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1.
RongZong Liu WonShik Choi Saket Jain Deepak Dinakaran Xia Xu Woo Hyun Han XiaoHong Yang Darryl D. Glubrecht Ronald B. Moore Hlne Lemieux Roseline Godbout 《Molecular oncology》2020,14(12):3100
Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid‐binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial‐to‐mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid β‐oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12''s role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP‐PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.
Abbreviations
- AR
- androgen receptor
- ATP
- adenosine triphosphate
- CN
- copy number
- CPT1
- carnitine palmitoyltransferase I
- CS
- citrate synthase
- EMT
- epithelial–mesenchymal transition
- ET
- electron transfer‐state
- FABP
- fatty acid‐binding protein
- LD
- lipid droplet
- OA
- oleic acid
- PCa
- prostate cancer
- PPAR
- peroxisome proliferator‐activated receptor
- PPRE
- peroxisome proliferator‐activated receptor response element
- TZD
- thiazolidinediones
2.
Romana Dolinschek Julia Hingerl Anke Benge Christian Zafiu Elisabeth Schüren EvaKathrin Ehmoser Daniela Lssner Ute Reuning 《Molecular oncology》2021,15(2):503
Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage‐dependent epithelial‐type tumor cells gain anoikis resistance, implicating integrins, including αvß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the αvß3 transmembrane conformational activation state in cells suspended in ascites. A high‐affinity and constitutively signaling‐competent αvß3 variant, which harbored unclasped transmembrane domains, was found to confer delayed anoikis onset, enhanced cisplatin resistance, and reduced cell proliferation in ascites or 3D‐hydrogels, involving p27kip upregulation. Moreover, it promoted EGF‐R expression and activation, prosurvival signaling, implicating FAK, src, and PKB/Akt. This led to the induction of the anti‐apoptotic factors Bcl‐2 and survivin suppressing caspase activation, compared to a signaling‐incapable αvß3 variant displaying firmly associated transmembrane domains. Dissecting the mechanistic players for αvß3‐dependent survival and peritoneal metastasis of ascitic ovarian cancer spheroids is of paramount importance to target their anchorage independence by reversing anoikis resistance and blocking αvß3‐triggered prosurvival signaling.
Abbreviations
- CLSM
- confocal laser scanning microscopy
- ECM
- extracellular matrix
- EGF‐R
- epidermal growth factor receptor
- EOC
- epithelial ovarian cancer
- FAK
- focal adhesion kinase
- FIGO
- Fédération Internationale de Gynécologie et d''Obstétrique
- GAPDH
- glyceraldehyde 3‐phosphate dehydrogenase)
- GpA
- glycophorin A
- IMD
- integrin‐mediated death
- MAPK
- mitogen‐activated protein kinases
- PI
- propidium iodide
- RGD
- Arg‐Gly‐Asp
- TMD
- transmembrane domain
3.
Xiaoman Dai Yanhui Zhang Xiaohan Lin Xiaoxing Huang Yi Zhang Chaorong Xue Wannan Chen Jianxin Ye Xinjian Lin Xu Lin 《Molecular oncology》2021,15(1):228
Salt‐inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial–mesenchymal transition via inhibition of AKT/GSK3β/β‐catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3β/β‐catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.
Abbreviations
- AMPK
- AMP‐activated protein kinase
- Co‐IP
- co‐immunoprecipitation
- EMT
- epithelial–mesenchymal transition
- GAPDH
- glyceraldehyde‐3‐phosphate dehydrogenase
- GC
- gastric cancer
- GEO
- Gene Expression Omnibus
- H&E
- hematoxylin and eosin
- IHC
- immunohistochemistry
- mTOR
- mechanistic target of rapamycin
- NC
- negative control
- PHLPP
- PH domain leucine‐rich repeat protein phosphatase
- PP2A
- protein phosphatase 2A
- qRT‐PCR
- quantitative real‐time polymerase chain reaction
- SIK2
- salt‐inducible kinase 2
- TCF/LEF
- T cell factor/lymphoid enhancer‐binding factor
- TCGA
- The Cancer Genome Atlas
4.
Evelina Miele Agnese Po Angela Mastronuzzi Andrea Carai Zein Mersini Besharat Natalia Pediconi Luana Abballe Giuseppina Catanzaro Claudia Sabato Enrico De Smaele Gianluca Canettieri Lucia Di Marcotullio Alessandra Vacca Antonello Mai Massimo Levrero Stefan M. Pfister Marcel Kool Felice Giangaspero Franco Locatelli Elisabetta Ferretti 《Molecular oncology》2021,15(2):523
Persistent mortality rates of medulloblastoma (MB) and severe side effects of the current therapies require the definition of the molecular mechanisms that contribute to tumor progression. Using cultured MB cancer stem cells and xenograft tumors generated in mice, we show that low expression of miR‐326 and its host gene β‐arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro‐survival function. Our models revealed that miR‐326 and ARRB1 are controlled by a bivalent domain, since the H3K27me3 repressive mark is found at their regulatory region together with the activation‐associated H3K4me3 mark. High levels of EZH2, a feature of MB, are responsible for the presence of H3K27me3. Ectopic expression of miR‐326 and ARRB1 provides hints into how their low levels regulate E2F1 activity. MiR‐326 targets E2F1 mRNA, thereby reducing its protein levels; ARRB1, triggering E2F1 acetylation, reverses its function into pro‐apoptotic activity. Similar to miR‐326 and ARRB1 overexpression, we also show that EZH2 inhibition restores miR‐326/ARRB1 expression, limiting E2F1 pro‐proliferative activity. Our results reveal a new regulatory molecular axis critical for MB progression.
Abbreviations
- ARRB1
- β‐arrestin1
- BTC
- bulk tumor cell
- CSCs
- cancer stem cells
- EZH2
- enhancer of zeste homolog 2
- GCP
- granule cell progenitors
- MB
- medulloblastoma
- OFC
- oncosphere‐forming cell
5.
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
6.
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
7.
8.
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
9.
Rong Deng Yanmin Guo Lian Li Jianfeng He Zhe Qiang Hailong Zhang Ran Chen Yanli Wang Xian Zhao Jianxiu Yu 《Molecular oncology》2021,15(1):279
Deubiquitinase BAP1 is an important tumor suppressor in several malignancies, but its functions and critical substrates in prostate cancer (PCa) remain unclear. Here, we report that the mRNA and protein expression levels of BAP1 are downregulated in clinical PCa specimens. BAP1 can physically bind to and deubiquitinate PTEN, which inhibits the ubiquitination‐mediated degradation of PTEN and thus stabilizes PTEN protein. Ectopically expressed BAP1 in PCa cells increases PTEN protein level and subsequently inhibits the AKT signaling pathway, thus suppressing PCa progression. Conversely, knockdown of BAP1 in PCa cells leads to the decrease in PTEN protein level and the activation of the Akt signaling pathway, therefore promoting malignant transformation and cancer metastasis. However, these can be reversed by the re‐expression of PTEN. More importantly, we found that BAP1 protein level positively correlates with PTEN in a substantial fraction of human cancers. These findings demonstrate that BAP1 is an important deubiquitinase of PTEN for its stability and the BAP1‐PTEN signaling axis plays a crucial role in tumor suppression.
Abbreviations
- BAP1
- the BRCA1‐associated protein 1
- DUBs
- deubiquitinases
- GEO
- Gene Expression Omnibus
- IP
- immunoprecipitation
- KEGG
- the Kyoto Encyclopedia of Genes and Genomes
- PCa
- prostate cancer
- PTEN
- phosphatase and tensin homolog deleted on chromosome 10
- qRT–PCR
- quantitative real‐time polymerase chain reaction
- TCGA
- the Cancer Genome Atlas
- USP
- the ubiquitin–proteasome system
- VM
- vasculogenic mimicry
10.
11.
Yawen Liu Dawei Wang Meng Zhou Hui Chen Huizhi Wang Jingyu Min Jiaxi Chen Shuhui Wu Xiufan Ni Youli Zhang Aihua Gong Min Xu 《Molecular oncology》2021,15(1):262
Increasing evidence demonstrates that Lin28B plays critical roles in numerous biological processes including cell proliferation and stemness maintenance. However, the molecular mechanisms underlying Lin28B nuclear translocation remain poorly understood. Here, we found for the first time that KRAS promoted Lin28B nuclear translocation through PKCβ, which directly bound to and phosphorylated Lin28B at S243. Firstly, we observed that Lin28B was upregulated in pancreatic cancer, contributing to cellular migration and proliferation. Furthermore, nuclear Lin28B upregulated TET3 messenger RNA and protein levels by blocking the production of mature let‐7i. Subsequently, increased TET3 expression could also promote the expression of Lin28B, thereby forming a Lin28B/let‐7i/TET3 feedback loop. Our results suggest that the KRAS/Lin28B axis drives the let‐7i/TET3 pathway to maintain the stemness of pancreatic cancer cells. These findings illuminate the distinct mechanism of Lin28B nuclear translocation and its important roles in KRAS‐driven pancreatic cancer, and have important implications for development of novel therapeutic strategies for this cancer.
Abbreviations
- CCK‐8
- cell counting kit‐8
- CSC
- cancer stem cells
- IP
- immunoprecipitation
- MUT
- mutant type
- NLS
- nuclear localization signal
- PC
- pancreatic cancer
- PCSC
- pancreatic cancer stem cells
- PKC
- protein kinase C
- WT
- wild‐type
12.
13.
《Molecular oncology》2021,15(5):1412
The cellular receptor Notch1 is a central regulator of T‐cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T‐cell acute lymphoblastic leukemia (T‐ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T‐ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti‐Notch therapies in T‐ALL models. In this work, we report that Notch1 upregulation in T‐ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1‐driven T‐ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1‐induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1‐driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1‐driven leukemia.
Abbreviations
- 7‐AAD
- 7‐Aminoactinomycin D
- BPTES
- bis‐2‐(5‐phenylacetamido‐1,2,4‐thiadiazol‐2‐yl)ethyl sulfide
- DON
- diazo‐5‐oxo‐L‐norleucine
- ECAR
- extracellular acidification rate
- GDH
- glutamate dehydrogenase
- GLS
- glutaminase
- GS
- glutamine synthetase
- GSI
- γ‐secretase inhibitor
- MSO
- L‐methionine sulfoximine
- mTORC1
- mammalian target of rapamycin complex 1
- NICD
- Notch intracellular domain
- PI
- propidium iodide
- RAP
- rapamycin
- T‐ALL
- T‐cell acute lymphoblastic leukemia
- TCA
- tricarboxylic acid
- αKG
- α‐ketoglutarate
14.
Rubn A. Bartolom Javier Robles ngela MartinRegalado Laura PintadoBerninches Miranda Burdiel Marta Jan Carmen Aizpurúa Juan I. Imbaud Jos Ignacio Casal 《Molecular oncology》2021,15(7):1849
Cadherin 6 (CDH6) is significantly overexpressed in advanced ovarian and renal cancers. However, the role of CDH6 in cancer metastasis is largely unclear. Here, we investigated the impact of CDH6 expression on integrin‐mediated metastatic progression. CDH6 preferentially bound to αIIbβ3 integrin, a platelet receptor scarcely expressed in cancer cells, and this interaction was mediated through the cadherin Arginine–glycine–aspartic acid (RGD) motif. Furthermore, CDH6 and CDH17 were found to interact with α2β1 in αIIbβ3low cells. Transient silencing of CDH6, ITGA2B, or ITGB3 genes caused a significant loss of proliferation, adhesion, invasion, and lung colonization through the downregulation of SRC, FAK, AKT, and ERK signaling. In ovarian and renal cancer cells, integrin αIIbβ3 activation appears to be a prerequisite for proper α2β1 activation. Interaction of αIIbβ3 with CDH6, and subsequent αIIbβ3 activation, promoted activation of α2β1 and cell adhesion in ovarian and renal cancer cells. Additionally, monoclonal antibodies specific to the cadherin RGD motif and clinically approved αIIbβ3 inhibitors could block pro‐metastatic activity in ovarian and renal tumors. In summary, the interaction between CDH6 and αIIbβ3 regulates α2β1‐mediated adhesion and invasion of ovarian and renal cancer metastatic cells and constitutes a therapeutic target of broad potential for treating metastatic progression. 相似文献
15.
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
16.
Sumit Agarwal Michael Behring HyungGyoon Kim Darshan S. Chandrashekar Balabhadrapatruni V. S. K. Chakravarthi Nirzari Gupta Prachi Bajpai Amr Elkholy Sameer Al Diffalha Pran K. Datta Martin J. Heslin Sooryanarayana Varambally Upender Manne 《Molecular oncology》2020,14(12):3007
Overexpression of TRIP13, a member of the AAA‐ATPase family, is linked with various cancers, but its role in metastasis is unknown in colorectal cancer (CRC). In the current study, we investigated the role TRIP13 in experimental metastasis and its involvement in regulation of WNT/β‐catenin and EGFR signaling pathways. Evaluation of formalin‐fixed paraffin‐embedded (FFPE) and frozen tissues of adenomas and CRCs, along with their corresponding normal samples, showed that TRIP13 was gradually increased in its phenotypic expression from adenoma to carcinoma and that its overexpression in CRCs was independent of patient''s gender, age, race/ethnicity, pathologic stage, and p53 and microsatellite instability (MSI) status. Moreover, liver metastases of CRCs showed TRIP13 overexpression as compared to matched adjacent liver tissues, indicating the biological relevance of TRIP13 in CRC progression and metastasis. TRIP13 knockdown impeded colony formation, invasion, motility, and spheroid‐forming capacity of CRC cells irrespective of their p53 and MSI status. Furthermore, xenograft studies demonstrated high expression of TRIP13 contributed to tumor growth and metastasis. Depletion of TRIP13 in CRC cells decreased metastasis and it was independent of the p53 and MSI status. Furthermore, TRIP13 interacted with a tyrosine kinase, FGFR4; this interaction could be essential for activation of the EGFR‐AKT pathway. In addition, we demonstrated the involvement of TRIP13 in the Wnt signaling pathway and in the epithelial–mesenchymal transition. Cell‐based assays revealed that miR‐192 and PNPT1 regulate TRIP13 expression in CRC. Additionally, RNA sequencing of CRC cells with TRIP13 knockdown identified COL6A3, TREM2, SHC3, and KLK7 as downstream targets that may have functional relevance in TRIP13‐mediated tumor growth and metastasis. In summary, our results demonstrated that TRIP13 promotes tumor growth and metastasis regardless of p53 and MSI status, and indicated that it is a target for therapy of CRC.
Abbreviations
- CIN
- chromosomal instability
- CRC
- colorectal cancer
- EMT
- epithelial–mesenchymal transition
- FFPE
- formalin‐fixed, paraffin‐embedded
- LEF
- lymphoid enhancer factor
- MS
- microsatellite
- MSI
- microsatellite instable
- MSS
- microsatellite stable
- NSG
- NOD/SCID/IL2γ receptor‐null
- NT
- nontargeting
- SAC
- spindle assembly checkpoint
- TCF
- T‐cell factor
- TRIP13
- thyroid hormone receptor interactor 13
- UAB
- University of Alabama at Birmingham
17.
PengXiang Wang YunFan Sun WeiXiang Jin JianWen Cheng HaiXiang Peng Yang Xu KaiQian Zhou LiMeng Chen Kai Huang SuiYi Wu Bo Hu ZeFan Zhang Wei Guo Ya Cao Jian Zhou Jia Fan XinRong Yang 《Molecular oncology》2021,15(9):2345
Circulating tumor cell (CTC) analysis holds great potential to be a noninvasive solution for clinical cancer management. A complete workflow that combined CTC detection and single‐cell molecular analysis is required. We developed the ChimeraX®‐i120 platform to facilitate negative enrichment, immunofluorescent labeling, and machine learning‐based identification of CTCs. Analytical performances were evaluated, and a total of 477 participants were enrolled to validate the clinical feasibility of ChimeraX®‐i120 CTC detection. We analyzed copy number alteration profiles of isolated single cells. The ChimeraX®‐i120 platform had high sensitivity, accuracy, and reproducibility for CTC detection. In clinical samples, an average value of > 60% CTC‐positive rate was found for five cancer types (i.e., liver, biliary duct, breast, colorectal, and lung), while CTCs were rarely identified in blood from healthy donors. In hepatocellular carcinoma patients treated with curative resection, CTC status was significantly associated with tumor characteristics, prognosis, and treatment response (all P < 0.05). Single‐cell sequencing analysis revealed that heterogeneous genomic alteration patterns resided in different cells, patients, and cancers. Our results suggest that the use of this ChimeraX®‐i120 platform and the integrated workflow has validity as a tool for CTC detection and downstream genomic profiling in the clinical setting.
Abbreviations
- ADABOOST
- AdaBoost classification trees
- AFP
- alpha‐fetoprotein
- AUC
- areas under the curve
- BC
- breast cancer
- BCLC
- barcelona clinic liver cancer
- BHL
- benign hepatic lesion
- CCD
- charge‐coupled device
- CHB
- chronic hepatitis B
- CK
- cytokeratin
- CNA
- copy number alteration
- CNLC
- Chinese staging for liver cancer
- CRC
- colorectal cancer
- CTC
- circulating tumor cell
- CTM
- circulating tumor microemboli
- CV
- coefficient of variation
- DAPI
- 4’,6‐diamidine‐2’‐phenylindole dihydrochloride
- EpCAM
- epithelial cell adhesion molecule
- FPR
- false‐positive rate
- GBM
- stochastic gradient boosting
- HCC
- hepatocellular carcinoma
- HD
- healthy donor
- ICC
- intrahepatic cholangiocarcinoma
- LC
- liver cirrhosis
- LCA
- lung cancer
- LOD
- limit of detection
- PBS
- phosphate‐buffered saline
- PCR
- polymerase chain reaction
- RF
- random forest
- ROC
- receiver operating characteristic
- SVM
- support vector machines
- TCGA
- The Cancer Genome Atlas
- TPR
- true‐positive rate
- TTR
- time to recurrence
- WBC
- white blood cell
- WGA
- whole‐genome amplification
- WGS
- whole‐genome sequencing
- XGB
- extreme gradient boosting
18.
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
19.
20.
Leptin, a hormone predominantly derived from adipose tissue, is well known to induce growth of breast cancer cells. However, its underlying mechanisms remain unclear. In this study, we examined the role of reprogramming of lipid metabolism and autophagy in leptin‐induced growth of breast cancer cells. Herein, leptin induced significant increase in fatty acid oxidation‐dependent ATP production in estrogen receptor‐positive breast cancer cells. Furthermore, leptin induced both free fatty acid release and intracellular lipid accumulation, indicating a multifaceted effect of leptin in fatty acid metabolism. These findings were further validated in an MCF‐7 tumor xenograft mouse model. Importantly, all the aforementioned metabolic effects of leptin were mediated via autophagy activation. In addition, SREBP‐1 induction driven by autophagy and fatty acid synthase induction, which is mediated by SREBP‐1, plays crucial roles in leptin‐stimulated metabolic reprogramming and are required for growth of breast cancer cell, suggesting a pivotal contribution of fatty acid metabolic reprogramming to tumor growth by leptin. Taken together, these results highlighted a crucial role of autophagy in leptin‐induced cancer cell‐specific metabolism, which is mediated, at least in part, via SREBP‐1 induction.
Abbreviations
- 2‐DG
- 2‐deoxyglucose
- 3‐MA
- 3‐methyladenine
- ACC‐1
- acetyl‐CoA carboxylase 1
- ACLY
- ATP citrate lyase
- ER
- estrogen receptor
- FADS1
- fatty acid desaturase 1
- FADS2
- fatty acid desaturase 2
- FAO
- fatty acid oxidation
- FAS
- fatty acid synthesis
- FASN
- fatty acid synthase
- FFA
- free fatty acid
- IHC
- immunohistochemistry
- SCD‐1
- stearoyl‐CoA desaturase‐1
- SREBP‐1
- sterol regulatory element‐binding protein 1