BACKGROUND: Long non-coding RNAs (LncRNAs) have been implicated as critical regulators of cancer tumorigenesis and progression. However, their functions and molecular mechanisms in colorectal cancer (CRC) still remain to be further elucidated.
METHODS: LINC00460 was identified by differential analysis between human CRC and normal tissues and verified by in situ hybridization (ISH) and qRT-PCR. We investigated the biological functions of LINC00460 in CRC by in vitro and in vivo experiments. We predicted the mechanism and downstream functional molecules of LINC00460 by bioinformatics analysis, and confirmed them by dual luciferase reporter gene assay, RNA immunoprecipitation (RIP), RNA pull-down, etc. RESULTS: LINC00460 was found to be significantly overexpressed in CRC and associated with poor prognosis. Overexpression of LINC00460 promoted CRC cell immune escape and remodeled a suppressive tumor immune microenvironment, thereby promoting CRC proliferation and metastasis. Mechanistic studies showed that LINC00460 served as a molecular sponge for miR-186-3p, and then promoted the expressions of MYC, CD47 and PD-L1 to facilitate CRC cell immune escape. We also demonstrated that MYC upregulated LINC00460 expression at the transcriptional level and formed a positive feedback loop.
CONCLUSIONS: The LINC00460/miR-186-3p/MYC feedback loop promotes CRC cell immune escape and subsequently facilitates CRC proliferation and metastasis. Our findings provide novel insight into LINC00460 as a CRC immune regulator, and provide a potential therapeutic target for CRC patients.

The acquired resistance of cancer to cisplatin (DDP) limits the efficacy of chemotherapy. The prognostic value of long noncoding RNA (lncRNA) LINC00460 has been reported in cervical cancer. However, its effect on DDP sensitivity in cervical cancer remains poorly understood. In present study, LINC00460 was screened out through bioinformatics analysis. The expression levels of mRNAs and proteins were measured by reverse transcription-quantitative PCR (RT-qPCR) or western blot analysis. The sensitivity to DDP was investigated using an CCK8 assay. Cell apoptosis was determined by flow cytometry. The differentially expressed genes that were associated with the poor prognosis of cervical cancer were screened, and their correlations with LINC00460 expression were explored using Pearson\'s correlation analysis. Tumor xenograft model was used to assess the effect of LINC00460 knockdown on DDP sensitivity in vivo. The interaction between miR-338-3p and LINC00460 or transforming growth factor β-induced protein (TGFBI) was confirmed by RNA immunoprecipitation (RIP) and luciferase reporter assays. LINC00460 expression was increased in cervical cancer tissues and cells. High expression of LINC00460 was associated with dismal prognosis in cervical cancer patients. Silencing of LINC00460 increased drug sensitivity and induced apoptosis in DDP-resistant-cervical cancer cells. LINC00460 knockdown enhanced DDP sensitivity in cervical cancer cells largely by downregulating TGFBI expression. LINC00460 knockdown enhanced the sensitivity of cervical cancer to DDP in vivo, and this effect was partly mediated by the downregulation of TGFBI. LINC00460 positively regulated TGFBI expression, possibly by acting as a sponge of miR-338-3p. LINC00460 knockdown contributed to DDP sensitivity of cervical cancer by downregulating TGFBI, providing a novel mechanism underlying the acquisition of DDP sensitivity.

Long noncoding RNAs (lncRNAs) have been demonstrated to participate in neuroblastoma cisplatin resistance and tumorigenesis. LncRNA LINC00460 was previously reported to play a critical regulatory role in many cancer development. Nevertheless, its role in modulating neuroblastoma cisplatin resistance has not been explored till now. Cisplatin-resistant neuroblastoma cell lines were established by exposing neuroblastoma cell lines to progressively increasing concentrations of cisplatin for 6 months. LINC00460, microRNA (miR)-149-5p, and delta-like ligand 1 (DLL1) mRNA expression was measured through RT-qPCR. The protein levels of DLL1, epithelial-to-mesenchymal transition (EMT) markers, and the Notch signaling-related molecules were measured via western blotting. The IC50 value for cisplatin, cell growth, metastasis and apoptosis were analyzed in cisplatin-resistant neuroblastoma cells. The binding between LINC00460 (or DLL1) and miR-149-5p was validated through dual-luciferase reporter assay. The murine xenograft model was established to perform in vivo assays. LINC00460 and DLL1 levels were elevated, while miR-149-5p level was reduced in cisplatin-resistant neuroblastoma cells. LINC00460 depletion attenuated IC50 values for cisplatin, weakened cell growth, metastasis, and EMT, and enhanced apoptosis in cisplatin-resistant neuroblastoma cells. Mechanically, LINC00460 sponged miR-338-3p to increase DLL1 level, thereby activating Notch signaling pathway. DLL1 overexpression antagonized LINC00460 silencing-induced suppression on neuroblastoma cell cisplatin resistance and malignant behaviors, while such effects were further reversed by treatment with DAPT, the inhibitor of Notch pathway. Additionally, LINC00460 knockdown further augmented cisplatin-induced impairment on tumor growth in vivo. LINC00460 contributes to neuroblastoma cisplatin resistance and tumorigenesis through miR-149-5p/DLL1/Notch pathway, providing new directions to improve the therapeutic efficacy of chemotherapy drugs applied in patients with neuroblastoma.

The long non-coding RNA (lncRNA) LINC00460 is involved in tumor growth, metastasis and drug resistance. The present study investigated the clinical significance of LINC00460 expression in patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer treated with osimertinib. Osimertinib-resistant cells we derived from EGFR-mutant non-small-cell lung cancer (NSCLC) cell lines, after which, small interfering RNA (siRNA)-mediated silencing and in vitro-transcribed (IVT), synthetic LINC00460 RNA transfection were used to investigate the effects of LINC00460 expression on acquired resistance to osimertinib. Reverse transcription-quantitative polymerase chain reaction was performed to evaluate LINC00460 expression in 54 samples (RNA extracted from the tumor tissues of 30 cases and cell-free RNA from 24 cases) obtained from patients with EGFR mutation-positive lung cancer who had received osimertinib as the initial treatment. The acquisition of osimertinib resistance increased the expression of LINC00460 in the EGFR-mutant NSCLC cell lines. By contrast, knockdown of LINC00460 in osimertinib-resistant cell lines increased their sensitivity to osimertinib, whereas treatment of NSCLC cells with IVT LINC00460 RNA decreased their sensitivity to osimertinib. The present study examined LINC00460 expression at the primary tumor site and demonstrated that compared with in the low-expression group (n=24), the high-expression group (n=6) had a significantly lower best overall response rate to osimertinib (16.6% vs. 60.0%; P=0.044), significantly shorter median progression-free survival (PFS; 224 days vs. 669 days; P=0.001) and significantly shorter median overall survival (724 days vs. not reached; P=0.011). Moreover, following osimertinib therapy, PFS was significantly shorter for patients with high LINC00460 expression in plasma cell-free RNA (n=12) than for those with low LINC00460 expression (n=12) (median PFS: 655 days vs. 210 days; P=0.020). In conclusion, the upregulation of LINC00460, the expression of which is implicated in osimertinib resistance, in the primary site and plasma of patients with EGFR mutation-positive lung cancer may be associated with a poor prognosis in those treated with osimertinib.

UNASSIGNED: Compelling evidence has manifested a strong association between aberrant expression of long noncoding RNAs (lncRNAs) and gastric carcinoma (GC) development. Nonetheless, biological impacts of differentially expressed lncRNAs (DElncRNAs) on GC are not scrutinized.
UNASSIGNED: Bioinformatics methods were employed for differential expression analysis and target gene prediction. MTT, colony formation, and Transwell methods were implemented for GC cell proliferation, migration, and invasion assessment. Western blot was implemented to test the protein level. The binding of genes was tested with dual-luciferase and RNA binding protein immunoprecipitation (RIP) approaches.
UNASSIGNED: Noticeably high level of LINC00460 was observed in GC tissues and cells. LINC00460 silencing constrained proliferation, migration, and invasion of GC cells. FISH and nuclear-cytoplasmic separation assays confirmed the main presentation of LINC00460 in the cytoplasm. Bioinformatics predicted that LINC00460 had binding sites to miRNA-143-5p, which was upregulated in GC. Dual luciferase and RIP experiments also confirmed the binding relationship. Concurrent silencing of LINC00460s and miRNA-133-5p rescued the repressive influence of sh-LINC004600 on GC cell proliferation, migration, and invasion. HMGA2 was predicted to be a target gene downstream of miRNA-143-5p, their binding relationship was validated via dual luciferase assays. Silencing HMGA2 constrained GC cell proliferation, invasion, and migration. LINC00460 modulated HMGA2 expression via binding miRNA-143-5p, thereby affecting proliferation, invasion, and migration of GC cells.
UNASSIGNED: These findings validated that LINC00460 could regulate HMGA2 via sponging miRNA-143-5p to facilitate GC proliferation, invasion, and migration, which provides a deeper understanding of lncRNAs in the development of GC.

Angiogenesis is a characteristic of tumor development and is key for tumor growth and metastasis. LINC00460 is a long non-coding RNA that plays important yet complex roles in cancer development and progression. Here, we explored the functional mechanism of action of LINC00460 in cervical cancer (CC) angiogenesis for the first time. We found that conditioned medium (CM) from LINC00460-knockdown CC cells attenuated human umbilical vein endothelial cell (HUVEC) migration, invasion, and tube formation, whereas LINC00460 upregulation had the opposite effects. Mechanistically, LINC00460 stimulated VEGFA transcription. Suppressing VEGF-A reversed the effects of CM from LINC00460-overexpressing CC cells on HUVEC angiogenesis. Recombinant VEGFA eliminated the suppressive effects of CM from LINC00460-knockdown CC cells. Furthermore, LINC00460 enhanced VEGFA expression and promoted angiogenesis by activating the NF-κB pathway. Our data illustrate that LINC00460 can promote angiogenesis by activating the NF-κB-VEGFA axis, suggesting that the axis is a promising target for blocking tumor angiogenesis.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignant tumors in the world. Research on long noncoding RNAs (LncRNAs) may illuminate tumorigenesis and progression of CRC.
METHODS: We screened long non-coding RNA LINC00460 as a new candidate, which promoted the development of CRC in two independent datasets (GSE39582 and GSE21510) from the Gene Expression Omnibus (GEO). In 98 CRC tissues, expression levels of LINC00460 were significantly increased in cancerous tissues compared to paired adjacent normal tissues (P < 0.001). In addition, in the most common CRC cell lines. LINC00460 expression was up-regulated compared to normal human intestinal epithelial cell line NCM460. siRNA was transfected into CRC cell lines. LINC00460 knockdown reduced cell invasion ability and did not affect cell proliferation. The association between LINC00460 expression and clinical pathological features and prognosis were also analyzed.
RESULTS: This increased expression was found to significantly correlate with lymph node metastasis (P = 0.002), distant metastasis (P = 0.045) and TNM stage (P < 0.001); but not related to age, gender, location of tumor, and histological grade. The overall survival (OS) in CRC patients with overexpression of LINC00460 was inferior to that with low expression (P = 0.0167). Multivariate Cox regression analyses indicated that LINC00460 expression, as well as TNM stage was an independent prognostic risk factor for patients with CRC.
CONCLUSIONS: These results showed that a higher expression level of LINC00460 might play an oncogenic role in colorectal cancer invasion and metastasis. It also proved that LINC00460 might be used as a potential diagnostic and prognostic biomarker in CRC patients.

BACKGROUND: Long intergenic non-coding RNA 460 (LINC00460) as a potential oncogene and Annexin A2 (ANXA2) as a promoter in different cancer progression processes was considered. A significant relationship between the LINC00460 and ANXA2 has been recently discovered in colorectal cancer (CRC). Therefore, defining molecular biomarkers accompanied by lesion histopathologic features can be a suggestive prognostic biomarker in precancerous polyps. This study aimed to investigate the elusive expression pattern of ANXA2 and LINC00460 in polyps.
METHODS: The construction of the co-expression and correlation network of LINC00460 and ANXA2 was plotted. LINC00460 and ANXA2 expression in 40 colon polyps was quantified by reverse transcription-real-time polymerase chain reaction. The receiver operating characteristic (ROC) curve was designed for distinguishing the high-risk precancerous lesion from the low-risk. Further, bioinformatics analysis was applied to find the shared MicroRNA-Interaction-Targets (MITs) between ANXA2 and LINC00460, and the associated pathways.
RESULTS: ANXA2 has a high co-expression rank with LINC00460 in the lncHUB database. Overexpression of ANXA2 and LINC00460 was distinguished in advanced adenoma polyps compared to the adjacent normal samples. The estimated AUC for ANXA2 and LINC00460 was 0.88 - 0.85 with 93%-90% sensitivity and 81%-70% specificity. In addition, eight MITs were shared between ANXA2 and LINC00460. Enrichment analysis detected several GO terms and pathways, including HIF-1α associated with cancer development.
CONCLUSIONS: In conclusion, the expression of the ANXA2 and LINC00460 were significantly elevated in pre-cancerous polyps, especially in high-risk adenomas. Collectively, ANXA2 and LINC00460 may be administered as potential prognostic biomarkers in patients with a precancerous large intestine lesion as an alarming issue.

Background: Emerging evidence suggests that long noncoding RNAs (lncRNAs) play an important role in the progression of multiple human cancers including breast cancer. In this study, we aimed to research novel functions of long intergenic noncoding RNA 460 (LINC00460) on cell proliferation and ferroptosis in breast cancer. Method: UALCAN, TANRIC, and GSE16446 data were used to analyze the expression of LINC00460 in breast cancer tissues. Furthermore, real-time quantitative PCR, western blot, cell proliferation assay, iron assay, and malondialdehyde (MDA) assay were applied to detect the function and mechanism of particular molecules. Results: The LINC00460 expression was significantly increased in breast cancer tissues compared with normal tissues. Importantly, patients with high LINC00460 expression showed a longer overall survival rate. LINC00460 knockdown markedly suppressed the proliferation of breast cancer cells and promoted ferroptosis. Mechanistic analysis revealed that LINC00460 promoted myelin and lymphocyte protein 2 (MAL2) expression by sponging miR-320a. Moreover, both miR-320a knockdown and MAL2 overexpression could reverse the effects of LINC00460 silencing on cell proliferation and ferroptosis. Conclusions: In summary, our results reveal an alternative mechanism by which breast cancer cells can acquire resistance to ferroptosis via the LINC00460/miR-320a/MAL2 axis.

Long intergenic noncoding ribonucleic acid (lncRNA) 460 is reportedly associated with carcinogenesis and progression in various types of cancer. However, the mechanisms underlying its action in cutaneous squamous cell carcinoma (CSCC) remain unclear. LINC00460 mRNA expression was analysed using data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cell growth, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2\'-deoxyuridine (EdU), transwell migration and invasion assays after inducing LINC00460 knockdown. A xenograft tumour model was used to determine the effects of LINC00460 on tumour growth and metastasis in vivo. To examine the interaction between LINC00460 and ELAVL1, RNA pulldown and RNA immunoprecipitation assays were performed. LINC00460 was found to be significantly upregulated in CSCC tissues and cell lines. Functionally, LINC00460 knockdown inhibited cell proliferation, migration, and invasion in vitro. Consistent with this, when LINC00460 expression decreased, CSCC tumorigenesis and metastasis in vivo were inhibited. Mechanistically, LINC00460 binds to embryonic lethal abnormal vision like RNA binding protein 1 (ELAVL1) and enhances its stability by inhibiting the β-transducin repeats-containing protein (β-TrCP)-mediated ubiquitination of ELAVL1. Moreover, the effect of LINC00460 silencing on the proliferation, migration, and invasion of CSCC cells could be reversed by overexpressing ELAVL1. Our findings demonstrated that LINC00460 plays a critical role in regulating ELAVL1 function. This highlights the potential targets for the clinical diagnosis and treatment of CSCC.