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1.
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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
3.
Xin Guo Aman Wang Wen Wang Ya Wang Huan Chen Xiaolong Liu Tian Xia Aijia Zhang Di Chen Huan Qi Ting Ling Hailong Piao Hongjiang Wang 《Molecular oncology》2021,15(2):642
Dependence on glutamine and acceleration of fatty acid oxidation (FAO) are both metabolic characteristics of triple‐negative breast cancer (TNBC). With the rapid growth of tumors, accelerated glutamine catabolism depletes local glutamine, resulting in glutamine deficiency. Studies have shown that the use of alternative energy sources, such as fatty acids, enables tumor cells to continue to proliferate rapidly in a glutamine‐deficient microenvironment. However, the detailed mechanisms behind this metabolic change are still unclear. Herein, we identified HRD1 as a regulatory protein for FAO that specifically inhibits TNBC cell proliferation under glutamine‐deficient conditions. Furthermore, we observed that HRD1 expression is significantly downregulated under glutamine deprivation and HRD1 directly ubiquitinates and stabilizes CPT2 through K48‐linked ubiquitination. In addition, the inhibition of CPT2 expression dramatically suppresses TNBC cell proliferation mediated by HRD1 knockdown in vitro and in vivo. Finally, we found that the glutaminase inhibitor CB839 significantly inhibited TNBC cell tumor growth, but not in the HRD1 knock‐downed TNBC cells. These findings provide an invaluable insight into HRD1 as a regulator of lipid metabolism and have important implications for TNBC therapeutic targeting.
Abbreviations
- CPT1A
- carnitine palmitoyltransferase 1A
- CPT2
- carnitine palmitoyltransferase 2
- FAO
- fatty acid oxidation
- GLS
- glutaminase
- HRD1
- HMG‐CoA reductase degradation protein 1
- LC‐MS
- liquid chromatography mass spectrometry
- TNBC
- triple‐negative breast cancer
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
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6.
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
7.
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
8.
9.
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
10.
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
11.
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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
14.
《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
15.
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
16.
17.
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
18.
Julius Semenas Tianyan Wang Azharuddin Sajid Syed Khaja AKM Firoj Mahmud Athanasios Simoulis Thomas Grundstrm Maria Fllman Jenny L. Persson 《Molecular oncology》2021,15(4):968
Selective ERα modulator, tamoxifen, is well tolerated in a heavily pretreated castration‐resistant prostate cancer (PCa) patient cohort. However, its targeted gene network and whether expression of intratumor ERα due to androgen deprivation therapy (ADT) may play a role in PCa progression is unknown. In this study, we examined the inhibitory effect of tamoxifen on castration‐resistant PCa in vitro and in vivo. We found that tamoxifen is a potent compound that induced a high degree of apoptosis and significantly suppressed growth of xenograft tumors in mice, at a degree comparable to ISA‐2011B, an inhibitor of PIP5K1α that acts upstream of PI3K/AKT survival signaling pathway. Moreover, depletion of tumor‐associated macrophages using clodronate in combination with tamoxifen increased inhibitory effect of tamoxifen on aggressive prostate tumors. We showed that both tamoxifen and ISA‐2011B exert their on‐target effects on prostate cancer cells by targeting cyclin D1 and PIP5K1α/AKT network and the interlinked estrogen signaling. Combination treatment using tamoxifen together with ISA‐2011B resulted in tumor regression and had superior inhibitory effect compared with that of tamoxifen or ISA‐2011B alone. We have identified sets of genes that are specifically targeted by tamoxifen, ISA‐2011B or combination of both agents by RNA‐seq. We discovered that alterations in unique gene signatures, in particular estrogen‐related marker genes are associated with poor patient disease‐free survival. We further showed that ERα interacted with PIP5K1α through formation of protein complexes in the nucleus, suggesting a functional link. Our finding is the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα, PIP5K1α/AKT network, and MMP9/VEGF signaling axis, providing a strategy to treat castration‐resistant ER‐positive subtype of prostate cancer tumors with metastatic potential.
Abbreviations
- CRPC
- castration‐resistant prostate cancer
- DHT
- dihydrotestosterone
- E2
- estradiol
- ERα
- estrogen receptor alpha
- GO
- gene ontology
- NG‐CHM
- Next‐Generation Clustered Heatmaps
- PCa
- prostate cancer
- TMAs
- tissue microarrays
19.
20.
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