrence risk.
Therefore, LINC00460 in combination with other lncRNAs or specific biomarkers can function as an independent prognostic indicator in diverse cancer types.

Conclusion and future perspectives
Numerous studies have confirmed that lncRNAs play critical roles in tumor development and progression in humans. This review mainly discusses research progress of the role, mechanism and clinical value of LINC00460 in a variety of human tumors. LINC00460 has been demonstrated to be upregulated in major types of human malignancies, regulating cellular events such as cell proliferation, apoptosis, migration, invasion, and chemoresistance. Thus, LINC00460 might be a potential candidate for treating diverse cancer types. Mechanistically, LINC00460 might modulate genes via a ceRNA mechanism or by interacting with RBPs. However, how LINC00460 is dysregulated in cancer remains incompletely defined. Regarding clinical application, LINC00460 dysregulation is associated with patient survival in many cancer types, and may also constitute a potent noninvasive molecular marker for diagnosing malignancies, indicating LINC00460 might represent a potential diagnostic and prognostic molecular marker. Overall, the above data indicate upregulation of and an oncogenic role for LINC00460 in human cancer. However, there is a need for additional basic and clinical experimental results before LINC00460 can be applied in the clinic. Firstly, the actual molecular mechanism and regulatory effect of LINC00460 needs to be further explored. Secondly, many of these findings were established in tissues and cancer cell lines, lacking clinical correlation. Thirdly, although strategies such as lentivirus or plasmid containing siRNA have been used to target LINC00460 in vitro, the in vivo delivery vector for therapeutic lncRNA is still need to be developed. In summary, basic research on LINC00460 has shown encouraging results, it is expected to achieve breakthroughs in diagnosis, prognosis evaluation, and treatment in clinical trials.