Non-coding RNA LINC00152 Research Articles

The emerging roles of LINC00511 in breast cancer development and therapy.

Breast cancer (BC) is associated with malignant tumors in women worldwide with persistently high incidence and mortality rates. The traditional therapies including surgery, chemotherapy, radiotherapy and targeted therapy have certain therapeutic effects on BC patients, but acquired drug resistance can lead to tumor recurrence and metastasis. This remains a clinical challenge that is difficult to solve during treatment. Therefore, continued research is needed to identify effective targets and treatment methods, to ultimately implement personalized treatment strategies. Several studies have implicated that the long non-coding RNA LINC00511 is closely linked to the occurrence, development and drug resistance of BC. Here we will review the structure and the mechanisms of action of lnc RNA LINC00511 in various cancers, and then explore its expression and its related regulatory mechanisms during BC. In addition, we will discuss the biological functions and the potential clinical applications of LINC00511 in BC.

Linc00673-V3 positively regulates autophagy by promoting Smad3-mediated LC3B transcription in NSCLC.

Since its first discovery, long noncoding RNA Linc00673 has been linked to carcinogenesis and metastasis of various human cancers. Linc00673 had five transcriptional isoforms and their biological functions remained to be explored. Here we have reported that Linc00673-V3, one of the isoforms of Linc00673, promoted non-small cell lung cancer chemoresistance, and increased Linc00673-V3 expression level was associated with enhanced autophagy. Mechanistically, we discerned the existence of a stem-loop configuration engendered by the 1-100-nt and 2200-2275-nt fragments within Linc00673-V3. This structure inherently interacted with Smad3, thereby impeding its ubiquitination and subsequent degradation orchestrated by E3 ligase STUB1. The accumulation of Smad3 contributed to autophagy via up-regulation of LC3B transcription and ultimately conferred chemoresistance in NSCLC. Our results revealed a novel transcriptional regulation network between Linc00673-V3, Smad3, and LC3B, which provided an important insight into the interplay between autophagy regulation and non-canonical function of Smad3. Furthermore, the results from in vivo experiments suggested Linc00673-V3 targeted antisense oligonucleotide as a promising therapeutic strategy to overcome chemotherapy resistance in NSCLC.

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.

Long noncoding RNA LINC00858 aggravates the progression of esophageal squamous cell carcinoma via regulating the miR-425-5p/ABL2 axis

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal cancers with high morbidity and mortality, which severely affects people's lives. Long intergenic non-protein coding RNA 858 (LINC00858) was confirmed to promote the progression of colorectal cancer and lung cancer. However, the role of lncRNA LINC00858 is still unknown in ESCC. Herein, the main purpose of research was to explore LINC00858 function and its impact on ESCC cell biological behaviors. RT-qPCR was used to test the expression of LINC00858, miR-425-5p and ABL proto-oncogene 2 (ABL2) in ESCC cells. Functional experiments such as EdU assay, CCK-8 assay, transwell assay and Western blot assay were conducted to investigate the biological behaviors of ESCC cells. Luciferase reporter assay and RIP assay were implemented to determine the binding situation among RNAs. LINC00858 expression was abnormally high in ESCC cells and down-regulation of LINC00858 could restrain the proliferation, invasion, migration and EMT process of ESCC cells. Furthermore, miR-425-5p was proved to be sponged by LINC00858 and was down-regulated in ESCC cells. Besides, we discovered that miR-425-5p could target ABL2. Moreover, knockdown of ABL2 reversed the promoting function of miR-425-5p inhibitor on ESCC progression. LINC00858 aggravated ESCC progression via regulating the miR-425-5p/ABL2 axis.

Long Noncoding RNA LINC00460 Promotes Hepatocellular Carcinoma Progression via Regulation of miR-342-3p/AGR2 Axis [Retraction

[This retracts the article DOI: 10.2147/OTT.S239258.].

LINC00460 knockdown sensitizes cervical cancer to cisplatin by downregulating TGFBI.

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 invivo. 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 invivo, 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 Non-coding RNA LINC00152 Requires EZH2 to Promote Mesothelioma Cell Proliferation, Migration, and Invasion.

Long non-coding RNAs (lncRNAs) establish gene regulatory networks in different human cancers and are involved in tumorigenesis. lncRNA LINC00152 is over-expressed in several malignant tumors and involved in tumorigenesis; however, its underlying regulatory mechanisms remain unclear. Mesothelioma, a cancer originating from mesothelial cells, is highly aggressive with a poor prognosis. Therefore, identification of new therapeutic targets is necessary for mesothelioma treatment. Here, we conducted bioinformatics analyses of LINC00152 and enhancer of zeste homolog 2 (EZH2) expression levels and their correlation with the prognosis of patients with mesothelioma. Small interfering RNAs targeting LINC00152 and EZH2 were transfected into mesothelioma cell lines to analyze their biological functions and regulatory mechanisms. High LINC00152 expression was associated with a poor prognosis of patients with mesothelioma. LINC00152 knockdown inhibited the proliferation, migration, and invasion of mesothelioma cell lines. These results suggest that LINC00152 is a tumor-promoting factor in mesothelioma. EZH2 is highly expressed in mesothelioma and other malignancies. Direct interaction between LINC00152 and EZH2 is associated with cancer development and progression. When EZH2 expression was suppressed, LINC00152 knockdown did not suppress the proliferation, migration, and invasion of mesothelioma cells. Therefore, the tumor-promoting effect of LINC00152 in mesothelioma was dependent on EZH2 expression. LINC00152 promotes mesothelioma cell proliferation, migration, and invasion in cooperation with EZH2, highlighting its potential as an effective therapeutic target for mesothelioma.

Single-Cell-Multiomics Demonstrates Molecular Efficacy of a Clinical Lentiviral Vector for Gene Therapy of RPS19-Deficient Diamond-Blackfan Anemia

It has previously been demonstrated that lentiviral vector-mediated gene transfer of human codon-optimized RPS19 to hematopoietic stem cells by the gene therapy vector (CLIN-LV-EFS-coRPS19-PRE*) corrects the anemic phenotype of RPS19-deficient mice, supporting development of this vector for clinical gene therapy of RPS19-deficient Diamond-Blackfan Anemia (DBA). In this study, we evaluate the molecular efficacy of CLIN-LV-EFS-coRPS19-PRE* in CD34+ cells from RPS19-deficient DBA patients. CD34+ cells from two healthy donors and three DBA patients with confirmed heterozygous mutations in RPS19 were transduced using GMP-like reagents according to a protocol developed for clinical use. To evaluate the therapeutic effect of RPS19-gene transfer, transduced (GT) and untransduced (Mock) CD34+ cells were cultured under conditions supporting erythroid and myeloid progenitor proliferation and differentiation. In order to obtain a comprehensive molecular characterization of the therapeutic mechanisms, cells from day 9 of culture were subjected to CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) analysis, a single-cell-multiomics method combining the advantages of FACS and scRNA-Seq for simultaneously analyzing transcriptomes alongside cell surface protein abundance at the single cell level. In GT cells, transduced (coRPS19-positive) cells were identified based on transgene expression. At day 9, 84-91% of erythroid progenitors in the GT-DBA samples expressed the coRPS19-transgene, while the frequency in myeloid progenitors was 29-56%. To reveal the molecular therapeutic effect of GT, we compared coRPS19-positive cells to Mock-treated cells from the same individuals. Expression of coRPS19 in DBA erythroid progenitor cells led to a significant induction of genes associated with terminal erythropoiesis (HEMGN, HBB, AHSP, EPB42 and GYPA) and down-regulation of genes associated with apoptosis and p53 activation (BAX, MDM2, ZMAT3 and MIR34AHG). GT also induced up-regulation of the large non-coding RNA LINC01133 and down-regulation of XACT. Interestingly, the two most-significantly changed genes in coRPS19-positive erythroid cells in all DBA samples were RPL22L1 and CD70. RPL22L1 is an RNA-binding component of the 60S ribosomal subunit that regulates pre-mRNA splicing but is not required for global cap-dependent translation. CD70 mRNA and protein exclusively expressed in erythroid progenitors in Mock-treated DBA samples and down-regulated in coRPS19-positive cells. CD70 is thus a new potential marker of DBA erythroid progenitor cells with a possible role in DBA pathogenesis. Myeloid progenitor DBA cells primarily responded to GT by up-regulation of ribosomal protein genes, suggesting RPS19-deficiency in myeloid progenitors leads to reduced ribosome biogenesis without the nucleolar stress observed in erythroid cells. To summarize, GT-induced changes in gene and protein expression agree with restoration of healthy ribosome biogenesis and elimination of nucleolar stress-induced p53 activation in erythroid progenitor cells responsible for the DBA phenotype, demonstrating molecular efficacy of CLIN-LV-EFS-coRPS19-PRE* supporting development for clinical gene therapy. In addition, the GT-induced reversal of RPS19-deficiency reveals several genes with potential relevance in DBA diagnostics and pathogenesis, such as RPL22L1 and CD70 for further investigation.

Effects of LINC00261 targeting miR-148a/WNT10b axis on the proliferation and apoptosis of colorectal cancer cells

ObjectiveColorectal cancer remains a significant challenge with high mortality rates. The aim of this study was to investigate the effect of targeting the microRNA-148a/WNT10b axis with the long non-coding RNA LINC00261 on the proliferation and apoptosis of colorectal cancer cells. MethodsIn vitro, small interfering RNA-LINC00261 and microRNA-148 inhibitor sequences were synthesized and transfected into SW480 cells. The study groups included a control group, small interfering RNA negative control group, small interfering RNA group, small interfering RNA negative control + microRNA -inhibitor group, small interfering RNA + microRNA -inhibitor group, and small interfering RNA + microRNA-negative control group. The transfection efficiency and expression levels of LINC00261 and miR-148a were evaluated by quantitative reverse transcription polymerase chain reaction. Cell proliferation, apoptosis, cell cycle distribution, and protein expression levels of WNT10b and β-catenin were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and Western blot, respectively. ResultsAfter small interfering RNA-LINC00261 transfection, a significant decrease in cell proliferation (p < 0.05) and an increase in apoptosis (p < 0.05) were observed, accompanied by cell cycle arrest in the G1 phase. Inhibition of LINC00261 by small interfering RNA resulted in increased microRNA-148a expression and decreased protein expression of WNT10b and β-catenin. However, the small interfering RNA + microRNA inhibitor group showed significantly increased levels of WNT10b and β-catenin protein expression. ConclusionsThese results suggest that silencing of long non-coding RNA LINC00261 could potentially affect the proliferation of SW480 cells by regulating the micro RNA -148a/WNT10b axis.

Retraction: ‘Long non-coding RNA LINC00346 contributes to cisplatin resistance in nasopharyngeal carcinoma by repressing miR-342-5p’ (2020), by Cui et al.

Retraction: ‘Long non-coding RNA LINC00346 contributes to cisplatin resistance in nasopharyngeal carcinoma by repressing miR-342-5p’ (2020), by Cui <i>et al.</i>

Retraction: 'Long non-coding RNA LINC00467 regulates hepatocellular carcinoma progression by modulating miR-9-5p/PPARA expression' (2019), by Cai et al.

Retraction: 'Long non-coding RNA LINC00467 regulates hepatocellular carcinoma progression by modulating miR-9-5p/PPARA expression' (2019), by Cai et al.

Expression of concern: 'Long non-coding RNA LINC00346 contributes to cisplatin resistance in nasopharyngeal carcinoma by repressing miR-342-5p' (2020), by Cui Z et al.

Expression of concern: 'Long non-coding RNA LINC00346 contributes to cisplatin resistance in nasopharyngeal carcinoma by repressing miR-342-5p' (2020), by Cui Z et al.

Expression of concern: 'Long non-coding RNA LINC00467 regulates hepatocellular carcinoma progression by modulating miR-9-5p/PPARA expression' (2019), by Cai K et al.

Expression of concern: 'Long non-coding RNA LINC00467 regulates hepatocellular carcinoma progression by modulating miR-9-5p/PPARA expression' (2019), by Cai K et al.

Upregulation of long non‑coding RNA LINC00460 in EGFR‑mutant lung cancer indicates a poor prognosis in patients treated with osimertinib.

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.

LINC00460 contributes to colorectal cancer cell invasion

ABSTRACT Research 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. Conclusion: 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.

LINC00525 promotes tumour growth and epithelial-mesenchymal transition as an oncogene in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumour in the oral cavity. OSCC is aggressive and prone to metastasis; it is associated with high mortality and short survival. In this study, we investigated the function of the long non-coding RNA LINC00525 in OSCC progression and the molecular mechanisms through in vitro and in vivo experiments. CCK8 assay was used to detect the effect of LINC00525 on cell viability; transwell migration and invasion assays and scratch assay were used to examine the role of LINC00525 in cell migration and invasion. Flow cytometry, RT-PCR and western blot were used to detect apoptosis indexes. Tumorigenic effects were investigated using mouse xenograft tumour models. LINC00525 was associated with OSCC survival and prognosis. LINC00525 knockdown decreased cell viability and epithelial-mesenchymal transition (EMT) properties and increased apoptosis and also shortened the cell cycle of OSCC cells in vitro. The downregulation of LINC00525 reduced the growth of OSCC tumour in vivo. LINC00525 can regulate OSCC cells via the apoptotic signalling pathway. Our results indicate that LINC00525 exhibits oncogenic functions in OSCC. LINC00525 may be a new promising and potential target for the treatment of OSCC.

Retraction: 'Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial-mesenchymal transition by regulating HIF-1α via miR-138'.

Open AccessMoreSectionsView PDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail Cite this article Cai Qiang, Wang Zhenqiang, Wang Shouhua, Weng Mingzhe, Zhou Di, Li Chen, Wang Jiandong, Chen Erzhen and Quan Zhiwei 2023Retraction: ‘Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial-mesenchymal transition by regulating HIF-1α via miR-138’Open Biol.13230036230036http://doi.org/10.1098/rsob.230036SectionOpen AccessRetractionRetraction: ‘Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial-mesenchymal transition by regulating HIF-1α via miR-138’ Qiang Cai Qiang Cai Google Scholar Find this author on PubMed Search for more papers by this author , Zhenqiang Wang Zhenqiang Wang Google Scholar Find this author on PubMed Search for more papers by this author , Shouhua Wang Shouhua Wang Google Scholar Find this author on PubMed Search for more papers by this author , Mingzhe Weng Mingzhe Weng Google Scholar Find this author on PubMed Search for more papers by this author , Di Zhou Di Zhou Google Scholar Find this author on PubMed Search for more papers by this author , Chen Li Chen Li Google Scholar Find this author on PubMed Search for more papers by this author , Jiandong Wang Jiandong Wang Google Scholar Find this author on PubMed Search for more papers by this author , Erzhen Chen Erzhen Chen Google Scholar Find this author on PubMed Search for more papers by this author and Zhiwei Quan Zhiwei Quan Google Scholar Find this author on PubMed Search for more papers by this author Qiang Cai Qiang Cai Google Scholar Find this author on PubMed Search for more papers by this author , Zhenqiang Wang Zhenqiang Wang Google Scholar Find this author on PubMed Search for more papers by this author , Shouhua Wang Shouhua Wang Google Scholar Find this author on PubMed Search for more papers by this author , Mingzhe Weng Mingzhe Weng Google Scholar Find this author on PubMed Search for more papers by this author , Di Zhou Di Zhou Google Scholar Find this author on PubMed Search for more papers by this author , Chen Li Chen Li Google Scholar Find this author on PubMed Search for more papers by this author , Jiandong Wang Jiandong Wang Google Scholar Find this author on PubMed Search for more papers by this author , Erzhen Chen Erzhen Chen Google Scholar Find this author on PubMed Search for more papers by this author and Zhiwei Quan Zhiwei Quan Google Scholar Find this author on PubMed Search for more papers by this author Published:10 February 2023https://doi.org/10.1098/rsob.230036This article retracts the followingResearch ArticleRETRACTED: Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial–mesenchymal transition by regulating HIF-1α via miR-138https://doi.org/10.1098/rsob.160247 Qiang Cai, Zhenqiang Wang, Shouhua Wang, Mingzhe Weng, Di Zhou, Chen Li, Jiandong Wang, Erzhen Chen and Zhiwei Quan volume 7issue 1Open Biology01 January 2017 Review history Review history is available via Web of Science at https://www.webofscience.com/api/gateway/wos/peer-review/10.1098/rsob.230036 Open Biol. 10, 20170247. (Published online 1 January 2017) (https://doi.org/10.1098/rsob.160247)Following an investigation, we have found that in figures 4, 5 and 6 of the manuscript, there appears to be multiple duplications, re-positioning and alterations to the western blot images. In further review of the images and the raw data supplied by the authors, we are unable to verify the conclusions of the paper or validity of the data.The image integrity standards and policies for the journal can be found here: https://royalsocietypublishing.org/doi/10.1098/rsob.200165.Prof. Jon Pines FRS Editor-in-Chief, Open BiologyOpen Biology Editorial Team Previous Article VIEW FULL TEXT DOWNLOAD PDF FiguresRelatedReferencesDetailsRelated articlesRETRACTED: Long non-coding RNA LINC00152 promotes gallbladder cancer metastasis and epithelial–mesenchymal transition by regulating HIF-1α via miR-13801 January 2017Open Biology This IssueFebruary 2023Volume 13Issue 2 Article InformationDOI:https://doi.org/10.1098/rsob.230036PubMed:36762718Published by:Royal SocietyOnline ISSN:2046-2441History: Manuscript received08/02/2023Manuscript accepted08/02/2023Published online10/02/2023 License:© 2023 The Authors.Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. Citations and impact Subjectsbiochemistry

Abstract A006: LINC00261 acts as a surrogate biomarker for tumor DNA mutational burden and immunotherapeutic response in lung adenocarcinoma

Abstract Defects in DNA repair allow for the age-dependent accumulation of mutations, which is significantly linked to the age-dependent increase in the development of neoplasia. Our lab has identified the long non-coding RNA LINC00261 as a critical activator of DNA damage signaling whose expression increases with age in normal lung tissue but is lost in the majority of Lung Adenocarcinomas (LUAD). We therefore undertook a mechanistic investigation on the relationship between LINC00261 function in lung and the accumulation of mutations by utilizing expression and mutational load data from The Cancer Genome Atlas, as well as in vitro mechanistic investigation into the functional relationship between LINC00261 and tumor mutational burden (TMB). Here we report (1) the observation of an age-dependent increase in LINC00261 expression in normal lung tissue within the TCGA adjacent non-tumor lung dataset; (2) a significant correlation between TMB and LINC00261 expression, where elevated LINC00261 levels are associated with decreased TMB; (3) LINC00261 effects on TMB were driven primarily by transition mutations, characteristic of defects in nucleotide excision repair. Standard of care treatment for disseminated LUAD often includes systemic platinum-based chemotherapies, including cisplatin, that act by inducing lethal levels of DNA damage. We observed that the presence of LINC00261 in LUAD causes cellular resistance to cisplatin-mediated DNA-damage in vitro. Our results suggest that patients with tumors expressing LINC00261 should be considered for non-platinum based therapeutic strategies. High mutational loads are also associated with the creation of neoantigens, allowing for immune recognition and when combined with PD-L1 expression levels can serve as an indicator for successful immunotherapy. Testing for PD-L1 expression is now standard of care, however exome sequencing to determine TMB is not often pursued outside academic medical centers due to expense, extensive bioinformatic involvement, and difficulty interpreting results. In addition, high levels of TMB does not always confer active neoantigen presentation as MHC Class II genes are often dysregulated in cancer. We therefore sought to determine if LINC00261 can function as a surrogate biomarker for TMB and provide complimentary indications to PD-L1 testing for successful immunotherapeutic response. Reintroduction of ectopic LINC00261 was able to activate expression of MHC Class II genes involved in neoantigen presentation. Conversely, Interferon gamma addition was able to induce endogenous expression of LINC00261 in vitro. Our results suggest there is a mechanistic relationship between LINC00261 expression and functional MHC Class II neoantigen presentation in LUAD. This was supported by observations that LINC00261 expression is significantly correlated to MHC Class II expression within TCGA LUAD cohort. Taken together, our results suggest LINC00261 shows promise as a biomarker of mutational burden and MHC Class II expression. Citation Format: Jonathan Castillo, Tianchun Xue, Mayela Norwood, Samantha Joseph, Crystal N. Marconett. LINC00261 acts as a surrogate biomarker for tumor DNA mutational burden and immunotherapeutic response in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A006.

The Role of Long Non-Coding RNA LINC00467 in Gastric Carcinoma: High Proliferation, Migration and Autophagy

The goal of this study is to investigate the role of long non-coding RNA LINC00467 in gastric carcinoma (GC) progression. Differential expressions of LINC00467 in GC samples were detected. By analyzing the follow-up data of recruited GC patients, the influence of LINC00467 on their prognosis was assessed. After knockdown of LINC00467 in SGC7901 and MKN45 cells, cell autophagy was examined by GFP-LC3 puncta assay and Western blot analyses on autophagy-associated genes. Additionally, cell growth and migration were assessed using cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), and transwell assays. The connection between LINC00467 and miR-18a-5p was studied through a luciferase assay and Pearson correlation analysis. Increased expression of LINC00467 was observed in GC samples and its elevated levels predicted a poor outcome for GC patients. The suppression of LINC00467 reduced the proliferative and migratory capacities of SGC7901 and MKN45 cells. LINC00467 level was closely linked to autophagy activity in GC. The level of miR-18a-5p was decreased in GC tissues and had an inverse correlation with LINC00467, which was established as the target of miR-18a-5p. Upregulated LINC00467 induces growth, metastasis and autophagy activity in GC through negatively regulating miR-18a-5p level, thus leading to the poor prognosis in GC patients.

Hypoxia-induced long non-coding RNA LINC00460 promotes p53 mediated proliferation and metastasis of pancreatic cancer by regulating the miR-4689/UBE2V1 axis and sequestering USP10.

Long non-coding RNAs are considered to be key regulatory factors of oncogenesis and tumor progression. It is reported that LINC00460 plays the role of oncogene in some tumors. However, LINC00460's role and mechanism of action in pancreatic cancer have not yet been fully elucidated. We identified LINC00460 by analyzing data from the Gene Expression Omnibus database. The role of LINC00460 in proliferation and metastasis was examined using CCK8, colony formation, wound healing, and transwell assays. The potential mechanisms of LINC00460 in regulating mRNA levels were elucidated by RNA pull-down, RNA immunoprecipitation, Chromatin immunoprecipitation, Co-immunoprecipitation, and Immunofluorescence assays. The results showed that LINC00460 was upregulated in pancreatic cancer cells and tissues. Highly expressed LINC00460 is significantly related to short survival of pancreatic cancer patients. Inhibition of LINC00460 attenuated pancreatic cancer cell proliferation and metastasis, whereas its overexpression reversed this effect. Mechanically, LINC00460 is induced by hypoxia, through binding of the hypoxia-inducible factor 1-α in the promoter region of LINC00460. Furthermore, LINC00460 functioned as an miR-4689 sponge to regulate the downstream target gene UBE2V1, enhancing the stability of mutant p53 in pancreatic cancer cells. LINC00460 also further promotes pancreatic cancer development by sequestering USP10, a cytoplasmic ubiquitin-specific protease that deubiquitinates p53 and enhances its stability. Collectively, our study demonstrated that LINC00460 is a hypoxia-induced lncRNA that plays the role of oncogene in pancreatic cancer by modulating the miR-4689/UBE2V1 axis, sequestering USP10, and ultimately enhancing the stability of mutant p53.