Long noncoding RNA Meg3 sponges miR-708 to inhibit intestinal tumorigenesis via SOCS3-repressed cancer stem cells growth

Abstract Background Colorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNA Meg3, which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by which Meg3 contributes to the malignant proliferation of colonic stem cells remains unclear. Methods We analyzed the expression levels of Meg3, miR-708, and SOCS3 in samples from Apc loss-of-function (Apcmin) mice and patients with CRC, particularly in colonic crypt cells. Apcmin mice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of the Meg3/miR-708/SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines. Findings The Meg3/miR-708/SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showed Meg3 levels negatively correlate with miR-708 levels both in clinical samples and in the Apcmin mouse model, which indicated that Meg3 acts as a competitive endogenous RNA (ceRNA) of miR-708. Then, miR-708 served as an oncogene, inducing neoplasia in both Apcmin mice and cultured colonic organoids. Put together, miR-708 appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling. Interpretation These data revealed that Meg3 sponges miR-708 to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. The Meg3/miR-708/SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.

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LncRNA GAPLINC Promotes Renal Cell Cancer Tumorigenesis by Targeting the miR-135b-5p/CSF1 Axis

Frontiers in Oncology ◽

10.3389/fonc.2021.718532 ◽

2021 ◽

Vol 11 ◽

Author(s):

Siyuan Wang ◽

Xiaorong Yang ◽

Wenjie Xie ◽

Shengqiang Fu ◽

Qiang Chen ◽

...

Keyword(s):

Renal Cell ◽

Noncoding Rna ◽

Cell Cancer ◽

Luciferase Reporter ◽

Loss Of Function ◽

Long Intergenic Noncoding Rna ◽

And Migration ◽

Molecular Therapeutic

BackgroundLong noncoding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Gastric adenocarcinoma-associated, positive CD44 regulator, long intergenic noncoding RNA (GAPLINC) is a recently identified lncRNA that can actively participate in the tumorigenesis of various cancers. Here, we investigated the functional roles and mechanism of GAPLINC in renal cell carcinoma (RCC) development.MethodsDifferentially expressed lncRNAs between RCC tissues and normal kidney tissues were detected by using a microarray technique. RNA sequencing was applied to explore the mRNA expression profile changes after GAPLINC silencing. After gain- and loss-of-function approaches were implemented, the effect of GAPLINC on RCC in vitro and in vivo was assessed by cell proliferation and migration assays. Moreover, rescue experiments and luciferase reporter assays were used to study the interactions between GAPLINC, miR-135b-5p and CSF1.ResultsGAPLINC was significantly upregulated in RCC tissues and cell lines and was associated with a poor prognosis in RCC patients. Knockdown of GAPLINC repressed RCC growth in vitro and in vivo, while overexpression of GAPLINC exhibited the opposite effect. Mechanistically, we found that GAPLINC upregulates oncogene CSF1 expression by acting as a sponge of miR-135b-5p.ConclusionTaken together, our results suggest that GAPLINC is a novel prognostic marker and molecular therapeutic target for RCC.

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Long non-coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis

Cancer Cell International ◽

10.1186/s12935-019-1093-6 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 9

Author(s):

Qun Dai ◽

Jingyi Deng ◽

Jinrong Zhou ◽

Zhuhong Wang ◽

Xiao-feng Yuan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Noncoding Rna ◽

Critical Role ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Marked Rise ◽

Hcc Cells

Abstract Background Accumulating evidence indicates that the long noncoding RNA taurine upregulated gene 1(TUG1) plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of TUG1 in hepatocellular carcinoma (HCC) remain largely unknown. Methods The expressions of TUG1, microRNA-216b-5p and distal-less homeobox 2 (DLX2) were detected by Quantitative real-time polymerase chain reaction (qRT-PCR). The target relationships were predicted by StarBase v.2.0 or TargetScan and confirmed by dual-luciferase reporter assay. The cell growth, apoptosis, migration and invasion were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow cytometry and Transwell assays, respectively. All protein expression levels were detected by western blot. Tumor xenografts were implemented to explore the role of TUG1 in vivo. Results We found that there was a marked rise in TUG1 expression in HCC tissues and cells, and knockdown of TUG1 repressed the growth and metastasis and promoted apoptosis of HCC cells. In particular, TUG1 could act as a ceRNA, effectively becoming a sink for miR-216b-5p to fortify the expression of DLX2. Additionally, repression of TUG1 impared the progression of HCC cells by inhibiting DLX2 expression via sponging miR-216b-5p in vitro. More importantly, TUG1 knockdown inhibited HCC tumor growth in vivo through upregulating miR-216b-5p via inactivation of the DLX2. Conclusion TUG1 interacting with miR-216b-5p contributed to proliferation, metastasis, tumorigenesis and retarded apoptosis by activation of DLX2 in HCC.

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Mesenchymal stem cell-derived exosomal microRNA-136-5p inhibits chondrocyte degeneration in traumatic osteoarthritis by targeting ELF3

Arthritis Research & Therapy ◽

10.1186/s13075-020-02325-6 ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Xue Chen ◽

Yuanyuan Shi ◽

Pan Xue ◽

Xinli Ma ◽

Junfeng Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mouse Model ◽

Cartilage Degeneration ◽

Clinical Samples ◽

Loss Of Function ◽

Post Traumatic ◽

Chondrocyte Migration

Abstract Background Emerging evidence suggests that microRNAs (miRs) are associated with the progression of osteoarthritis (OA). In this study, the role of exosomal miR-136-5p derived from mesenchymal stem cells (MSCs) in OA progression is investigated and the potential therapeutic mechanism explored. Methods Bone marrow mesenchymal stem cells (BMMSCs) and their exosomes were isolated from patients and identified. The endocytosis of chondrocytes and the effects of exosome miR-136-5p on cartilage degradation were observed and examined by immunofluorescence and cartilage staining. Then, the targeting relationship between miR-136-5p and E74-like factor 3 (ELF3) was analyzed by dual-luciferase report assay. Based on gain- or loss-of-function experiments, the effects of exosomes and exosomal miR-136-5p on chondrocyte migration were examined by EdU and Transwell assay. Finally, a mouse model of post-traumatic OA was developed to evaluate effects of miR-136-5p on chondrocyte degeneration in vivo. Results In the clinical samples of traumatic OA cartilage tissues, we detected increased ELF3 expression, and reduced miR-136-5p expression was determined. The BMMSC-derived exosomes showed an enriched level of miR-136-5p, which could be internalized by chondrocytes. The migration of chondrocyte was promoted by miR-136-5p, while collagen II, aggrecan, and SOX9 expression was increased and MMP-13 expression was reduced. miR-136-5p was verified to target ELF3 and could downregulate its expression. Moreover, the expression of ELF3 was reduced in chondrocytes after internalization of exosomes. In the mouse model of post-traumatic OA, exosomal miR-136-5p was found to reduce the degeneration of cartilage extracellular matrix. Conclusion These data provide evidence that BMMSC-derived exosomal miR-136-5p could promote chondrocyte migration in vitro and inhibit cartilage degeneration in vivo, thereby inhibiting OA pathology, which highlighted the transfer of exosomal miR-136-5p as a promising therapeutic strategy for patients with OA.

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The E3 Ubiquitin Ligase NEDD4-1 Mediates Temozolomide-Resistant Glioblastoma through PTEN Attenuation and Redox Imbalance in Nrf2–HO-1 Axis

International Journal of Molecular Sciences ◽

10.3390/ijms221910247 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10247

Author(s):

Hao-Yu Chuang ◽

Li-Yun Hsu ◽

Chih-Ming Pan ◽

Narpati Wesa Pikatan ◽

Vijesh Kumar Yadav ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Lines ◽

Biological Effects ◽

Critical Role ◽

Clinical Samples ◽

Redox Imbalance ◽

Signaling Axis ◽

Resistant Cells

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is highly resistant to chemotherapy, and tumor recurrence is common. Neuronal precursor cell-expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ligase that controls embryonic development and animal growth. NEDD4-1 regulates the tumor suppressor phosphatase and tensin homolog (PTEN), one of the major regulators of the PI3K/AKT/mTOR signaling axis, as well as the response to oxidative stress. Methods: The expression levels of NEDD4-1 in GBM tissues and different cell lines were determined by quantitative real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo assays were performed to explore the biological effects of NEDD4-1 on GBM cells. Temozolomide (TMZ)-resistant U87MG and U251 cell lines were specifically established to determine NEDD4-1 upregulation and its effects on the tumorigenicity of GBM cells. Subsequently, miRNA expression in TMZ-resistant cell lines was investigated to determine the dysregulated miRNA underlying the overexpression of NEDD4-1. Indole-3-carbinol (I3C) was used to inhibit NEDD4-1 activity, and its effect on chemoresistance to TMZ was verified. Results: NEDD4-1 was significantly overexpressed in the GBM and TMZ-resistant cells and clinical samples. NEDD4-1 was demonstrated to be a key oncoprotein associated with TMZ resistance, inducing oncogenicity and tumorigenesis of TMZ-resistant GBM cells compared with TMZ-responsive cells. Mechanistically, TMZ-resistant cells exhibited dysregulated expression of miR-3129-5p and miR-199b-3p, resulting in the induced NEDD4-1 mRNA-expression level. The upregulation of NEDD4-1 attenuated PTEN expression and promoted the AKT/NRF2/HO-1 oxidative stress signaling axis, which in turn conferred amplified defense against reactive oxygen species (ROS) and eventually higher resistance against TMZ treatment. The combination treatment of I3C, a known inhibitor of NEDD4-1, with TMZ resulted in a synergistic effect and re-sensitized TMZ-resistant tumor cells both in vitro and in vivo. Conclusions: These findings demonstrate the critical role of NEDD4-1 in regulating the redox imbalance in TMZ-resistant GBM cells via the degradation of PTEN and the upregulation of the AKT/NRF2/HO-1 signaling pathway. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.

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Long non-coding RNA NORAD promotes pancreatic cancer stem cell proliferation and self-renewal by blocking microRNA-202-5p-mediated ANP32E inhibition

Journal of Translational Medicine ◽

10.1186/s12967-021-03052-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yu-Shui Ma ◽

Xiao-Li Yang ◽

Yu-Shan Liu ◽

Hua Ding ◽

Jian-Jun Wu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cell Viability ◽

Luciferase Reporter ◽

Cell Cycle Distribution ◽

Loss Of Function ◽

Self Renewal

Abstract Background Cancer stem cells (CSCs) are key regulators in the processes of tumor initiation, progression, and recurrence. The mechanism that maintains their stemness remains enigmatic, although the role of several long noncoding RNAs (lncRNAs) has been highlighted in the pancreatic cancer stem cells (PCSCs). In this study, we first established that PCSCs overexpressing lncRNA NORAD, and then investigated the effects of NORAD on the maintenance of PCSC stemness. Methods Expression of lncRNA NORAD, miR-202-5p and ANP32E in PC tissues and cell lines was quantified after RNA isolation. Dual-luciferase reporter assay, RNA pull-down and RIP assays were performed to verify the interactions among NORAD, miR-202-5p and ANP32E. We then carried out gain- and loss-of function of miR-202-5p, ANP32E and NORAD in PANC-1 cell line, followed by measurement of the aldehyde dehydrogenase activity, cell viability, apoptosis, cell cycle distribution, colony formation, self-renewal ability and tumorigenicity of PC cells. Results LncRNA NORAD and ANP32E were upregulated in PC tissues and cells, whereas the miR-202-5p level was down-regulated. LncRNA NORAD competitively bound to miR-202-5p, and promoted the expression of the miR-202-5p target gene ANP32E thereby promoting PC cell viability, proliferation, and self-renewal ability in vitro, as well as facilitating tumorigenesis of PCSCs in vivo. Conclusion Overall, lncRNA NORAD upregulates ANP32E expression by competitively binding to miR-202-5, which accelerates the proliferation and self-renewal of PCSCs.

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miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy

Gut ◽

10.1136/gutjnl-2019-318830 ◽

2019 ◽

Vol 69 (7) ◽

pp. 1309-1321 ◽

Cited By ~ 9

Author(s):

Wen-Ping Xu ◽

Jin-Pei Liu ◽

Ji-Feng Feng ◽

Chang-Peng Zhu ◽

Yuan Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Critical Role ◽

Luciferase Reporter ◽

Loss Of Function ◽

Sorafenib Treatment ◽

Transmission Electron ◽

Reporter Assays ◽

Hcc Cells

ObjectiveAutophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis.DesignGain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality.ResultsThe expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment.ConclusionsDysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients’ responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

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Single-Cell Profiling of Coding and Noncoding Genes in Human Dopamine Neuron Differentiation

Cells ◽

10.3390/cells10010137 ◽

2021 ◽

Vol 10 (1) ◽

pp. 137

Author(s):

Fredrik Nilsson ◽

Petter Storm ◽

Edoardo Sozzi ◽

David Hidalgo Gil ◽

Marcella Birtele ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Single Cell ◽

Noncoding Rna ◽

Early Stage ◽

Cell Type ◽

Cell Type Specificity ◽

Neuron Differentiation ◽

Cell Therapies

Dopaminergic (DA) neurons derived from human pluripotent stem cells (hPSCs) represent a renewable and available source of cells useful for understanding development, developing disease models, and stem-cell therapies for Parkinson’s disease (PD). To assess the utility of stem cell cultures as an in vitro model system of human DA neurogenesis, we performed high-throughput transcriptional profiling of ~20,000 ventral midbrain (VM)-patterned stem cells at different stages of maturation using droplet-based single-cell RNA sequencing (scRNAseq). Using this dataset, we defined the cellular composition of human VM cultures at different timepoints and found high purity DA progenitor formation at an early stage of differentiation. DA neurons sharing similar molecular identities to those found in authentic DA neurons derived from human fetal VM were the major cell type after two months in culture. We also developed a bioinformatic pipeline that provided a comprehensive long noncoding RNA landscape based on temporal and cell-type specificity, which may contribute to unraveling the intricate regulatory network of coding and noncoding genes in DA neuron differentiation. Our findings serve as a valuable resource to elucidate the molecular steps of development, maturation, and function of human DA neurons, and to identify novel candidate coding and noncoding genes driving specification of progenitors into functionally mature DA neurons.

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Hypoxia preconditioning promotes mesenchymal stem cells survival and vascularization through the activation of MALAT1/miR-195/VEGFA axis

10.21203/rs.3.rs-17014/v1 ◽

2020 ◽

Author(s):

Jingying Hou ◽

Lingyun Wang ◽

Zhengfei Yang ◽

Guanghui Zheng ◽

Tianzhu Guo ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Noncoding Rna ◽

Underlying Mechanism ◽

Luciferase Reporter ◽

Angiogenic Potential ◽

Hypoxia Exposure ◽

Hypoxia Preconditioning ◽

Endothelial Growth Factor

Abstract Background: Previous studies have demonstrated that hypoxia preconditioning (HP) can promote mesenchymal stem cells (MSCs) survival and vascularization. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a newly discovered regulator of MSCs viability and differentiation. Evidences have indicated that MALAT1 can be strongly induced by hypoxia. This study aimed to investigate the role of MALAT1 in HP mediated MSCs survival and vascularization as well as the relevant underlying mechanism in vitro.Methods: MSCs were obtained from C57BL/6 mice and cultured in vitro. Cells at the third passage were divided into the following groups: normoxia (N), hypoxia preconditioning (HP), HP + MALAT1, HP + MALAT1 NC, HP+si-MALAT1 and HP +si-MALAT1 NC. The normoxia group was cultured in 20% O2 for 24 h. All the other groups were exposed to hypoxia (1% O2) for 24 hours. MALAT1 and relevant scramble RNA were transfected in the HP+MALAT1 and HP+MALAT1 NC groups respectively. HP+si-MALAT1 and HP +si-MALAT1 NC groups were transfected with MALAT1 siRNA and relevant siRNA scramble respectively. MSCs proliferation, apoptosis and vascular densities were evaluated. Bioinformatics and dual luciferase reporter assay were performed. Relevant biomarkers were examined in different experimental groups.Results: MSCs survival and vascularization were significantly enhanced in the HP group. Transfection of MALAT1 further strengthened the viability and angiogenic potential of MSCs in the condition of HP, whereas its knockdown attenuated cells survival and vascularization. MALAT1 and vascular endothelial growth factor A (VEGFA) were obviously increased after hypoxia exposure, while miR-195 was decreased. miR-195 targeted and downregulated VEGFA. miR-195 was a target of MALAT1. Overexpression of MALAT1 led to a decreased level of miR-195, accompanied with an augmented expression of VEGFA. However, both miR-195 and VEGFA exhibited contrary alterations after MALAT1 blockage. Conclusion: HP enhanced MSCs survival and vascularization potential in vitro, and the activation of MALAT1/miR-195/VEGFA axis might be involved in this procedure. This study reveals a new molecular mechanism of HP mediated MSCs survival and vascularization. It will be conducive for the development of novel strategies to improve the therapeutic efficiency of MSCs based on HP.

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Salinomycin inhibits epigenetic modulator EZH2 to enhance Death Receptors in Colon Cancer Stem Cells

10.1101/2020.02.03.932269 ◽

2020 ◽

Author(s):

Anup Kumar Singh ◽

Ayushi Verma ◽

Akhilesh Singh ◽

Rakesh Kumar Arya ◽

Shrankhla Maheshwari ◽

...

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Critical Role ◽

Death Receptors ◽

Clinical Samples ◽

Human Colon Cancer

AbstractDrug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumor cells is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotype such as spheroid formation in-vitro and tumorigenic potential in-vivo in colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.

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A novel lncRNA ROPM-mediated lipid metabolism governs breast cancer stem cell properties

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01194-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Shuiqing Liu ◽

Yan Sun ◽

Yixuan Hou ◽

Liping Yang ◽

Xueying Wan ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Phospholipid Metabolism ◽

Luciferase Reporter ◽

Breast Cancer Patients ◽

Loss Of Function ◽

Gain And Loss

Abstract Background Cancer stem cells (CSCs) are considered as the major cause to tumor initiation, recurrence, metastasis, and drug resistance, driving poor clinical outcomes in patients. Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cancer development and progression. However, limited lncRNAs involved in CSCs have been reported. Methods The novel lncROPM (a regulator of phospholipid metabolism) in breast CSCs (BCSCs) was identified by microarray and validated by qRT-PCR in BCSCs from breast cancer cells and tissues. The clinical significance of lncROPM was evaluated in two breast cancer cohorts and TANRIC database (TCGA-BRCA, RNAseq data). Gain- and loss-of-function assays were performed to examine the role of lncROPM on BCSCs both in vitro and in vivo. The regulatory mechanism of lncROPM was investigated by bioinformatics, RNA FISH, RNA pull-down, luciferase reporter assay, and actinomycin D treatment. PLA2G16-mediated phospholipid metabolism was determined by UHPLC-QTOFMS system. Cells’ chemosensitivity was assessed by CCK8 assay. Results LncROPM is highly expressed in BCSCs. The enhanced lncROPM exists in clinic breast tumors and other solid tumors and positively correlates with malignant grade/stage and poor prognosis in breast cancer patients. Gain- and loss-of-function studies show that lncROPM is required for the maintenance of BCSCs properties both in vitro and in vivo. Mechanistically, lncROPM regulates PLA2G16 expression by directly binding to 3'-UTR of PLA2G16 to increase the mRNA stability. The increased PLA2G16 significantly promotes phospholipid metabolism and the production of free fatty acid, especially arachidonic acid in BCSCs, thereby activating PI3K/AKT, Wnt/β-catenin, and Hippo/YAP signaling, thus eventually involving in the maintenance of BCSCs stemness. Importantly, lncROPM and PLA2G16 notably contribute to BCSCs chemo-resistance. Administration of BCSCs using clinic therapeutic drugs such as doxorubicin, cisplatin, or tamoxifen combined with Giripladib (an inhibitor of cytoplasmic phospholipase A2) can efficiently eliminate BCSCs and tumorigenesis. Conclusions Our study highlights that lncROPM and its target PLA2G16 play crucial roles in sustaining BCSC properties and may serve as a biomarker for BCSCs or other cancer stem cells. Targeting lncROPM-PLA2G16 signaling axis may be a novel therapeutic strategy for patients with breast cancer.

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