Identification of a prognostic ferroptosis-related lncRNA signature in the tumor microenvironment of lung adenocarcinoma

Ferroptosis is closely linked to various cancers, including lung adenocarcinoma (LUAD); however, the factors involved in the regulation of ferroptosis-related genes are not well established. In this study, we identified and characterized ferroptosis-related long noncoding RNAs (lncRNAs) in LUAD. In particular, a coexpression network of ferroptosis-related mRNAs and lncRNAs from The Cancer Genome Atlas (TCGA) was constructed. Univariate and multivariate Cox proportional hazards analyses were performed to establish a prognostic ferroptosis-related lncRNA signature (FerRLSig). We obtained a prognostic risk model consisting of 10 ferroptosis-related lncRNAs: AL606489.1, AC106047.1, LINC02081, AC090559.1, AC026355.1, FAM83A-AS1, AL034397.3, AC092171.5, AC010980.2, and AC123595.1. High risk scores according to the FerRLSig were significantly associated with poor overall survival (hazard ratio (HR) = 1.412, 95% CI = 1.271–1.568; P < 0.001). Receiver operating characteristic (ROC) curves and a principal component analysis further supported the accuracy of the model. Next, a prognostic nomogram combining FerRLSig with clinical features was established and showed favorable predictive efficacy for survival risk stratification. In addition, gene set enrichment analysis (GSEA) revealed that FerRLSig is involved in many malignancy-associated immunoregulatory pathways. Based on the risk model, we found that the immune status and response to immunotherapy, chemotherapy, and targeted therapy differed significantly between the high-risk and low-risk groups. These results offer novel insights into the pathogenesis of LUAD, including the contribution of ferroptosis-related lncRNAs, and reveal a prognostic indicator with the potential to inform immunological research and treatment.
Picture for Identification of a prognostic ferroptosis-related lncRNA signature in the tumor microenvironment of lung adenocarcinoma

Integrative analysis reveals the prognostic value and functions of splicing factors implicated in hepatocellular carcinoma

Splicing factors (SFs) play critical roles in the pathogenesis of various cancers through regulating tumor-associated alternative splicing (AS) events. However, the clinical value and biological functions of SFs in hepatocellular carcinoma (HCC) remain obscure. In this study, we identified 40 dysregulated SFs in HCC and established a prognostic model composed of four SFs (DNAJC6, ZC3H13, IGF2BP3, DDX19B). The predictive efficiency and independence of the prognostic model were confirmed to be satisfactory. Gene Set Enrichment Analysis (GSEA) illustrated the risk score calculated by our prognostic model was significantly associated with multiple cancer-related pathways and metabolic processes. Furthermore, we constructed the SFs-AS events regulatory network and extracted 108 protein-coding genes from the network for following functional explorations. Protein–protein interaction (PPI) network delineated the potential interactions among these 108 protein-coding genes. GO and KEGG pathway analyses investigated ontology gene sets and canonical pathways enriched by these 108 protein-coding genes. Overlapping the results of GSEA and KEGG, seven pathways were identified to be potential pathways regulated by our prognostic model through triggering aberrant AS events in HCC. In conclusion, the present study established an effective prognostic model based on SFs for HCC patients. Functional explorations of SFs and SFs-associated AS events provided directions to explore biological functions and mechanisms of SFs in HCC tumorigenesis.
Picture for Integrative analysis reveals the prognostic value and functions of splicing factors implicated in hepatocellular carcinoma

miR-4293 upregulates lncRNA WFDC21P by suppressing mRNA-decapping enzyme 2 to promote lung carcinoma proliferation

Non-coding RNAs (ncRNAs) involve in diverse biological processes by post-transcriptional regulation of gene expression. Emerging evidence shows that miRNA-4293 plays a significant role in the development of non-small cell lung cancer. However, the oncogenic functions of miR-4293 have not been studied. Our results demonstrated that miR-4293 expression is markedly enhanced in lung carcinoma tissue and cells. Moreover, miR-4293 promotes tumor cell proliferation and metastasis but suppresses apoptosis. Mechanistic investigations identified mRNA-decapping enzyme 2 (DCP2) as a target of miR-4293 and its expression is suppressed by miR-4293. DCP2 can directly or indirectly bind to WFDC21P and downregulates its expression. Consequently, miR-4293 can further promote WFDC21P expression by regulating DCP2. With a positive correlation to miR-4293 expression, WFDC21P also plays an oncogenic role in lung carcinoma. Furthermore, knockdown of WFDC21P results in functional attenuation of miR-4293 on tumor promotion. In vivo xenograft growth is also promoted by both miR-4293 and WFDC21P. Overall, our results establish oncogenic roles for both miR-4293 and WFDC21P and demonstrate that interactions between miRNAs and lncRNAs through DCP2 are important in the regulation of carcinoma pathogenesis. These results provided a valuable theoretical basis for the discovery of lung carcinoma therapeutic targets and diagnostic markers based on miR-4293 and WFDC21P.
Picture for miR-4293 upregulates lncRNA WFDC21P by suppressing mRNA-decapping enzyme 2 to promote lung carcinoma proliferation

LncRNA NEAT1 regulated diabetic retinal epithelial-mesenchymal transition through regulating miR-204/SOX4 axis

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

Coexpression network architecture reveals the brain-wide and multiregional basis of disease susceptibility

Gene networks have yielded numerous neurobiological insights, yet an integrated view across brain regions is lacking. We leverage RNA sequencing in 864 samples representing 12 brain regions to robustly identify 12 brain-wide, 50 cross-regional and 114 region-specific coexpression modules. Nearly 40% of genes fall into brain-wide modules, while 25% comprise region-specific modules reflecting regional biology, such as oxytocin signaling in the hypothalamus, or addiction pathways in the nucleus accumbens. Schizophrenia and autism genetic risk are enriched in brain-wide and multiregional modules, indicative of broad impact; these modules implicate neuronal proliferation and activity-dependent processes, including endocytosis and splicing, in disease pathophysiology. We find that cell-type-specific long noncoding RNA and gene isoforms contribute substantially to regional synaptic diversity and that constrained, mutation-intolerant genes are primarily enriched in neurons. We leverage these data using an omnigenic-inspired network framework to characterize how coexpression and gene regulatory networks reflect neuropsychiatric disease risk, supporting polygenic models.

Deep-Learning Method Helps Predict Sequencing Depth From DNA Probes

CHICAGO – Researchers from NuProbe, Rice University, and Microsoft Research UK have developed a novel deep-learning method to predict DNA sequencing depth from the sequence of DNA probes with up to 99 percent accuracy. The researchers developed the predictive computational method, described in a paper published this week in Nature...

Table of Contents - Volume 12, Issue 15

View the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 15. https://www.oncotarget.com/archive/v12/i15/ Cover Paper - “Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells” https://doi.org/10.18632/oncotarget.28020 Research Paper - “RNA expression differences in prostate tumors and tumor-adjacent stroma between Black and White Americans” https://doi.org/10.18632/oncotarget.28024 Research Paper - “Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis” https://doi.org/10.18632/oncotarget.28011 Research Paper - “The impact of neoadjuvant concurrent chemoradiation on exosomal markers (CD63 and CD9) expression and their prognostic significance in patients with rectal adenocarcinoma” https://doi.org/10.18632/oncotarget.28025 Research Paper - “Identification of miR-203a, mir-10a, and miR-194 as predictors for risk of lymphovascular invasion in head and neck cancers” https://doi.org/10.18632/oncotarget.28022 Research Paper - “JunD accentuates arecoline-induced disruption of tight junctions and promotes epithelial-to-mesenchymal transition by association with NEAT1 lncRNA” https://doi.org/10.18632/oncotarget.28026 Research Paper - “Actionability evaluation of biliary tract cancer by genome transcriptome analysis and Asian cancer knowledgebase” https://doi.org/10.18632/oncotarget.28021 Editorial - “Multidisciplinary clinics in prostate cancer” https://doi.org/10.18632/oncotarget.27984 (PDF Download) Research Perspective - “Developing next generation immunomodulatory drugs and their combinations in multiple myeloma” https://doi.org/10.18632/oncotarget.27973 Keywords - chromosome instability, prostate cancer, sulforaphane, exosomes, head neck cancer, miRNA, arecoline, biliary tract cancer, multiple myeloma, cancer, science, research, oncology About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com/ or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/oncotargetyoutube Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget Oncotarget is published by Impact Journals, LLC. Please visit https://www.impactjournals.com/ or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957.

Curcumin attenuates Adriamycin-resistance of acute myeloid leukemia by inhibiting the lncRNA HOTAIR/miR-20a-5p/WT1 axis

Acute myeloid leukemia (AML) is a common subtype of leukemia, and a large proportion of patients with AML eventually develop drug resistance. Curcumin exerts cancer suppressive effects and increases sensitivity to chemotherapy in several diseases. This study aimed to investigate the mechanism by which curcumin affects the resistance of AML to Adriamycin by regulating HOX transcript antisense RNA (HOTAIR) expression. Cell viability, colony-formation, flow cytometry, and Transwell assays were used to assess cell proliferation, apoptosis, and migration. A dual-luciferase reporter assay was used to verify the interaction between microRNA (miR)-20a-5p and HOTAIR or Wilms’ tumor 1 (WT1). RT-qPCR and Western blotting assays were performed to detect gene and protein expression. The results showed that curcumin suppressed the resistance to Adriamycin, inhibited the expression of HOTAIR and WT1, and promoted the expression of miR-20a-5p in human acute leukemia cells (HL-60) or Adriamycin-resistant HL-60 cells (HL-60/ADR). Furthermore, curcumin suppressed proliferation and promoted apoptosis of HL-60/ADR cells. Overexpression of HOTAIR reversed the regulatory effect of curcumin on apoptosis and migration and restored the effect of curcumin on inducing the expression of cleaved caspase3, Bax, and P27. In addition, HOTAIR upregulated WT1 expression by targeting miR-20a-5p, and inhibition of miR-20a-5p reversed the regulation of Adriamycin resistance by curcumin in AML cells. Finally, curcumin inhibited Adriamycin resistance by suppressing the HOTAIR/miR-20a-5p/WT1 pathway in vivo. In short, curcumin suppressed the proliferation and migration, blocked the cell cycle progression of AML cells, and sensitized AML cells to Adriamycin by regulating the HOTAIR/miR-20a-5p/WT1 axis. These findings suggest a potential role of curcumin and HOTAIR in AML treatment.

A phosphatidic acid-binding lncRNA SNHG9 facilitates LATS1 liquid–liquid phase separation to promote oncogenic YAP signaling

Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid–liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).

The long noncoding RNA HOTAIRM1 controlled by AML1 enhances glucocorticoid resistance by activating RHOA/ROCK1 pathway through suppressing ARHGAP18

Acquired resistance to glucocorticoids (GCs) is an obstacle to the effective treatment of leukemia, but the molecular mechanisms of steroid insensitivity have not been fully elucidated. In this study, we established an acquired GC-resistant leukemia cell model and found a long noncoding RNA, HOTAIRM1, was overexpressed in the resistant cells by transcriptional profiling, and was higher expressed in patients with poor prognosis. The whole-genome-binding sites of HOTAIRM1 were determined by ChIRP-seq (chromatin isolation by RNA purification combined with sequencing) analysis. Further study determined that HOTAIRM1 bound to the transcriptional inhibitory region of ARHGAP18 and repressed the expression of ARHGAP18, which led to the increase of RHOA/ROCK1 signaling pathway and promoted GC resistance through antiapoptosis of leukemia cells. The inhibition of ROCK1 in GC-resistant cells could restore GCs responsiveness. In addition, HOTAIRM1 could also act as a protein sequester to prevent transcription factor AML1(acute myeloid leukemia 1) from binding to the regulatory region of ARHGAP18 by interacting with AML1. At last, we also proved AML1 could directly activate the expression of HOTAIRM1 through binding to the promoter of HOTAIRM1, which enriched the knowledge on the regulation of lncRNAs. This study revealed epigenetic causes of glucocorticoid resistance from the perspective of lncRNA, and laid a foundation for the optimization of glucocorticoid-based leukemia treatment strategy in clinic.

Chasing RNA and its Secrets About Diseases

To say that a scientist is carrying out “cutting edge research” may be a cliché. But for Xiangbo Ruan, Ph.D., newly arrived at Johns Hopkins All Children’s Hospital in St. Petersburg, Florida, and an assistant professor in the Division of Endocrinology, Diabetes and Metabolism, “cutting edge” is a true and accurate assessment of his research. To unravel secrets of ribonucleic acid (RNA), present in all living cells, Ruan is using high-tech methods to “slice and dice” strands of RNA at the molecular level to better understand how RNA modifications affect human organs and potentially cause disease.

Oncotarget: LAPAS1 is required for S phase progression and cell proliferation

Oncotarget published "A novel E2F1-regulated lncRNA, LAPAS1, is required for S phase progression and cell proliferation" which reported that long non-coding RNAs are major regulators of many cellular processes, including cell cycle progression and cell proliferation. Inhibition of LAPAS1 expression increases the percentage of S phase cells, and its silencing...

Researchers Investigate Link between LncRNA MORT (ZNF667-AS1) and Gynecological Cancer

Newswise — Long non‑coding RNAs (lncRNAs) play a critical role in tumorigenesis. LncRNAs can beclassified into tumor suppressor genes or oncogenes, depending on their function within the cellular context and the signalling pathways in which they are involved. These regulatory RNAs are potential therapeutic targets for cancer due to their tissue and tumor specificity.

PNAS Papers on Inflammatory Bowel Disease Telomeres, Mosquito MicroRNAs, More

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted this week. An MD Anderson Cancer Center-led team describes a role for altered telomere function in inflammatory bowel disease-related inflammation. Following from prior intestinal epithelium findings in a mouse model of IBD, the researchers used a fluorescence in situ hybridization assay, RNA sequencing, and other approaches to look at the consequences of telomere dysfunction in intestinal biopsy samples from individuals with older-onset IBD and in organoid models of Crohn's disease or ulcerative colitis. Their results point to inflammatory activation in the presence of telomere dysfunction via enhanced expression of an IBD driver called precursor of interleukin 19 (pro-IL-18), which is part of a pathway with ATM and YAP1. "In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production," the authors report, noting that such data "support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease."

Identification of a seven-long non-coding RNA signature associated with Jab1/CSN5 in predicting hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, accounting for over 700,000 deaths each year. The lack of predictive and prognostic biomarkers for HCC, with effective therapy, remains a significant challenge for HCC management. Long non-coding RNAs (lncRNAs) play a key role in tumorigenesis and have clinical value as potential biomarkers in the early diagnosis and prediction of HCC. Jun activation domain-binding protein 1 (Jab1, also known as COP9 signalosome subunit 5, CSN5) is a potential oncogene that plays a critical role in the occurrence of HCC. Here, we performed a comprehensive analysis for Jab1/CSN5-associated lncRNAs to predict the prognosis of HCC. The differentially expressed (DE) lncRNAs between in HCC were analyzed based on the TCGA RNA-seq data. We detected 1031 upregulated lncRNAs in 371 HCC tissues and identified a seven-lncRNA signature strongly correlated with Jab1/CSN5 (SNHG6, CTD3065J16.9, LINC01604, CTD3025N20.3, KB-1460A1.5, RP13-582O9.7, and RP11-29520.2). We further evaluated the prognostic significance of these lncRNAs by GEPIA (http://gepia.cancer-pku.cn/). The expression data in 364 liver tumors indicated that this seven-lncRNA signature could better predict worse survival in HCC patients. Moreover, 35 clinical HCC samples were evaluated to assess the validity and reproducibility of the bioinformatic analysis. We found that the targeted lncRNAs were upregulated, with a strong association with Jab1/CSN5 and prognostic value in HCC. Functional enrichment analysis by Gene Ontology (GO) showed that these seven prognostic lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer. Overall, our findings demonstrate the clinical implication of Jab1/CSN5 with the seven‐lncRNAs in predicting survival for patients with HCC.

LncRNA RCAT1 promotes tumor progression and metastasis via miR-214-5p/E2F2 axis in renal cell carcinoma

Renal cell carcinoma is the second malignant tumors in the urinary system with high mortality and morbidity. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in tumor development and progression. In the current study, based on the publicly available data obtained from GEO and TCGA database, we identified five prognosis-related lncRNAs with the ability to predict the prognosis of patients with renal cell carcinoma. Among them, the uncharacterized and upregulated lncRNA RCAT1 (renal cancer-associated transcript 1) was identified as the key lncRNA. Our data further revealed that the expression of lncRNA RCAT1 was significantly upregulated in renal cell carcinoma tissues and cells. Gain-of-function and loss-of-function studies showed that lncRNA RCAT1 promoted cell proliferation, migration, and invasion in vitro and in vivo. Furthermore, we verified that lncRNA RCAT1 could abundantly sponge miR-214-5p, which served as a tumor suppressor in renal cell carcinoma. Significantly, miR-214-5p overexpression could attenuate the promotion of cell proliferation and metastasis induced by lncRNA RCAT1. Moreover, we found that E2F2 was a direct target of miR-214-5p, and lncRNA RCAT1 could protect E2F2 from miR-214-5p-mediated degradation. Taken together, our findings suggested that lncRNA RCAT1 could enhance the malignant phenotype of renal cell carcinoma cells by modulating miR‐214‐5p/E2F2 axis, and lncRNA RCAT1 might be a novel prognostic biomarker and a potential therapeutic target for renal cell carcinoma.

Junk No Longer: ERVs Are “Integral” and “Important Components” of Immune Responses

Viruses and immunity are hot topics these days, and a new article in the Journal of Virology, “Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections,” has the potential to be a paradigm-shifter on the standard view that endogenous retroviruses (ERVs) are junk DNA. Consider this first line from the abstract. Though the authors are certainly not supportive of intelligent design, (ID), it’s another example of a line from a paper that sounds like it could have been written by a proponent of ID: