LINC01503 promotes the cell proliferation, migration and invasion of triple-negative breast cancer as a ceRNA to elevate SPNS2 expression by sponging miR-335-5p.

Objective: Triple-negative breast cancer (TNBC) is a common cancer with high aggressiveness and high mortality in women. Recently, a plenty of studies have indicated that long non-coding RNAs (lncRNAs) exert the crucial function in human cancers, TNBC is included. The carcinogenicity of lncRNA long intergenic non-protein coding RNA 1503 (LINC01503) has been confirmed in several cancers, nevertheless, its function in TNBC still unclear. Therefore, our study aimed to reveal the underlying mechanism of LINC01503 in TNBC. Methods: In our study, RT-qPCR was performed to detect the expression of LINC01503 in TNBC cells. The proliferative, invasive, migratory and apoptotic abilities of TNBC cells were detected by functional assay such as CCK-8, clone formation, EdU staining, transwell, and flow cytometry. RIP, RNA pull down, and luciferase assay revealed interactions between LINC01503, miR-335-5p, and sphingolipid transporter protein 2 (SPNS2). Finally, rescue experiments were performed to validate the previous results. Results: LINC01503 expression was singularly high in TNBC cells. LINC01503 knockdown could restrain cell proliferation, invasion and migration, but accelerated cell apoptosis in TNBC. What's more, miR-335-5p could be sponged by LINC01503 in TNBC. We also found that overexpressed miR-335-5p could inhibit cell proliferation, migration and invasion and facilitates cell apoptosis. Moreover, SPNS2 was the target gene of miR-335-5p and it functioned as an oncogene in TNBC cells. Finally, we found that overexpressed SPNS2 or inhibited miR-335-5p could reverse the suppressive function of silencing LINC01503 on TNBC progression. Conclusion: LINC01503 could facilitate cell proliferation, migration and invasion of TNBC by sponging miR-335-5p to elevate SPNS2 expression.

[Isoliquiritigenin Modulates the Effect of LINC01503 
on Lung Squamous Carcinoma Cells].

BACKGROUND: Isoliquiritigenin (ISL) is an important pharmacological constituent of Glycyrrhiza glabra, which possesses a range of physiological and pharmacological activities, as well as significant antitumor activity, and can be used as a potential drug for targeted cancer therapy. LINC01503 is an oncogene, which has been closely associated with the malignant biological processes of many cancers. The aim of this study was to investigate the effects of ISL on the proliferation, apoptosis, invasion and migration of lung squamous carcinoma cells by regulating LINC01503. METHODS: Plasma was collected from lung squamous carcinoma patients and healthy individuals treated at Tangshan People's Hospital from January 2021 to December 2022. The expression of LINC01503 in lung squamous carcinoma plasma, tissues and cells was detected by real-time quantitative fluorescence polymerase chain reaction (qRT-PCR). Lung squamous carcinoma cells were treated with different concentrations of ISL for 24 h, and LINC01503 expression was detected by qRT-PCR. The cells were treated in groups: si-NC group, si-LINC01503 group, DMSO (0.1% dimethyl sulfone) group, ISL group, pc DNA3.1(+)-NC group, pc DNA3.1(+)-LINC01503 group, ISL+pc DNA3.1(+)-NC group and ISL+pc DNA3.1(+)- LINC01503 groups. CCK-8 assay, clone formation assay, flow cytometry, Transwell assay and scratch assay were used to explore the effect of LINC01503 on the functional phenotype of lung squamous carcinoma cells. RESULTS: Fluorescence in situ hybridization results showed that the average fluorescence intensity of LINC01503 in tissue microarrays of lung squamous carcinoma patients was higher than that in paracancerous tissues (P<0.05). The expression of LINC01503 in the plasma of patients with lung squamous carcinoma was higher than that in the plasma of healthy individuals (P<0.05). Knockdown of LINC01503 inhibited the proliferation, invasion and migration of lung squamous carcinoma cells and promoted apoptosis (P<0.05). ISL inhibited the proliferation, invasion, migration and promoted apoptosis of lung squamous carcinoma cells (P<0.05). Overexpression of LINC01503 followed by intervention with ISL reversed the promotional effect of overexpression of LINC01503 on the proliferation, invasion and migration of lung squamous carcinoma cells as well as the inhibitory effect on apoptosis (P<0.05). CONCLUSIONS: LINC01503 was highly expressed in lung squamous carcinoma, and LINC01503 could promote the proliferation, invasion and migration of lung squamous carcinoma cells and inhibit the apoptosis, ISL could inhibit the proliferation, invasion and migration of lung squamous carcinoma cells and promote apoptosis of lung squamous carcinoma cells by regulating the expression of LINC01503.

LINC01503 in cancer: from molecular mechanisms to therapeutic implications.

Long non-coding RNAs (lncRNAs) are fundamental agents that govern tumor growth and metastasis across a spectrum of cancer types. Linc01503 is a novel lncRNA situated on human chromosome 19, and it is intricately linked with the pathogenesis of multiple human cancers, underscoring its substantial role and significance in cancer development. It has been recognized as a pivotal contributor to inducing malignant behaviors in lung cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, liver cancer and pancreatic cancer, among others. The dysregulation of linc01503 has been shown to strongly associate with advanced clinicopathological factors and foretell an unfavorable prognosis, indicating its prospective clinical significance as a valuable biomarker and therapeutic target for individuals with cancer. The primary objective of the current work is to present the intricate molecular pathways governed by linc01503 and its profound clinical relevance in the context of carcinogenesis. We also focus on the future prospects of linc01503-based clinical application. This will help us to better understand the regulatory mechanism of carcinogenesis and provide new ideas for precision molecular medicine.

lncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Roles, underlying mechanisms and clinical significances of LINC01503 in human cancers.

Long intergenic non-coding RNA 01503 (LINC01503) is a long non-coding RNA (lncRNA) located on human chromosome 9q34.11. There is compelling evidence indicating that LINC01503 is upregulated in multiple types of tumors and functions as a tumor stimulator. The upregulation of LINC01503 was significantly associated with the risk of 12 tumors and showed a strong correlation with clinicopathological characteristics and poor prognosis in 9 tumors. The expression of LINC01503 is regulated by transcription factors such as TP63, EGR1, c-MYC, GATA1 and AR. The downstream regulatory mechanisms of LINC01503 are complex and multifaceted. LINC01503, as a competing endogenous RNA (ceRNA), regulates gene expression by competitively inhibiting miRNA. LINC01503 may also regulate gene expression via interacting with biomolecules or recruiting chromatin-modifying complexes. In addition, LINC01503 can abnormally activate the ERK/MAPK, PI3K/AKT and Wnt/ß-catenin signaling pathways to enhance tumor progression. Here, this review presents an overview of the latest research progress of LINC01503 in the field of oncology, summarizes its comprehensive network involved in multiple cancer molecular mechanisms, and explores its potential applications in cancer diagnosis, prognosis, and treatment.

The transcript ENST00000444125 of lncRNA LINC01503 promotes cancer stem cell properties of glioblastoma cells via reducing FBXW1 mediated GLI2 degradation.

LINC010503 is a novel oncogenic lncRNA in multiple cancers. In this study, we further explored the expression of LINC010503 transcripts and their regulations on the glioblastoma (GBM) stem cell (GSC) properties. LINC01503 transcription patterns in GBM and normal brain tissues were compared using RNA-seq data from Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA)-GBM. GBM cell lines (U251 and U87) were used as in vitro cell models for cellular and molecular studies. The results showed that ENST00000444125 was the dominant transcript of LINC01503 in both normal and tumor tissues. Its expression was significantly elevated in the tumor group and associated with poor survival outcomes. LINC01503 had both cytoplasmic and nuclear distribution. It positively modulated the expression of multiple GSC markers, including CD133, SOX2, NESTIN, ALDH1A1, and MSI1, and tumorsphere formation in U251 and U87 cells. RNA pull-down and RIP-qPCR assay confirmed an interaction between ENST00000444125 and GLI2. ENST00000444125 positively regulated the half-life of the GLI2 protein in GBM cells. ENST00000444125 overexpression reduced GLI2 ubiquitination and partially attenuated FBXW1 overexpression induced GLI2 ubiquitination. ENST00000444125 overexpression could activate Wnt/ß-catenin signaling in GBM cells. However, these activating effects were remarkedly hampered when GLI2 was knocked down. In conclusion, this study revealed that LINC01503 might have isoform-specific dysregulation in GBM. Among the two major transcripts expressed in GBM cells, ENST00000444125 might be the major functional transcript. Its upregulation might enhance the GSC properties of GBM cells via reducing FBXW1-mediated proteasomal degradation of GLI2.

GATA1-induced upregulation of LINC01503 promotes carboplatin resistance in ovarian carcinoma by upregulating PD-L1 via sponging miR-766-5p.

BACKGROUND: Ovarian Carcinoma (OCa) is a high-mortality malignancy derived from female reproductive system. Increasing evidence has identified long non-coding RNAs (lncRNAs) as important regulators in OCa chemoresistance. In this study, we intended to explore the role of LINC01503 in OCa resistance to carboplatin (CBP). METHODS: Gene expression was measured by reverse transcription-quantitative PCR (RT-qPCR) in OCa cells. Western blot was adopted to detect protein levels of GATA1, PD-L1, E-cadherin, N-cadherin, Vimentin, Bcl-2, Bax, cleaved caspase-3. To assess the effects of LINC01503 on the resistance of OCa cells to CBP, Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and flow cytometry experiments were performed to evaluate half-maximal inhibitory concentration (IC50), cell viability, migrative and invasive ability, as well as cell apoptosis. Dual-luciferase reporter assay was employed to assess the associations between the genes. RESULTS: LINC01503 was upregulated in CBP-resistant OCa cells. LINC01503 knockdown reduced CBP resistance in OCa cells. Besides, GATA-binding protein 1 (GATA1) activated LINC01503 transcription in CBP-resistant OCa cells. MiR-766-5p was lowly expressed in CBP-resistant cells and confirmed as a target for LINC01503. In addition, miR-766-5p overexpression increased CBP sensitivity in OCa cells. PD-L1 was verified as the target of miR-766-5p. Besides, LINC01503 upregulated PD-L1 level by regulating miR-766-5p. Furthermore, rescue experiments showed that PD-L1 overexpression abrogated the inhibited impacts of blocking LINC01503 on CBP resistance in OCa cells. CONCLUSION: GATA1-induced LINC01503 expedited CBP resistance in OCa cells via the miR-766-5p/PD-L1 axis, providing a new target for improving the efficacy of OCa chemotherapy.

Upregulation of LINC01503 promotes cervical cancer progression by targeting the miR-615-3p/CCND1 axis.

Mounting evidence indicates that long non-coding RNAs influence the progression of cervical cancer, but the precise function of LINC01503 in the pathogenesis of the disease remains unknown. Here, we found higher levels of LINC01503 in cervical cancer tissues. High LINC01503 expression was associated with enhanced progression of cervical cancer as indicated by advanced FIGO stage, increased metastasis of tumor cells to lymph nodes, and invasion into deeper cervical tissues. LINC01503 inhibition markedly suppressed the invasion and proliferative ability of tumor cells. Mechanistically, LINC01503 was demonstrated to negatively modulate the expression of miR-615-3p in cervical cancer. CCND1 was found to be a target of miR-615-3p. Rescue experiments indicated that LINC01503 inhibition suppressed the invasion and proliferative ability of the tumor cells, a phenomenon that was reversed following miR-615-3p inhibition or CCND1 overexpression. Collectively, these data indicate that LINC01503 enhances the progression of cervical cancer cells via interaction with miR-615-3p/CCND1 axis.

Long Non-coding RNA LINC01503 Promotes Gastric Cancer Cell Proliferation and Invasion by Regulating Wnt Signaling.

BACKGROUND: Previous studies have indicated that the dysregulation of long non-coding RNAs plays an important role in tumors. LINC01503 is a newly discovered lncRNA that promotes development of various tumor types. However, the function of LINC01503 in gastric cancer has not been reported yet. AIMS: To explore the function of LINC01503 in gastric cancer development and the underlying molecular biological regulatory mechanisms. METHODS: LINC01503 expression in tissues and cell lines of gastric cancer were determined through qRT-PCR. Transwell assay and cell number counting experiments were employed to detect the cell invasion and proliferation. C-myc, cyclin D1, and ß-catenin expressions were analyzed through Western blot and qRT-PCR. RESULTS: LINC01503 was highly expressed in gastric cancer tissues and cell lines, which was correlated with poor prognosis. Knockdown of LINC01503 suppressed gastric cancer cell proliferation and invasion, whereas overexpression of LINC01503 showed a reverse trend. Silencing LINC01503 significantly inhibited the expression of c-myc, cyclin D1, and ß-catenin. Overexpressing ß-catenin rescued the inhibitory effects, induced by LINC01503 silencing, on gastric cancer cell proliferation and metastasis. CONCLUSIONS: This research reported that the elevated expression of LINC01503 could promote proliferation and metastasis of gastric cancer through positively regulating the Wnt/ß-catenin pathway.

Long Non-coding RNA LINC01503 Promotes Gastric Cardia Adenocarcinoma Progression via miR-133a-5p/VIM Axis and EMT Process.

BACKGROUND: LINC01503 has been reported to act as a candidate oncogenic lncRNA in several types of human cancer. However, the functions and underlying mechanisms of LINC01503 in gastric cardia adenocarcinoma (GCA) remain unclear. AIMS: To investigate the roles and underlying mechanisms of LINC01503 in GCA progression. MATERIALS AND METHODS: Gene expressions were detected by quantitative real-time PCR (qRT-PCR). Gain-of-function assays were performed to evaluate the function of LINC01503 in gastric cancer cells. Bioinformatics analysis, luciferase reporter assay, and RIP assay were performed to identify associations among LINC01503, miR-133a-5p, and VIM. RESULTS: The expression level of LINC01503 was significantly elevated in GCA tissues and cell lines. High expression of LINC01503 was correlated with lymph node metastasis, TNM stage, and poor prognosis of GCA patients. Knockdown of LINC01503 significantly reduced proliferation, migration, and invasion ability in GC cells. LINC01503 might function as a competing endogenous RNA (ceRNA) via sponging miR-133a-5p to upregulate the expression of VIM. Furthermore, overexpression of LINC01503 promoted the progression of epithelial mesenchymal transition (EMT) in vitro. CONCLUSION: LINC01503 serves as an oncogenic lncRNA to promote GCA progression via affecting LINC01503/miR-133a-5p/VIM axis and EMT process. LINC01503 not only has a critical role in GCA progression but also provide a novel potential biomarker in predicting prognosis for GCA patients.

EGR1-mediated linc01503 promotes cell cycle progression and tumorigenesis in gastric cancer.

OBJECTIVES: Long non-coding RNAs (lncRNAs) are key mediators in various malignancies. Linc01503 was previously elucidated to promote gastric cancer (GC) cell invasion. However, the upstream mechanism of linc01503 and its involvement in GC cell cycle, apoptosis and tumorigenesis still remain unclear. MATERIALS AND METHODS: Bioinformatics analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were implicated to detect linc01503 level in GC. The role of linc01503 was detected by in vitro functional assays and in vivo xenograft tumour models. The association between linc01503 and its upstream effector was identified by chromatin immunoprecipitation (ChIP) assays. The mechanistic model of linc01503 was clarified using subcellular separation, fluorescence in situ hybridization, RNA-sequencing, RNA immunoprecipitation (RIP) and ChIP assays. RESULTS: Linc01503 was remarkably elevated in GC and tightly linked with the overall survival of patients with GC. The key transcription factor early growth response protein 1 (EGR1) critically activated the transcription of linc01503. Functionally, linc01503 knockdown resulted in the activation of apoptosis and G1/G0 phase arrest in GC. Mechanistically, linc01503 interacted with histone modification enzyme enhancer of zeste 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1), thereby mediating the transcriptional silencing of dual-specificity phosphatase 5 (DUSP5) and cyclin-dependent kinase inhibitor 1A (CDKN1A) in GC. CONCLUSIONS: EGR1-activated linc01503 could epigenetically silence DUSP5/CDKN1A expression to mediate cell cycle progression and tumorigenesis, implicating it as a prospective target for GC therapeutics.

LINC01503/miR-342-3p facilitates malignancy in non-small-cell lung cancer cells via regulating LASP1.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the major types of lung cancer, which is a prevalent human disease all over the world. LncRNA LINC01503 is a super-enhancer-driven long non-coding RNA that is dysregulated in several types of human cancer. However, its role in NSCLC remains unknown. METHODS: Thirty NSCLC patients were recruited between April 2012 and April 2016. Luciferase reporter assay, qRT-PCR, Cell Counting Kit-8 (CCK-8), Transwell migration assay, RNA pull-down assay, western blotting, 5-ethynyl-29-deoxyuridine (EdU) assays, and flow cytometry were utilized to characterize the roles and relationships among LINC01503, miR-342-3p, and LASP1 in NSCLC. The transplanted mouse model was built to examine their biological functions in vivo. RESULTS: We demonstrated that the expression of lncRNA LINC01503 and LIM and SH3 domain protein 1 (LASP1) were upregulated and miR-342-3p was downregulated in NSCLC samples and cell lines. Functional experiments revealed that inhibiting the expression of LINC01503 or over-expression of miR-342-3p inhibited NSCLC growth and metastasis both in vitro and in vivo. In addition, LINC01503 could bind to miR-342-3p and affect the expression of LASP1. CONCLUSION: These results provide a comprehensive analysis of the roles of LINC01503 as a competing endogenous RNA (ceRNA) in NSCLC progression.

Long non-coding RNA LINC01503 promotes the progression of hepatocellular carcinoma via activating MAPK/ERK pathway.

Background: Increasing evidence has implicated that lncRNAs (long non-coding RNAs) play significant roles in carcinogenesis and progression of HCC (hepatocellular carcinoma). LINC01503 is a new lncRNA related to several tumors. Nonetheless, its role in HCC still remains unclear. Methods: The expression levels of LINC01503 in HCC, normal liver tissues as well as HCC cell lines were evaluated by TCGA (The Cancer Genome Atlas) and real-time PCR assay, respectively. The relationship between LINC01503 levels and the prognosis of patients with HCC was evaluated using Kaplan-Meier survival analysis. Then the potential biological functions and pathways related to LINC01503 were investigated by GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis, and GSEA v4.0.1 software was employed. Furthermore, the influence of LINC01503 on the proliferation and apoptosis of HCC cells was confirmed using CCK8 assay, flow cytometry, and clone formation assay in cell experiments. Also the pro-tumor effect of LINC01503 was verified by mice xenograft experiment in vivo. In addition, the functional pathway of LINC01503 was proved by western blot and rescue experiments. Results: LINC01503 was highly expressed in HCC and positively correlated with large tumor size, high tumor grade, advanced tumor stage, and poor prognosis of HCC patients. Silencing LINC01503 with shRNA significantly restrained the proliferation of MHCC-97H HCC cells and strengthened the apoptosis, while up-regulation of LINC01503 in Huh7 HCC cells contributed to the contrary effects. Besides, LINC01503 promoted tumor growth of nude mice transplanted with liver cancer cells. Mechanistically, MAPK/ERK signaling pathway was activated by LINC01503, inhibition of which could alleviate the pro-tumor effect of LINC01503, consistent with the forecast of GSEA (Gene Set Enrichment Analysis). Conclusion: LINC01503 is highly expressed in HCC and promotes the progression of HCC via MAPK/ERK pathway, which maybe a new potential biomarker and therapeutic target for HCC.

LncRNA LINC01503 aggravates the progression of cervical cancer through sponging miR-342-3p to mediate FXYD3 expression.

Cervical cancer (CC), an aggressive malignancy, has a high risk of relapse and death, mainly occurring in females. Accumulating investigations have confirmed the critical role of long noncoding RNAs (lncRNAs) in diverse cancers. LncRNA LINC01503 has been reported as an oncogene in several cancers. Nonetheless, its role and molecular mechanism in CC have not been explored. In the present study, we found that FXYD3 expression was considerably up-regulated in CC tissues and cells. Moreover, FXYD3 deficiency conspicuously hampered cell proliferation and migration while facilitated cell apoptosis in CC cells. Subsequently, molecular mechanism experiments implied that FXYD3 was a downstream target gene of miR-342-3p, and FXYD3 expression was reversely mediated by miR-342-3p. Moreover, we discovered that LINC01503 acted as the endogenous sponge for miR-342-3p. Besides, LINC01503 negatively regulated miR-342-3p expression and positively regulated FXYD3 expression in CC. Rescue assays revealed that LINC01503 depletion-induced repression on CC progression could be partly recovered by miR-342-3p inhibition, and then the co-transfection of sh-FXYD3#1 rescued this effect. Conclusively, LINC01503 aggravated CC progression through sponging miR-342-3p to mediate FXYD3 expression, providing promising therapeutic targets for CC patients.

Long non-coding RNA LINC01503 promotes colorectal cancer cell proliferation and invasion by regulating miR-4492/FOXK1 signaling.

Increasing evidence indicates that long non-coding RNAs (lncRNAs) are closely associated with the progression of human cancer, including colorectal cancer (CRC). A previous study suggested that lncRNA LINC01503 promotes squamous cell carcinoma progression. However, the function of LINC01503 in CRC has remained elusive. The present study indicated that LINC01503 was significantly upregulated in CRC tissues compared with that in adjacent normal tissues as detected by reverse transcription-quantitative polymerase chain reaction. It was demonstrated that knockdown of long intergenic non-protein coding RNA (LINC)01503 markedly inhibited the proliferation and invasion of CRC cells, whereas overexpression of LINC01503 had the opposite effects, as indicated by Cell Counting kit-8 and Transwell assays. Mechanistically, it was revealed that LINC01503 serves as a sponge for microRNA (miR)-4492, which targets forkhead box K1 (FOXK1) in CRC cells. In addition, luciferase reporter assays demonstrated the direct binding of miR-4492 mimics to LINC01503 and to a sequence in the 3'-untranslated region of FOXK1. Furthermore, it was demonstrated that overexpression of LINC01503 reduced the availability of miR-4492 in CRC cells. Furthermore, miR-4492 mimics inhibited FOXK1 expression, while simultaneous overexpression of LINC01503 abolished this effect. Finally, it was demonstrated that restoration of FOXK1 abolished the inhibitory effect of LINC01503 knockdown on CRC cell proliferation and invasion. Taken together, the present results suggested that LINC01503 promotes CRC progression via acting as a competing endogenous RNA for miR-4492/FOXK1.