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1.
《Molecular oncology》2021,15(1):43
Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next‐generation sequencing (NGS)‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods were compared using 72 plasma samples, from EGFR‐mutant non‐small‐cell lung cancer (NSCLC) patients progressing on a first‐line tyrosine kinase inhibitor (TKI). NGS platforms as well as high‐sensitivity PCR‐based methodologies showed excellent agreement for EGFR‐sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false‐positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.
Abbreviations
- BEAMing
- beads, emulsion, amplification, and magnetics
- cfDNA
- circulating free DNA, cell‐free DNA
- cobas
- cobas® EGFR Mutation Test v2 (Roche Diagnostics)
- ctDNA
- circulating tumor DNA
- CUSUM
- cumulative sum
- ddPCR
- droplet digital polymerase chain reaction
- dPCR
- digital polymerase chain reaction
- EGFR
- epidermal growth factor receptor
- FFPE
- formalin‐fixed, paraffin‐embedded
- ICC
- intraclass correlation coefficient
- MAF
- mutant allele frequency
- NGS platforms
- Ion S5™ XL and GeneRead™
- NGS
- next‐generation sequencing
- NSCLC
- non‐small‐cell lung cancer
- PNA‐Q‐PCR
- peptic nucleic acid probe‐based real‐time polymerase chain reaction
- Therascreen
- Therascreen EGFR Plasma RGQ PCR Kit (QIAgen)
- TKI
- tyrosine kinase inhibitor
2.
Joan Frigola Alejandro Navarro Caterina Carbonell Ana Callejo Patricia Iranzo Susana Cedrs Alex MartinezMarti Nuria Pardo Nadia SaoudiGonzalez Debora Martinez Jose Jimenez Irene Sansano Francesco M. Mancuso Paolo Nuciforo Luis M. Montuenga Montse SnchezCespedes Aleix Prat Ana Vivancos Enriqueta Felip Ramon Amat 《Molecular oncology》2021,15(4):887
3.
Koji Fukuda Sakiko Otani Shinji Takeuchi Sachiko Arai Shigeki Nanjo Azusa Tanimoto Akihiro Nishiyama Katsuhiko Naoki Seiji Yano 《Cancer science》2021,112(9):3784
Leptomeningeal carcinomatosis (LMC) occurs frequently in non–small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR‐TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third‐generation EGFR‐TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR‐mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next‐generation sequencing. We detected the Kirsten rat sarcoma (KRAS)‐G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS‐G12V overexpression in parental cells revealed the involvement of KRAS‐G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS‐G12V–harboring osimertinib‐resistant LMC in EGFR‐mutant NSCLC. 相似文献
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Liang Liu Tamjeed Ahmed William J. Petty Stefan Grant Jimmy Ruiz Thomas W. Lycan Umit Topaloglu PingChieh Chou Lance D. Miller Gregory A. Hawkins Martha A. AlexanderMiller Stacey S. ONeill Bayard L. Powell Ralph B. DAgostino Jr. Reginald F. Munden Boris Pasche Wei Zhang 《Molecular oncology》2021,15(2):462
KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin‐remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS‐mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK‐IMPACT Clinical Sequencing (MSK‐CT) cohorts; and KRAS‐mutant patients with LUAD who received immune checkpoint inhibitor‐based immunotherapy treatment from (c) the MSK‐IMPACT (MSK‐IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS‐mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e‐04 for disease‐free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS‐TP53 comutant (KP) and KRAS‐only mutant (K) patients; in the MSK‐CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression‐free survival (PFS; P = 0.0091) in the MSK‐IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.
Abbreviations
- DCB
- durable clinical benefit
- DFS
- disease‐free survival
- K
- KRAS‐only mutant
- KL
- KRAS‐STK11 comutant
- KP
- KRAS‐TP53 comutant
- KS
- KRAS‐SMARCA4 comutant
- LUAD
- lung adenocarcinoma
- LUSC
- lung squamous carcinoma
- MSK‐CT
- the MSK‐IMPACT clinical sequencing cohort
- MSK‐IO
- MSK‐IMPACT cohort
- NSCLC
- non‐small‐cell lung cancer
- OS
- overall survival
- PFS
- progression‐free survival
- TCGA
- The Cancer Genome Atlas
- WFBCCC
- the Wake Forest Baptist Comprehensive Cancer Center
8.
Esther Coronado Yania Yaez Enrique Vidal Luis Rubio Francisco VeraSempere Antonio Jos CaadaMartínez Joaquín Panadero Adela Caete Ruth Ladenstein Victoria Castel Jaime Font de Mora 《Molecular oncology》2021,15(2):364
High‐risk neuroblastoma (NB) patients with 11q deletion frequently undergo late but consecutive relapse cycles with fatal outcome. To date, no actionable targets to improve current multimodal treatment have been identified. We analyzed immune microenvironment and genetic profiles of high‐risk NB correlating with 11q immune status. We show in two independent cohorts that 11q‐deleted NB exhibits various immune inhibitory mechanisms, including increased CD4+ resting T cells and M2 macrophages, higher expression of programmed death‐ligand 1, interleukin‐10, transforming growth factor‐beta‐1, and indoleamine 2,3‐dioxygenase 1 (P < 0.05), and also higher chromosomal breakages (P ≤ 0.02) and hemizygosity of immunosuppressive miRNAs than MYCN‐amplified and other 11q‐nondeleted high‐risk NB. We also analyzed benefits of maintenance treatment in 83 high‐risk stage M NB patients focusing on 11q status, either with standard anti‐GD2 immunotherapy (n = 50) or previous retinoic acid‐based therapy alone (n = 33). Immunotherapy associated with higher EFS (50 vs. 30, P = 0.028) and OS (72 vs. 52, P = 0.047) at 3 years in the overall population. Despite benefits from standard anti‐GD2 immunotherapy in high‐risk NB patients, those with 11q deletion still face poor outcome. This NB subgroup displays intratumoral immune suppression profiles, revealing a potential therapeutic strategy with combination immunotherapy to circumvent this immune checkpoint blockade.
Abbreviations
- 11q‐del
- 11q‐deleted
- ADCC
- antibody‐dependent cellular cytotoxicity
- CDC
- complement‐dependent cytotoxicity
- COJEC
- chemotherapeutic agents cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide
- CTLA‐4
- cytotoxic T lymphocyte antigen 4
- EFS
- event‐free survival
- FISH
- fluorescence in situ hybridization
- HR
- hazard ratio
- ICI
- immune checkpoint inhibitor
- IDO1
- indoleamine 2,3‐dioxygenase 1
- IFN‐γ
- interferon‐γ
- IL‐10
- interleukin 10
- INRG
- International Neuroblastoma Risk Group
- miR
- microRNA
- MLPA
- multiplex ligation‐dependent probe amplification
- MMR
- mismatch repair
- MNA
- MYCN amplification
- MS
- metastatic special stage
- MSI
- microsatellite instability
- NB
- neuroblastoma
- NCA
- numerical chromosome aberrations
- NOS
- nitric oxide synthase
- OS
- overall survival
- PD‐1
- programmed cell death protein 1
- PD‐L1
- programmed death‐ligand 1
- SCA
- segmental chromosome aberrations
- TAM
- tumor‐associated macrophages
- Tfh
- follicular helper T cells
- TGF‐β
- tumor growth factor‐β
- TMB
- tumor mutational burden
- TME
- tumor microenvironment
- TNF‐α
- tumor necrosis factor‐α
- Treg
- regulatory T cells
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Sofia Mastoraki Ioanna Balgkouranidou Emily Tsaroucha Apostolos Klinakis Vassilis Georgoulias Evi Lianidou 《Molecular oncology》2021,15(9):2412
MLL3 histone methyltransferase, encoded by the KMT2C gene, is a tumor suppressor that has an essential role in cell‐type‐specific gene expression. We evaluated the prognostic significance of KMT2C promoter methylation as a circulating epigenetic biomarker in plasma cell‐free DNA (cfDNA) in non‐small cell lung cancer (NSCLC). We examined the methylation status of KMT2C promoter using a novel highly specific and sensitive real‐time methylation‐specific PCR (MSP) assay in (a) operable NSCLC: 48 fresh‐frozen NSCLC tissues, their corresponding adjacent non‐neoplastic tissues, and 48 matched plasma samples; (b) metastatic NSCLC: 91 plasma samples; and (c) 60 plasma samples from healthy donors (HD). KMT2C promoter methylation in plasma cfDNA was detected in 7/48 (14.6%) patients with operable and in 18/91 (19.8%) patients with advanced NSCLC but in none (0/60, 0%) of the plasma samples from HD. In operable NSCLC, in corresponding adjacent non‐neoplastic tissue samples, KMT2C promoter methylation was detected in 3/48 (6.3%) cases. Moreover, in operable NSCLC, KMT2C promoter methylation in plasma cfDNA was related to reduced disease‐free survival (ΗR = 0.239; P = 0.001) and worse overall survival (OS; HR = 0.342, P = 0.023). In metastatic NSCLC, KMT2C promoter methylation in plasma cfDNA was related to worse progression‐free survival (PFS; HR = 0.431; P = 0.005) and worse OS (HR = 0.306; P < 0.001). Our data strongly suggest that the detection of KMT2C promoter methylation in plasma cfDNA predicts poor prognosis in patients with both operable and metastatic NSCLCs. KMT2C promoter methylation in plasma cfDNA therefore merits further evaluation and validation as a noninvasive circulating epigenetic biomarker.
Abbreviations
- cfDNA
- cell‐free DNA
- CTCs
- circulating tumor cells
- gDNA
- genomic DNA
- HD
- healthy donors
- MSP
- methylation‐specific PCR
- NSCLC
- non‐small cell lung cancer
- SB
- sodium bisulfite
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Abril Marcela HerreraSolorio Irlanda PeraltaArrieta Leonel Armas Lpez Nallely HernndezCigala Criselda Mendoza Milla Blanca Ortiz Quintero Rodrigo Cataln Crdenas Priscila Pineda Villegas Evelyn Rodríguez Villanueva Cynthia G. Trejo Iriarte Joaquín Zúiga Oscar Arrieta Federico vilaMoreno 《Molecular oncology》2021,15(4):1110
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Lara Paula Fernndez María Merino Gonzalo Colmenarejo Juan MorenoRubio Ruth SnchezMartínez Adriana QuijadaFreire Marta Gmez de Cedrn Guillermo Reglero Enrique Casado María Sereno Ana Ramírez de Molina 《Molecular oncology》2020,14(12):3135
Lung cancer is one of the most common cancers, still characterized by high mortality rates. As lipid metabolism contributes to cancer metabolic reprogramming, several lipid metabolism genes are considered prognostic biomarkers of cancer. Statins are a class of lipid‐lowering compounds used in treatment of cardiovascular disease that are currently studied for their antitumor effects. However, their exact mechanism of action and specific conditions in which they should be administered remains unclear. Here, we found that simvastatin treatment effectively promoted antiproliferative effects and modulated lipid metabolism‐related pathways in non‐small cell lung cancer (NSCLC) cells and that the antiproliferative effects of statins were potentiated by overexpression of acyl‐CoA synthetase long‐chain family member 3 (ACSL3). Moreover, ACSL3 overexpression was associated with worse clinical outcome in patients with high‐grade NSCLC. Finally, we found that patients with high expression levels of ACSL3 displayed a clinical benefit of statins treatment. Therefore, our study highlights ACSL3 as a prognostic biomarker for NSCLC, useful to select patients who would obtain a clinical benefit from statin administration.
Abbreviations
- 3‐HMGCR
- 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase
- 95% CI
- 95% confidence intervals
- ACSL3
- acyl‐CoA synthetase long‐chain family member 3
- ACSLs
- long‐chain acyl‐CoA synthetases
- ALP
- alkaline phosphatase
- APOA1
- apolipoprotein A1
- ATCC
- American Type Culture Collection
- CASP9
- caspase 9
- ECAR
- extracellular acidification rate
- ECOG
- Eastern Cooperative Oncology Group
- EMT
- epithelial‐to‐mesenchymal transition
- ER
- endoplasmic reticulum
- FAs
- fatty acids
- FFPE
- formalin‐fixed, paraffin‐embedded
- GTEx
- genotype‐tissue expression
- HR
- Hazard ratio
- IC50
- half‐maximal inhibitory concentration
- LDH
- lactate dehydrogenase
- MTT
- 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium
- NID1
- nidogen 1
- No ORF
- no open reading frame
- NSCLC
- non‐small cell lung cancer
- OCR
- oxygen consumption rate
- OS
- overall survival
- PGE2
- prostaglandins E2
- RETN
- resistin
- TCGA
- The Cancer Genome Atlas
- TMA
- tumor tissue microarray
14.
Valentina Panzeri Isabella Manni Alessia Capone Chiara Naro Andrea Sacconi Silvia Di Agostino Luisa de Latouliere Andrea Montori Emanuela Pilozzi Giulia Piaggio Gabriele Capurso Claudio Sette 《Molecular oncology》2021,15(2):579
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Most patients present with advanced disease at diagnosis, which only permits palliative chemotherapeutic treatments. RNA dysregulation is a hallmark of most human cancers, including PDAC. To test the impact of RNA processing dysregulation on PDAC pathology, we performed a bioinformatics analysis to identify RNA‐binding proteins (RBPs) associated with prognosis. Among the 12 RBPs associated with progression‐free survival, we focused on MEX3A because it was recently shown to mark an intestinal stem cell population that is refractory to chemotherapeutic treatments, a typical feature of PDAC. Increased expression of MEX3A was correlated with higher disease stage in PDAC patients and with tumor development in a mouse model of PDAC. Depletion of MEX3A in PDAC cells enhanced sensitivity to chemotherapeutic treatment with gemcitabine, whereas its expression was increased in PDAC cells selected upon chronic exposure to the drug. RNA‐sequencing analyses highlighted hundreds of genes whose expression is sensitive to MEX3A expression, with significant enrichment in cell cycle genes. MEX3A binds to its target mRNAs, like cyclin‐dependent kinase 6 (CDK6), and promotes their stability. Accordingly, knockdown of MEX3A caused a significant reduction in PDAC cell proliferation and in progression to the S phase of the cell cycle. These findings uncover a novel role for MEX3A in the acquisition and maintenance of chemoresistance by PDAC cells, suggesting that it may represent a novel therapeutic target for PDAC.
Abbreviations
- CLIP
- UV‐crosslink and RNA immunoprecipitation
- DFS
- disease‐free survival
- DR
- drug resistant
- EMT
- mesenchymal transition
- MC
- MITO‐Cre
- MKC
- MITO‐Kras‐Cre
- PARG
- poly (ADP‐ribose) glycohydrolase
- PDAC
- pancreatic ductal adenocarcinoma
- PI
- propidium iodide
- RBPs
- RNA‐binding proteins
- RNA‐seq
- RNA sequencing
- RNP
- ribonucleoprotein
- TGCA
- The Cancer Genome Atlas
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Jia Liu Yang Zhan Jiefu Wang Junfeng Wang Jiansheng Guo Dalu Kong 《Molecular oncology》2020,14(12):3211
Metastasis accounts for poor prognosis of cancers and related deaths. Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play critical roles in several types of cancer. However, which lncRNAs contribute to metastasis of colon cancer is still largely unknown. In this study, we found that lncRNA LINC01578 was correlated with metastasis and poor prognosis of colon cancer. LINC01578 was upregulated in colon cancer, associated with metastasis, advanced clinical stages, poor overall survival, disease‐specific survival, and disease‐free survival. Gain‐of‐function and loss‐of‐function assays revealed that LINC01578 enhanced colon cancer cell viability and mobility in vitro and colon cancer liver metastasis in vivo. Mechanistically, nuclear factor kappa B (NF‐κB) and Yin Yang 1 (YY1) directly bound to the LINC01578 promoter, enhanced its activity, and activated LINC01578 expression. LINC01578 was shown to be a chromatin‐bound lncRNA, which directly bound NFKBIB promoter. Furthermore, LINC01578 interacted with and recruited EZH2 to NFKBIB promoter and further repressed NFKBIB expression, thereby activating NF‐κB signaling. Through activation of NF‐κB, LINC01578 further upregulated YY1 expression. Through activation of the NF‐κB/YY1 axis, LINC01578 in turn enhanced its own promoter activity, suggesting that LINC01578 and NF‐κB/YY1 formed a positive feedback loop. Blocking NF‐κB signaling abolished the oncogenic roles of LINC01578 in colon cancer. Furthermore, the expression levels of LINC01578, NFKBIB, and YY1 were correlated in clinical tissues. Collectively, this study demonstrated that LINC01578 promoted colon cancer metastasis via forming a positive feedback loop with NF‐κB/YY1 and suggested that LINC01578 represents a potential prognostic biomarker and therapeutic target for colon cancer metastasis.
Abbreviations
- ChIP
- chromatin immunoprecipitation
- ChIRP
- chromatin isolation by RNA purification
- COAD
- colon adenocarcinoma
- CPAT
- Coding‐Potential Assessment Tool
- CPC
- coding potential calculator
- DFS
- disease‐free survival
- DSS
- disease‐specific survival
- EdU
- 5‐ethynyl‐2''‐deoxyuridine
- H&E
- hematoxylin and eosin
- HR
- hazard ratio
- IHC
- immunohistochemistry
- IKK
- IκB kinase
- IκB
- inhibitory κB
- lncRNAs
- long noncoding RNAs
- NC
- negative control
- NCBI
- National Center for Biotechnology Information
- NF‐κB
- nuclear factor kappa B
- qRT‐PCR
- quantitative real‐time polymerase chain reaction
- RIP
- RNA immunoprecipitation
- RPISeq
- RNA‐Protein Interaction Prediction
- TCGA
- The Cancer Genome Atlas
- TNF
- tumor necrosis factor
- TUNEL
- TdT‐mediated dUTP Nick‐End Labeling
- YY1
- Yin Yang 1
16.
JeongYun Choi Haeseung Lee EunJi Kwon HyeonJoon Kong OkSeon Kwon HyukJin Cha 《Molecular oncology》2021,15(2):679
The acquisition of chemoresistance remains a major cause of cancer mortality due to the limited accessibility of targeted or immune therapies. However, given that severe alterations of molecular features during epithelial‐to‐mesenchymal transition (EMT) lead to acquired chemoresistance, emerging studies have focused on identifying targetable drivers associated with acquired chemoresistance. Particularly, AXL, a key receptor tyrosine kinase that confers resistance against targets and chemotherapeutics, is highly expressed in mesenchymal cancer cells. However, the underlying mechanism of AXL induction in mesenchymal cancer cells is poorly understood. Our study revealed that the YAP signature, which was highly enriched in mesenchymal‐type lung cancer, was closely correlated to AXL expression in 181 lung cancer cell lines. Moreover, using isogenic lung cancer cell pairs, we also found that doxorubicin treatment induced YAP nuclear translocation in mesenchymal‐type lung cancer cells to induce AXL expression. Additionally, the concurrent activation of TGFβ signaling coordinated YAP‐dependent AXL expression through SMAD4. These data suggest that crosstalk between YAP and the TGFβ/SMAD axis upon treatment with chemotherapeutics might be a promising target to improve chemosensitivity in mesenchymal‐type lung cancer.
Abbreviations
- AUC
- area under the curve
- AXL
- AXL receptor tyrosine kinase
- BCL2
- B‐cell lymphoma 2
- CTD2
- cancer target discovery and development
- CTGF
- connective tissue growth factor
- DEG
- differentially expressed genes
- DOXO
- doxorubicin
- EMT
- epithelial–mesenchymal transition
- Eto
- etoposide
- FDA
- Food and Drug Administration
- ITGB3
- integrin beta‐3
- MAPK
- mitogen‐activated protein kinase
- MMP2
- matrix metalloproteinase‐2
- MMP9
- matrix metalloproteinase‐9
- mRNA
- messenger RNA
- NF‐κB
- nuclear factor kappa‐light‐chain‐enhancer of activated B cells
- SBE
- SMAD binding element
- SERPINE1
- serpin family E member 1
- siRNA
- small interfering RNA
- ssGSEA
- single‐sample gene set enrichment analysis
- TCGA
- The Cancer Genome Atlas
- TGFβ
- transforming growth factor beta
- YAP
- Yes‐associated protein
- YAP8SA
- mutants of inhibitory phosphorylation site at eight serine to Alanine of YAP
- ZEB1
- zinc finger E‐box binding homeobox 1
- ZEB2
- zinc finger E‐box‐binding homeobox 2
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Chen Jin Jie Zhao ZhiPing Zhang Ming Wu Jian Li Bo Liu Xin Bin Liao YuXiang Liao JingPing Liu 《Molecular oncology》2021,15(2):596
Gliomas are the most common type of primary brain tumors. CircRNA ephrin type‐B receptor 4 (circEPHB4) is a circular RNA derived from the receptor tyrosine kinase EPHB4. However, the clinical significance and the specific roles of circEPHB4 in gliomas and glioma cancer stem cells (CSC) have not been studied. Here, we found that circEPHB4 (hsa_circ_0081519) and SOX10 were up‐regulated and microRNA (miR)‐637 was down‐regulated in glioma tissues and cell lines. Consistently, circEPHB4 was positively correlated with SOX10 but negatively correlated with miR‐637. The altered expressions of these molecules were independently associated with overall survival of patients. CircEPHB4 up‐regulated SOX10 and Nestin by directly sponging miR‐637, thereby stimulating stemness, proliferation and glycolysis of glioma cells. Functionally, silencing circEPHB4 or increasing miR‐637 levels in glioma cells was sufficient to inhibit xenograft growth in vivo. In conclusion, the circEPHB4/miR‐637/SOX10/Nestin axis plays a central role in controlling stem properties, self‐renewal and glycolysis of glioma cells and predicts the overall survival of glioma patients. Targeting this axis might provide a therapeutic strategy for malignant gliomas.
Abbreviations
- ANOVA
- analysis of variance
- circEPHB4
- circRNA ephrin type‐B receptor 4
- circRNA
- circular RNA
- HK2
- hexokinase 2
- mRNA
- messenger RNA
- miRNA
- microRNA
- PDK1
- pyruvate dehydrogenase kinase 1
- PI
- propidium iodide
- PKM2
- pyruvate kinase M2
- qRT‐PCR
- quantitative real‐time polymerase chain reaction
- RIP
- RNA immunoprecipitation
- SD
- standard deviation
- shcircEPHB4
- short hairpin RNA specifically targeting circEPHB4
19.
Danmei Zhou Kehan Ren Meili Wang Jigang Wang Ermin Li Chenjian Hou Ying Su Yiting Jin Qiang Zou Ping Zhou Xiuping Liu 《Molecular oncology》2021,15(2):543
Long non‐coding RNAs (lncRNAs) are emerging as key molecules in various cancers, yet their potential roles in the pathogenesis of breast cancer are not fully understood. Herein, using microarray analysis, we revealed that the lncRNA RACGAP1P, the pseudogene of Rac GTPase activating protein 1 (RACGAP1), was up‐regulated in breast cancer tissues. Its high expression was confirmed in 25 pairs of breast cancer tissues and 8 breast cell lines by qRT‐PCR. Subsequently, we found that RACGAP1P expression was positively correlated with lymph node metastasis, distant metastasis, TNM stage, and shorter survival time in 102 breast cancer patients. Then, in vitro and in vivo experiments were designed to investigate the biological function and regulatory mechanism of RACGAP1P in breast cancer cell lines. Overexpression of RACGAP1P in MDA‐MB‐231 and MCF7 breast cell lines increased their invasive ability and enhanced their mitochondrial fission. Conversely, inhibition of mitochondrial fission by Mdivi‐1 could reduce the invasive ability of RACGAP1P‐overexpressing cell lines. Furthermore, the promotion of mitochondrial fission by RACGAP1P depended on its competitive binding with miR‐345‐5p against its parental gene RACGAP1, leading to the activation of dynamin‐related protein 1 (Drp1). In conclusion, lncRNA RACGAP1P promotes breast cancer invasion and metastasis via miR‐345‐5p/RACGAP1 pathway‐mediated mitochondrial fission.
Abbreviations
- CDS
- coding sequence
- ceRNAs
- competitive endogenous RNAs
- Drp1
- dynamin‐related protein 1
- FFPE
- formalin‐fixed paraffin‐embedded
- lncRNAs
- long non‐coding RNAs
- miRNAs
- microRNAs
- RACGAP1
- Rac GTPase activating protein 1
- TCGA
- The Cancer Genome Atlas