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1.
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
2.
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
3.
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
4.
Kazuko Sakai Takayuki Takahama Mototsugu Shimokawa Koichi Azuma Masayuki Takeda Terufumi Kato Haruko Daga Isamu Okamoto Hiroaki Akamatsu Shunsuke Teraoka Akira Ono Tatsuo Ohira Toshihide Yokoyama Nobuyuki Yamamoto Kazuhiko Nakagawa Kazuto Nishio 《Molecular oncology》2021,15(1):126
The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).
Abbreviations
- CIs
- confidence intervals
- ctDNA
- circulating tumor DNA
- ddPCR
- droplet digital PCR
- EGFR
- epidermal growth factor receptor
- MFs
- mutant fractions
- NGS
- next‐generation sequencing
- NSCLC
- non‐small cell lung cancer
- ORR
- overall response rate
- OS
- overall survival
- PD
- progressive disease
- PFS
- progression‐free survival
- PR
- partial response
- SD
- stable disease
- TKI
- tyrosine kinase inhibitor
5.
《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
6.
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
7.
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
8.
9.
10.
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
11.
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
12.
ZeWen Xiao Wendy Wu Chunlong Wu Man Li Fuming Sun Lu Zheng Gaojing Liu Xiaoling Li Zhiyuan Yun Jiebing Tang Yang Yu Shengnan Luo Wenji Sun Xiaohong Feng Qian Cheng Xue Tao Shuangxiu Wu Ji Tao 《Molecular oncology》2021,15(1):138
Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma‐to‐carcinoma sequence associated with specific molecular alterations, including the 5‐hydroxymethylcytosine (5hmC) signature in circulating cell‐free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome‐wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early‐stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC‐modified regions (DhMRs) were gathered into four clusters: Disease‐enriched, AD‐enriched, Disease‐lost, and AD‐lost, with no overlap. AD‐related clusters, AD‐enriched and AD‐lost, displayed the unique 5hmC signals in AD patients. Disease‐enriched and Disease‐lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD‐enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC‐modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease‐enriched and Disease‐lost DhMR clusters demonstrated similar epigenetic modifications, while AD‐enriched and AD‐lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC‐gain characteristics, consistent with the ‘parallel’ evolution hypothesis in adenoma, either developed through the adenoma‐to‐carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early‐stage CRC and assess adenoma malignancy with large‐scale follow‐up studies in the future.
Abbreviations
- 5hmC
- 5‐hydroxymethylcytosine
- AD
- precancerous adenoma
- cfDNA
- cell‐free DNA
- CRC
- colorectal cancer
- DhmR
- differential 5hmC‐modified regions
- gDNA
- genomics DNA
- HC
- healthy control
- hMRs
- 5hmC‐modified regions
13.
14.
15.
The oncogenic fusion protein nucleophosmin‐anaplastic lymphoma kinase (NPM‐ALK), found in anaplastic large‐cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remains unclear. We herein demonstrated that NPM‐ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM‐ALK interacted with Epstein–Barr virus nuclear antigen 1‐binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM‐ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G0/G1‐phase cell cycle arrest in Ba/F3 cells transformed by NPM‐ALK and ALCL patient‐derived Ki‐JK cells, but not ALCL patient‐derived SUDH‐L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM‐ALK and Ki‐JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC‐0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, an essential component of mTORC1. These results suggest that the knockdown of EBP2 triggered p53 activation through the Akt‐mTORC1 pathway in NPM‐ALK‐positive cells. Collectively, the present results revealed the critical repressive mechanism of p53 activity by EBP2 and provide a novel therapeutic strategy for the treatment of ALCL.
Abbreviations
- ALCL
- anaplastic large‐cell lymphoma
- EBP2
- EBNA1‐binding protein 2
- IMT
- inflammatory myofibroblastic tumors
- mTOR
- mechanistic target of rapamycin
- mTORC1
- mTOR complex 1
- NoLS
- nucleolar localization signal
- NPM1
- nucleophosmin 1
- NPM‐ALK
- nucleophosmin‐anaplastic lymphoma kinase
- NSCLC
- non‐small cell lung cancer
- TPM3
- tropomyosin 3
16.
Debora Bencivenga Emanuela Stampone Arianna Aulitto Annunziata Tramontano Clementina Barone Aide Negri Domenico Roberti Silverio Perrotta Fulvio Della Ragione Adriana Borriello 《Molecular oncology》2021,15(4):915
CDKN1B haploinsufficiency promotes the development of several human cancers. The gene encodes p27Kip1, a protein playing pivotal roles in the control of growth, differentiation, cytoskeleton dynamics, and cytokinesis. CDKN1B haploinsufficiency has been associated with chromosomal or gene aberrations. However, very few data exist on the mechanisms by which CDKN1B missense mutations facilitate carcinogenesis. Here, we report a functional study on a cancer‐associated germinal p27Kip1 variant, namely glycine9‐>arginine‐p27Kip1 (G9R‐p27Kip1) identified in a parathyroid adenoma. We unexpectedly found that G9R‐p27Kip1 lacks the major tumor suppressor activities of p27Kip1 including its antiproliferative and pro‐apoptotic functions. In addition, G9R‐p27Kip1 transfection in cell lines induces the formation of more numerous and larger spheres when compared to wild‐type p27Kip1‐transfected cells. We demonstrated that the mutation creates a consensus sequence for basophilic kinases causing a massive phosphorylation of G9R‐p27Kip1 on S12, a residue normally never found modified in p27Kip1. The novel S12 phosphorylation appears responsible for the loss of function of G9R‐p27Kip1 since S12AG9R‐p27Kip1 recovers most of the p27Kip1 tumor suppressor activities. In addition, the expression of the phosphomimetic S12D‐p27Kip1 recapitulates G9R‐p27Kip1 properties. Mechanistically, S12 phosphorylation enhances the nuclear localization of the mutant protein and also reduces its cyclin‐dependent kinase (CDK)2/CDK1 inhibition activity. To our knowledge, this is the first reported case of quantitative phosphorylation of a p27Kip1 variant on a physiologically unmodified residue associated with the loss of several tumor suppressor activities. In addition, our findings demonstrate that haploinsufficiency might be due to unpredictable post‐translational modifications due to generation of novel consensus sequences by cancer‐associated missense mutations.
Abbreviations
- 1D/WB
- monodimensional western blotting
- 2D/WB
- two‐dimensional western blotting
- CDK
- cyclin‐dependent kinase
- CHX
- cycloheximide
- G9R‐p27
- glycine9‐>arginine‐p27
- IUPs
- intrinsically unstructured proteins
- mAbs
- monoclonal antibodies
- MEN
- multiple endocrine neoplasia
- MENX
- multiple endocrine neoplasia X
- PTMs
- post‐translational modifications
- rAbs
- rabbit antibodies
- TSG
- tumor suppressor gene
- wt‐p27
- wild‐type p27
17.
18.
Dongwei Dou Xiaoyang Ren Mingli Han Xiaodong Xu Xin Ge Yuanting Gu Xinxing Wang Song Zhao 《Molecular oncology》2021,15(2):697
Circular RNAs (circRNAs) have been shown to modulate gene expression and participate in the development of multiple malignancies. The purpose of this study was to investigate the role of circ_0008039 in breast cancer (BC). The expression of circ_0008039, miR‐140‐3p, and spindle and kinetochore‐associated protein 2 (SKA2) was detected by qRT‐PCR. Cell viability, colony formation, migration, and invasion were evaluated using methylthiazolyldiphenyl‐tetrazolium bromide (MTT) assay, colony formation assay, and transwell assay, respectively. Glucose consumption and lactate production were measured using commercial kits. Protein levels of hexokinase II (HK2) and SKA2 were determined by western blot. The interaction between miR‐140‐3p and circ_0008039 or SKA2 was verified by dual‐luciferase reporter assay. Finally, a mouse xenograft model was established to investigate the roles of circ_0008039 in BC in vivo. We found that circ_0008039 and SKA2 were upregulated in BC tissues and cells, while miR‐140‐3p was downregulated. Knockdown of circ_0008039 suppressed BC cell proliferation, migration, invasion, and glycolysis. Moreover, miR‐140‐3p could bind to circ_0008039 and its inhibition reversed the inhibitory effect of circ_0008039 interference on proliferation, migration, invasion, and glycolysis in BC cells. SKA2 was verified as a direct target of miR‐140‐3p and its overexpression partially inhibited the suppressive effect of miR‐140‐3p restoration in BC cells. Additionally, circ_0008039 positively regulated SKA2 expression by sponging miR‐140‐3p. Consistently, silencing circ_0008039 restrained tumor growth via increasing miR‐140‐3p and decreasing SKA2. In conclusion, circ_0008039 downregulation suppressed BC cell proliferation, migration, invasion, and glycolysis partially through regulating the miR‐140‐3p/SKA2 axis, providing an important theoretical basis for treatment of BC.
Abbreviations
- ANOVA
- analysis of variance
- BC
- breast cancer
- circRNAs
- circular RNAs
- DMSO
- dimethyl sulfoxide
- ECAR
- extracellular acidification rate
- ECL
- enhanced chemiluminescence
- FBS
- fetal bovine serum
- HK2
- hexokinase II
- MEGM
- mammary epithelial growth medium
- miR‐140‐3p
- microRNA‐140‐3p
- MTT
- methylthiazolyldiphenyl‐tetrazolium bromide
- PBS
- phosphate‐buffered saline
- PRKAR1B
- protein kinase A regulatory subunit R1‐beta
- SD
- standard ± deviation
- SKA2
- spindle and kinetochore‐associated protein 2
19.
The study of extracellular vesicles (EVs), especially in the liquid biopsy field, has rapidly evolved in recent years. However, most EV studies have focused on RNA or protein content and DNA in EVs (EV‐DNA) has largely been unnoticed. In this review, we compile current evidence regarding EV‐DNA and provide an extensive discussion on EV‐DNA biology. We look into EV‐DNA biogenesis and mechanisms of DNA loading into EVs, as well as describe the particularly significant function of DNA‐carrying EVs in the maintenance of cellular homeostasis, intracellular communication, and immune response modulation. We also examine the current role of EV‐DNA in the clinical setting, specifically in cancer, infections, pregnancy, and prenatal diagnosis.
Abbreviations
- BBB
- blood–brain barrier
- cfDNA
- cell‐free DNA
- cGAS
- cyclic GMP‐AMP synthase
- ctDNA
- circulating tumor DNA
- ds
- double‐stranded
- EGFR
- epidermal growth factor receptor
- EV‐DNA
- DNA in extracellular vesicles
- EV‐mtDNA
- mtDNA in extracellular vesicles
- EVs
- extracellular vesicles
- gDNA
- genomic DNA
- HBV
- hepatitis B virus
- HPV
- human papillomavirus
- IFN1
- interferon type 1
- ILVs
- intraluminal vesicles
- MAFs
- mean frequencies
- MN
- micronuclei
- mtDNA
- mitochondrial DNA
- MVBs
- multivesicular bodies
- NGS
- next‐generation sequencing
- NSCLC
- non‐small‐cell lung cancer
- PCR
- polymerase chain reaction
- PDAC
- pancreatic ductal adenocarcinoma
- ss
- single‐stranded
- STING
- stimulator of interferon genes
20.
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