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Research Paper Volume 13, Issue 21 pp 24171-24191
LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability
Relevance score: 11.742513Peng-Ping Li, Rong-Guo Li, Yu-Qing Huang, Jin-Pian Lu, Wei-Jun Zhang, Zhen-Yu Wang
Keywords: chemotherapy resistance, autophagy, genomic instability (GIN), triple negative breast cancer (TNBC), DNA damage response (DDR)
Published in Aging on November 5, 2021
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Research Paper Volume 13, Issue 15 pp 19306-19316
LncRNA-HAGLR motivates triple negative breast cancer progression by regulation of WNT2 via sponging miR-335-3p
Relevance score: 14.071408Liting Jin, Chenggang Luo, Xinhong Wu, Manxiu Li, Shun Wu, Yaojun Feng
Keywords: triple negative breast cancer, lncRNA HAGLR, miR-335-3p, WNT2, tumor progression
Published in Aging on August 10, 2021
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Research Paper Volume 13, Issue 15 pp 19486-19509
A combined hypoxia and immune gene signature for predicting survival and risk stratification in triple-negative breast cancer
Relevance score: 17.411417Xia Yang, Xin Weng, Yajie Yang, Meng Zhang, Yingjie Xiu, Wenfeng Peng, Xuhui Liao, Meiquan Xu, Yanhua Sun, Xia Liu
Keywords: triple-negative breast cancer, risk stratification, hypoxia, immune, survival
Published in Aging on August 2, 2021
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Research Paper Volume 13, Issue 14 pp 18191-18222
Formononetin relieves the facilitating effect of lncRNA AFAP1-AS1-miR-195/miR-545 axis on progression and chemo-resistance of triple-negative breast cancer
Relevance score: 14.204147Jingjing Wu, Wen Xu, Lina Ma, Jiayu Sheng, Meina Ye, Hao Chen, Yuzhu Zhang, Bing Wang, Mingjuan Liao, Tian Meng, Yue Zhou, Hongfeng Chen
Keywords: lncRNA AFAP1-AS1, miR-195/miR-545, triple-negative breast cancer, formononetin, chemo-resistance
Published in Aging on July 21, 2021
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Research Paper Volume 13, Issue 13 pp 17177-17189
Carbon nanotubes (CNT)-loaded ginsenosides Rb3 suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer
Relevance score: 15.333985Xiao Luo, Hui Wang, Degang Ji
Keywords: triple-negative breast cancer, progression, CNTs, Rg3, PD-1/PD-L1 axis
Published in Aging on June 10, 2021
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Research Paper Volume 13, Issue 9 pp 12514-12525
Capsanthin induces G1/S phase arrest, erlotinib-sensitivity and inhibits tumor progression by suppressing EZH2-mediated epigenetically silencing of p21 in triple-negative breast cancer cells
Relevance score: 15.465921Jia-Yan Wu, Yi-Chung Chien, I-Chen Tsai, Chih-Chiang Hung, Wei-Chien Huang, Liang-Chih Liu, Yung-Luen Yu
Keywords: capsanthin, triple-negative breast cancer (TNBC), EZH2, p21, erlotinib
Published in Aging on May 2, 2021
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Research Paper Volume 13, Issue 5 pp 7211-7227
Follistatin-like 1 deficiency impairs T cell development to promote lung metastasis of triple negative breast cancer
Relevance score: 11.3382845Jie Ma, Ying Yang, Lulu Wang, Xiaowei Jia, Tao Lu, Yiyan Zeng, Li Liu, Yan Gao
Keywords: follistatin-like 1, lung metastasis, triple negative breast cancer, thymus medullary epithelial cells, T cell development
Published in Aging on February 26, 2021
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Research Paper Volume 13, Issue 4 pp 5485-5505
Tumor microenvironment characterization in triple-negative breast cancer identifies prognostic gene signature
Relevance score: 17.060125Yan Qin, Jiehua Deng, Lihua Zhang, Jiaxing Yuan, Huawei Yang, Qiuyun Li
Keywords: tumor microenvironment, triple-negative breast cancer, immune checkpoint
Published in Aging on February 1, 2021
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Research Paper Volume 13, Issue 3 pp 4522-4551
Hsa_circ_0000199 facilitates chemo-tolerance of triple-negative breast cancer by interfering with miR-206/613-led PI3K/Akt/mTOR signaling
Relevance score: 13.094165Hongchang Li, Wen Xu, Zhihua Xia, Weiyan Liu, Gaofeng Pan, Junbin Ding, Jindong Li, Jianfa Wang, Xiaofeng Xie, Daowen Jiang
Keywords: hsa_circ_0000199, triple-negative breast cancer, miR-613, miR-206, PI3K/Akt/mTOR signaling
Published in Aging on January 20, 2021
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Research Paper Volume 13, Issue 1 pp 228-240
Downregulation of miR-155-5p enhances the anti-tumor effect of cetuximab on triple-negative breast cancer cells via inducing cell apoptosis and pyroptosis
Relevance score: 15.571937Wen Xu, Changfeng Song, Xiaotong Wang, Yueqi Li, Xue Bai, Xin Liang, Jingjing Wu, Jianwen Liu
Keywords: triple-negative breast cancer, microRNA 155-5p, cetuximab, apoptosis, pyroptosis
Published in Aging on January 5, 2021
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Research Paper Volume 13, Issue 1 pp 1153-1175
Construction of an mRNA-miRNA-lncRNA network prognostic for triple-negative breast cancer
Relevance score: 15.465921Yuan Huang, Xiaowei Wang, Yiran Zheng, Wei Chen, Yabing Zheng, Guangliang Li, Weiyang Lou, Xiaojia Wang
Keywords: triple-negative breast cancer, biomarker, competing endogenous RNA, prognosis
Published in Aging on January 3, 2021
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Research Paper Volume 13, Issue 1 pp 424-436
LncRNA HAND2-AS1 suppressed the growth of triple negative breast cancer via reducing secretion of MSCs derived exosomal miR-106a-5p
Relevance score: 14.181563Li Xing, Xiaolong Tang, Kaikai Wu, Xiong Huang, Yi Yi, Jinliang Huan
Keywords: triple negative breast cancer, exosome, miR-106a-5p, MSCs, HAND2-AS1
Published in Aging on December 3, 2020
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Research Paper Volume 12, Issue 14 pp 14775-14790
The circular RNA circEIF3M promotes breast cancer progression by promoting cyclin D1 expression
Relevance score: 17.060125Xiujuan Li, Zhaojun Ren, Yufeng Yao, Jun Bao, Qiao Yu
Keywords: circEIF3M, miR-33a, triple-negative breast cancer, CCND1
Published in Aging on July 11, 2020
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Research Paper Volume 12, Issue 13 pp 13023-13037
The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer
Relevance score: 14.937864Hui-Yu Lin, Chia-Hao Kuei, Hsun-Hua Lee, Che-Hsuan Lin, Jing-Quan Zheng, Hui-Wen Chiu, Chi-Long Chen, Yuan-Feng Lin
Keywords: gαh, autophagy, Akt/mTORC1, metastasis, triple-negative breast cancer
Published in Aging on July 1, 2020
The mTORC1-related pathway is putatively activated in ER(-) breast cancer with high-level Gαh expression and lung metastasis. (A) Flowchart of the gene enrichment analysis (GSEA) using the transcription profiling of the top 10% upregulated and downregulated genes in ER(-) breast cancer tissues that were defined with low-level Gαh expression without lung metastasis or high-level Gαh expression with lung metastasis in a Kaplan-Meier analysis based on the GSE5327 data set. (B) The enrichment score (ES) derived from the correlation between the MTORC1 gene set and the queried gene signatures was plotted as the green curve. The parameters including the normalized enrichment score (NES), nominal p values and false discovery rates (FDRs) are shown as inserts. (C) Transcriptional profiling of the MTORC1 gene set in the groups is shown in A. The statistical significance was analyzed by Student’s t-test. (D) Correlation of the expression of Gαh mRNA levels and MTORC1 gene in the groups is shown in A. (E and F) Results from the Kaplan-Meier analyses of the transcriptional levels of the mTORC1 gene set alone (E) or combined with the mRNA levels of Gαh (F) against ER(-) breast cancer patients from the GSE5327 data set.
The phosphorylation of Akt and mTORC1 positively correlates with cell invasion ability and is regulated by the Gαh-PLC-δ1 pathway in TNBC cells. (A) Results from the western blot analysis for the Gαh, phosphorylated Akt (p-Akt), Akt, p-mTOR, mTOR and GAPDH proteins derived from the indicated TNBC cell lines. (B) Giemsa staining of the invaded cells of the tested TNBC cell lines after a 16-hour invasion assay. (C) Correlation of mRNA expression levels between Gαh and the mTORC1 gene set in a panel of breast cancer cell lines derived from the Cancer Cell Line Encyclopedia (CCLE) database. Spearman’s correlation test was used to estimate the statistical significance. (D–E) Results from the western blot analysis for the Gαh, p-Akt, Akt, p-mTOR, mTOR and GAPDH proteins derived from the parental (PT) HCC1806 cells without (vector control, VC) or with Gαh overexpression (D) and the parental MDA-MD231 cells without (nonsilenced, NS) or with Gαh knocked down using two independent shRNA clones (E). (F–H) MDA-MD231 cells treated without or with 10 μM Gαh/PLC-δ1 protein-protein interaction (PPI) inhibitor for 2 hours were subjected to a reciprocal immunoprecipitation for detecting the PPI of Gαh/PLC-δ1 (F), Western blot analysis for measuring the protein levels of p-Akt, Akt, p-mTOR, mTOR and GAPDH (G), and immunofluorescent staining for visualizing the intracellular protein levels of p-Akt and p-mTOR (H). In A, D, E, G, GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group.
The Gαh-PLC-δ1 axis promotes autophagosome degradation in TNBC cells. (A) Results from the Western blot analysis for LC3-I/II, p62 and GAPDH proteins derived from the indicated TNBC cell lines. (B) Correlation of mRNA expression levels of Gαh and the autophagy-related gene set in a panel of breast cancer cell lines derived from the Cancer Cell Line Encyclopedia (CCLE) database. Spearman’s correlation test was used to estimate the statistical significance. (C–E) Results from the Western blot analysis of the LC3-I/II, p62 and GAPDH proteins derived from the parental (PT) HCC1806 cells without (vector control, VC) or with Gαh overexpression (C) and the parental MDA-MD231 cells without (nonsilenced, NS) or with Gαh knocked down using two independent shRNA clones (D), and MDA-MD231 cells treated without or with 10 μM Gαh/PLC-δ1 protein-protein interaction (PPI) inhibitor for 2 hours (E). In A, C, D, E, GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group.
The inhibition of autophagy initiation by 3-MA rescues the metastatic potential of the Gαh-silenced MDA-MB231 cells in vitro and in vivo. (A) The results from the Western blot analysis for the LC3-I/II, p62 and GAPDH proteins derived from MDA-MD231 cells without (NS) or with Gαh knocked down (KD) in the absence or presence of the autophagy inhibitor 3-MA (3 or 10 mM). GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group. (B–C) Giemsa staining (B) and cell number (C) of the invaded MDA-MD231 cell variants shown in A. Data obtained from three independent experiments are presented as the mean ± SEM. Letters indicate the significant differences at p<0.01 analyzed by nonparametric Friedman test. (D and E) H&E stained lung tissues (D) and the number of lung tumor colonies tumors (E) derived from the mice (n=5) transplanted with MDA-MD231 cell variants, shown in A, through tail vein injection for 4 weeks. Tumors are shown in red circles. Statistical significance was determined by nonparametric Mann-Whitney U test.
The inhibition of mTORC1 activity by rapamycin restores autophagy function but compromises the cellular invasion and lung metastatic abilities of Gαh-overexpressing HCC1806 cells. (A) Results from the Western blot analysis of the LC3-I/II, p62 and GAPDH proteins derived from HCC1806 cells without (VC) or overexpression Gαh (OE) in the absence or presence of the mTOR inhibitor rapamycin (RAPA) (30 or 100 μM). GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group. (B–C) Giemsa staining (B) and cell number (C) for the invaded HCC1806 cell variants shown in A. Data obtained from three independent experiments are presented as the mean ± SEM. Letters indicate the significant differences at p<0.01 analyzed by nonparametric Friedman test. (D and E) H&E staining of lung tissues (D) and the number of lung tumor colonies (E) derived from mice (n=5) transplanted with the HCC1806 cell variants, shown in A, through tail vein injection for 4 weeks. Tumors are shown in red circles. Statistical significance was analyzed by nonparametric Mann-Whitney U test.
The signature of the combined Gαh upregulation and low levels of autophagy activity increases the likelihood of lung metastasis in ER(-) breast cancer patients. (A) Transcriptional profiling of the autophagy-related gene set in the groups shown in Figure1A. The statistical significance was analyzed by Student’s t-test. (B) Correlation of the expression levels of Gαh mRNA and the autophagy-related gene set in the stratified groups. (C and D) Results from the Kaplan-Meier analyses for the transcriptional level of the autophagy-related gene set alone (G) or combined with the mRNA level of Gαh (D) against ER(-) breast cancer patients from the GSE5327 data set.
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Research Paper Volume 12, Issue 11 pp 10983-11003
The circRNA circIFI30 promotes progression of triple-negative breast cancer and correlates with prognosis
Relevance score: 15.969981Lei Xing, Rui Yang, Xiaosong Wang, Xiaying Zheng, Xin Yang, Luyu Zhang, Rong Jiang, Guosheng Ren, Junxia Chen
Keywords: circIFI30, miR-520b-3p, triple-negative breast cancer, CD44
Published in Aging on June 4, 2020
Expression profile of circRNA in TNBC and para-carcinoma tissues by RNA sequencing and characterization of circIFI30. (A) Hierarchical cluster analysis of all target circRNAs in the TNBC and matched para-carcinoma tissues was shown. Each column represents a sample and each row represents a circRNA. Red strip represents high relative expression and green strip represents low relative expression. (B) The cluster heat map showed the top 10 up-regulated and down-regulated circRNAs. (C) The genomic locus of the circIFI30 and the back-spliced junction of circIFI30 were indicated, the back-splice junction sequence was validated by Sanger sequencing. (D) PCR product of circIFI30 was confirmed by agarose gel electrophoresis. (E) CircIFI30, linear IFI30 and GAPDH were amplified from cDNA or gDNA in MDA-MB-231 cells with divergent and convergent primers, respectively. Divergent primers amplified circIFI30 in cDNA but not genomic DNA (gDNA). (F) RNase R treatment was used to evaluate the exonuclease resistance of circIFI30 in MDA-MB-231 cells. GAPDH was measured as a control. (G) Nuclear-cytoplasmic fractionation assay showed that circIFI30 was mainly localized in the cytoplasm of MDA-MB-231 cells. GAPDH was considered as a cytoplasmic control. U6 was used as a nuclear control.
circIFI30 is up-regulated in TNBC and associated with the progression and poor prognosis of TNBC patients. (A) Relative expression of circIFI30 in TNBC tissues and adjacent non-tumor tissues was detected by qRT-PCR (n = 38). (B) Relative expression of circIFI30 in cell lines was determined by qRT-PCR. (C) ROC curve was applied to evaluate the diagnostic value of circIFI30 for TNBC. (D) Representative images of circIFI30 expression in TNBC tissues were detected by ISH assays. Scale bar, 100 μm. (E) Dot distribution graph of circIFI30 ISH staining scores was shown in TNBC patients with different pathological grades. (F) Kaplan-Meier survival curve of overall survival in 78 patients with TNBC according to the circIFI30 expression. Patients were stratified into high expression and low expression group by median expression. Data were showed as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
circIFI30 promotes TNBC cell proliferation. (A) Relative expression of circIFI30 was determined in TNBC cells transfected with circIFI30 expression vector, mock, sh-circ or sh-NC by qRT-PCR. (B) The cell viability was measured in TNBC cells transfected with indicated vectors by CCK-8 assay. (C, D) The cell proliferation ability was detected in TNBC cells after transfection with indicated plasmids by EdU assay. Scale bar, 50 μm. (E, F) Cell survival was evaluated in TNBC cells transfected with indicated plasmids by colony formation assay. Data were showed as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
circIFI30 increases TNBC cell migration and invasion and modulates cell cycle and apoptosis. (A, B) The cell migration capacity was detected by wound healing assay after transfection with indicated vectors (magnification, × 50). Scale bar, 200 μm. (C, D) The cell invasion ability was determined by transwell assay after overexpression or knockdown of circIFI30 (magnification, × 100). Scale bar, 100 μm. (E, F) The cell cycle progression was analyzed by flow cytometry after transfected with indicated plasmids. (G, H) The apoptosis rate detected by flow cytometry after downregulation of circIFI30. (I, J) The apoptotic cells were observed by Hoechst 33342 (magnification, ×100, scale bar, 100 μm) and TUNEL staining (magnification, × 100, scale bar, 100 μm) assays after knockdown of circIFI30. (K) The expression levels of apoptosis-related proteins were determined by western blot. Data were showed as mean ± SD, *P < 0.05, **P < 0.01.
circIFI30 facilitates tumorigenesis and metastasis of TNBC cells in vivo. (A, B) Representative images of xenograft tumors of each group and tumor weight analysis were shown. (C) Growth curves of xenograft tumors were measured once a week. (D, E) HE staining of tumor and lung sections were showed. The microvessels of the tumors and metastatic nodules of the lungs were indicated by arrows (magnification, × 100, scale bar, 100 μm). (F) IHC staining was applied to analyze the protein levels of CD44 and EMT-related molecules (magnification, × 200, scale bar, 100 μm). Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
circIFI30 functions as a sponge for miR-520b-3p. (A) The miR-520b-3p binding site on circIFI30 was predicted by targetScan and miRanda. (B) FISH was performed to observe the cellular location of circIFI30 in TNBC cells (magnification, × 200, scale bar, 50 μm) and tissues (magnification, × 100, scale bar, 50 μm). (C) Relative expression of miR-520b-3p in TNBC tissues and adjacent non-tumor tissues was determined by qRT-PCR (n = 38). (D) Schematic illustration of circIFI30-WT and circIFI30-Mut luciferase reporter vectors was shown. (E) The relative luciferase activities were detected in 293 T cells after transfection with circIFI30-WT or circIFI30-Mut and miR-520b-3p mimics or miR-NC, respectively. (F, G) Anti-AGO2 RIP was executed in MDA-MB-231 cells after transfection with miR-520b-3p mimic or miR-NC, followed by western blot and qRT-PCR to detect AGO2 protein, circIFI30 and miR-520b-3p, respectively. (H) RNA pull-down with a biotin-labeled circIFI30 probe was executed in MDA-MB-231 cells, followed by qRT-PCR and RT-PCR to detect the enrichment of circIFI30 and miR-520b-3p. (I) The relative expression of miR-520b-3p was detected by qRT-PCR after transfection with indicated vectors. Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
circIFI30 promotes cell proliferation, migration and invasion through circIFI30/miR-520b-3p/CD44 axis. (A) The cell viability was determined after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by CCK8 assay. (B, C) The cell proliferation was detected after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by EdU assay (magnification, × 100, scale bar, 100 μm). (D, E) The cell survival was measured after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by colony formation assay. (F, G) The cell migration capacity was detected after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by wound healing assays (magnification, × 50). Scale bar, 200 μm. (H, I) The cell invasion ability was determined after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by transwell assays (magnification, × 100, scale bar, 100 μm). (J, K) Relative expressions of CD44 and EMT-related molecules at protein level in cells transfected with indicated vectors, miR-520b-3p mimics or inhibitors were determined by western blot. Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
CD44 is directly targeted by miR-520b-3p and regulated by circIFI30. (A) Schematic illustration of CD44 3’UTR-WT and CD44 3’UTR-Mut luciferase reporter vectors was shown. (B) Luciferase reporter assay demonstrated that CD44 is direct target of miR-520b-3p. (C, D) Relative mRNA and protein levels of CD44 were detected after TNBC cells were transfected with miR-520b-3p mimics or inhibitors using qRT-PCR and western blot, respectively. (E) Pearson correlation analysis between the expression of circIFI30 and CD44 was shown in 38 TNBC tissues. (F) Relative expression of CD44 was detected by qRT-PCR in cells transfected with indicated vectors, miR-520b-3p or inhibitors. (G) The schematic diagram illustrates how circifi30 might promote EMT, tumorigenesis and metastasis of TNBC through circIFI30/miR-520b-3p/CD44 axis. Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
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Research Paper Volume 12, Issue 10 pp 9621-9632
Pyrrolo [3,4-b]-quinolin-9-amine compound FZU-0038-056 suppresses triple-negative breast cancer partially through inhibiting the expression of Bcl-2
Relevance score: 13.69559Danping Wang, Zhi Nie, Xiaoyan Jiang, Jinxiang Ye, Zhimin Wei, Dating Cheng, Chenyang Wang, Yingying Wu, Rong Liu, Haijun Chen, Ceshi Chen, Chunyan Wang
Keywords: triple-negative breast cancer, tetrahydro-β-carboline derivatives, apoptosis, Bcl-2
Published in Aging on May 23, 2020
Identification of FZU-0038-056 as a potent anti-cancer compound in TNBC cell lines. (A) The HCC1806 and HCC1937 breast cancer cell lines were treated with 42 different compounds (10 μM) for 48 hours. DMSO was used as the negative control. Cell viability was measured using SRB assays. FZU-0038-056 and FZU-0038-058 labeled with an asterisk were selected for further studies. (B) Four different TNBC cell lines, two ER positive breast cancer cell lines and one human immortalized breast cell line were treated with DMSO control or FZU-0038-056/FZU-0038-058 at indicated concentrations (2.5, 5 and 10 μM, respectively) for 48 hours. Cell viability was measured using SRB assay. (C) The chemical structures of FZU-0038-056 and FZU-0038-058.
FZU-0038-056 induces apoptosis in HCC1806 and HCC1937 cells. (A) The cell morphology changes of HCC1806 and HCC1937 cells after the treatment of FZU-0038-056 (10μM) for 12 hours. (B) HCC1806 and HCC1937 cells were stained with Annexin V/PI and analyzed by flow cytometry analysis after the cells were treated with FZU-0038-056 (2.5, 5, 10 μM) for 24 hours. DMSO was added as the negative control. (C, D) The percentages of Annexin V-positive cells from panel B are shown. ** p < 0.01.
FZU-0038-056 decreases the expression of anti-apoptosis proteins and increased p38 phosphorylation in HCC1806 and HCC1937 cells. (A) HCC1806 and HCC1937 cells were treated with FZU-0038-056 (2.5, 5, 10 μM) for 24 hours. Cell lysates were collected for immunoblotting to test the protein levels of cleaved Caspase-3, and PARP, Bcl-2, XIAP, Mcl-1; Bax, Bak and DR5. β-actin was used as the loading control. The quantification data of cl-caspase-3 and Bcl-2 protein expression were shown under the immunoblot images. (B) HCC1806 and HCC1937 cells were treated with FZU-0038-056 (2.5, 5, 10 μM) for 24 hours. The protein levels of p38, p-p38, AKT, p-AKT, ERK, p-ERK, JNK and p-JNK were examined by WB. GAPDH was used as the loading control. The quantification data of p-p38 protein expression was shown under the immunoblot images.
FZU-0038-056 induces TNBC apoptosis not through activating p38. (A, B) HCC1806 and HCC1937 cells were transfected with siRNAs targeting p38 for 36 hours, and treated with FZU-0038-056 (5 μM) or DMSO for 24 hours. Cell lysates were collected for WB assay. The quantification data of p-p38 protein expression was shown under the immunoblot images. (C, D) HCC1806 and HCC1937 cells were transfected with siRNA for 36 hours, then treated with FZU-0038-056 (1.25, 2.5, 5 μM) or DMSO for 48 hours. Cell viability was measured via the SRB assay.
FZU-0038-056 induced apoptosis partially via inhibiting Bcl-2 in HCC1806 cells. (A) Bcl-2 was overexpressed in HCC1806 cells through a lentivirus system. (B) Overexpression of Bcl-2 reduced the cell viability inhibition triggered by FZU-0038-056. Cell viability was measured by the SRB assay. *p < 0.05. (C) FZU-0038-056-induced apoptosis were partially rescued by the overexpression of Bcl-2 compared with the control cells, as measured by Annexin V staining and flow cytometry analysis. Annexin V positive cell populations were quantified and shown on the right side. *p < 0.05. (D) FZU-0038-056-induced apoptosis were partially rescued by the overexpression of Bcl-2, as measured by Caspase-3 and PARP cleavage. The cells were treated with DMSO or FZU-0038-056 (10 μM) for 24 hours, and cell lysates were collected for WB analysis. β-actin was used as loading control.
FZU-0038-056 suppresses HCC1806 xenograft tumor growth in nude mice. (A) FZU-0038-056 suppresses HCC1806 xenograft tumor growth in nude mice. Tumors were collected after the mice were treated with FZU-0038-056, vehicle, or cisplatin for 20 days. (B) FZU-0038-056 significantly reduced HCC1806 xenograft weights. Average tumor weights are graphed (n=5). **p < 0.01. (C) Tumor growth was significantly suppressed by FZU-0038-056 (15 mg/kg) and cisplatin (8 mg/kg) compared with vehicle control. **p < 0.01, *p < 0.05. (D) Compared to vehicle control, FZU-0038-056 (15 mg/kg) did not significantly reduce the mouse body weights although cisplatin (8 mg/kg) reduced the mouse body weights significantly.
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Research Paper Volume 12, Issue 4 pp 3594-3616
LncRNA FAM83H-AS1 promotes triple-negative breast cancer progression by regulating the miR-136-5p/metadherin axis
Relevance score: 13.148844Chunyong Han, Yiwei Fu, Ni Zeng, Jian Yin, Qian Li
Keywords: triple-negative breast cancer (TNBC), FAM83H-AS1, miR-136-5p, metadherin (MTDH)
Published in Aging on February 17, 2020
FAM83H-AS1 is upregulated in TNBC tissues and predicts worse overall survival. (A) Expression profiles of FAM83H-AS1 in TNBC and normal breast tissues using the human lncRNA microarray dataset GSE76250. The p value was calculated by Wilcoxon rank-sum test. (B) Expression profiles of FAM83H-AS1 in TNBC and normal breast tissues using the GEPIA 2 dataset. (C) Overall survival rates in low and high FAM83H-AS1 expression groups in TNBC patients using the GEPIA2 dataset. (D) qRT-PCR of FAM83H-AS1 expression in human TNBC and adjacent control tissues. (E) qRT-PCR of FAM83H-AS1 mRNA in MDA-MB-231, MDA-MB-436, MDA-MB-468, and MCF-10A cells.
FAM83H-AS1 suppression inhibits TNBC cell proliferation, migration, and invasion. (A) qRT-PCR of FAM83H-AS1 expression in TNBC cells transfected with si-control or si-FAM83H-AS1 RNA. (B, C) Proliferation of TNBC cells transfected with si-control or si-FAM83H-AS1 RNA, analyzed by CCK8 assay. (D, E) Wound healing assay of the migration capacity of MDA-MB-231 and MDA-MB-468 cells transfected with si-control or si-FAM83H-AS1. (F, G) Migration and invasion of MDA-MB-231 and MDA-MB-468 cells transfected with si-control or si-FAM83H-AS1. Scale bars, 100 μm. * p < 0.05 compared to controls.
FAM83H-AS1 functions as a sponge for miR-136-5p. (A) Predicted binding site of miR-136-5p in the FAM83H-AS1 sequence and mutated nucleotides. (B, C) Overexpression of miR-136-5p repressed the luciferase activity in TNBC cells transfected with FAM83H-AS1-Wt assessed by luciferase reporter assays. (D) Relative FAM83H-AS1 expression in TNBC cells transfected with mimic control, miR-136-5p mimic, inhibitor control, or miR-136-5p inhibitor. (E) Relative miR-136-5p expression in TNBC cells transfected with si-control, si-FAM83H-AS1, pcDNA-control, or pcDNA-FAM83H-AS1. (F) qRT-PCR analysis of miR-136-5p expression in human TNBC and adjacent control tissues. (G) qRT-PCR analysis of miR-136-5p levels in TNBC cell lines MDA-MB-231, MDA-MB-436, and MDA-MB-468, and a control breast epithelial cell line MCF-10A. (H) RIP assay demonstrating the enrichment of FAM83H-AS1 and miR-136-5p. * p < 0.05 compared to controls.
Overexpression of miR-136-5p reduces TNBC cell proliferation, migration, and invasion. (A) Relative miR-136-5p expression in TNBC cells transfected with mimic control or miR-136-5p mimic. (B, C) Proliferation of TNBC cells transfected with mimic control or miR-136-5p mimic, analyzed by CCK8 assay. (D, E) Wound healing assay of the migration capacity of TNBC cells transfected with mimic control or miR-136-5p mimic. (F, G) Migration and invasion of TNBC cells transfected with mimic control or miR-136-5p mimic, analyzed by transwell assays. Scale bars, 100 μm. * p < 0.05 compared to controls.
FAM83H-AS1 promotes TNBC cell proliferation, migration, and invasion through inhibiting miR-136-5p. (A) Relative miR-136-5p expression in TNBC cells transfected with control, si- FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor evaluated by qRT-PCR. (B, C) Proliferation of TNBC cells transfected with control, si-FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor, analyzed by CCK8 assay. (D, E) Wound healing assay of the migration of MDA-MB-231 and MDA-MB-468 cells transfected with control, si-FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor. (F, G) Migration and invasion of TNBC cells transfected with control, si-FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor, assessed by transwell assays. * p < 0.05 compared to controls.
MiR-136-5p suppresses MTDH expression in TNBC cells. (A) Predicted binding site of miR-136-5p in MTDH sequence and mutated nucleotides. (B) MTDH expression in TNBC tissues analyzed using GEPIA 2 dataset. (C) qRT-PCR analysis of MTDH expression in human TNBC tissues. (D) qRT-PCR analysis of MTDH expression in MDA-MB-231, MDA-MB-436, MDA-MB-468, and MCF-10A cells. (E) MTDH expression in TNBC cells transfected with mimic control or miR-136-5p mimic. (F, G) Western blot analysis of MTDH protein levels in TNBC cells transfected with mimic control or miR-136-5p mimic. (H, I) Overexpression of miR-136-5p represses the luciferase activity in TNBC cells transfected with MTDH-Wt, evaluated by luciferase reporter assays. (J) Correlation between FAM83H-AS1 and MTDH expression in breast cancer tissues analyzed by Spearman’s rank test using the GEPIA 2 dataset. * p < 0.05 compared to controls.
MiR-136-5p inhibits proliferation, migration, and invasion of TNBC cells through suppressing MTDH. (A, B) Western blot analyses in TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (C) Expression of MTDH in TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (D, E) CCK8 assay utilized to evaluate cell proliferation of TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (F, G) Wound healing assay used to determine migration of TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (H, I) Migration and invasion of TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH, analyzed by transwell assays. * p < 0.05 compared to controls.
FAM83H-AS1 promotes tumor growth in TNBC xenograft mouse model. (A, B) Tumor volume measured every 5 days in mice injected with TNBC cells transfected with sh-control or sh-FAM83H-AS1. (C) Tumor weight in mice injected with TNBC cells transfected with sh-control or sh-FAM83H-AS1. (D, E) Tumor size measured in mice injected with TNBC cells transfected with LV-control or LV-FAM83H-AS1. (F) Tumor weight in mice injected with TNBC cells transfected with LV-control or LV-FAM83H-AS1. * p < 0.05 compared to controls.
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Research Paper Volume 11, Issue 24 pp 12043-12056
CircAHNAK1 inhibits proliferation and metastasis of triple-negative breast cancer by modulating miR-421 and RASA1
Relevance score: 14.937864Weikai Xiao, Shaoquan Zheng, Yutian Zou, Anli Yang, Xinhua Xie, Hailin Tang, Xiaoming Xie
Keywords: biomarker, triple negative breast cancer, circAHNAK1, miR-421, RASA1
Published in Aging on December 19, 2019
circANNAK1 is down-regulated and associated with malignant progression and poor prognosis of TNBC. (A) Expression of circAHNAK1 in breast cancer cell lines. (B) Expression of circAHNAK1 in breast cancer tissues and normal adjacent tissues. (C, D)The effect of circAHNAK1 expression on OS and DFS in patients with TNBC. *** P <0.001.
Overexpression of circAHNAK1 inhibits proliferation and metastasis of TNBC. (A)Successfully established two breast cancer cell lines that overexpress circAHNAK1; (B) CCK-8 assay to evaluate the effect of circAHNAK1 on cell proliferation; (C) Colony formation assay to evaluate the effect of circAHNAK1 on cell colony forming ability; (D) Number of clones quantified by ImageJ; (E) Transwell invasion assay to evaluate the effect of circAHNAK1 on cell invasion; (F) ImageJ quantifies the number of invading cells; (G) Wound healing assay evaluates the effect of circAHNAK1 on wound closure; (H) ImageJ quantifies the extent of wound healing; (I) Xenograft model to evaluate the effect of circAHNAK1 on tumor proliferation in vivo; (J) Effect of circAHNAK1 on proliferation in vivo by tumor weight; (K) Representative images of luciferase signaling to assess the effects of circAHNAK1 on lung metastasis in vivo; (L) Representative images of HE staining of lung metastatic nodule sections; (M) Quantification of the number of lung metastatic nodules.
circAHNAK1 can act as a sponge for miR-421. (A) The expression levels of nuclear control (18S), cytoplasmic control (β-actin) and circAHNAK1 were detected; (B) Prediction of the binding site of miR-421 in the circAHNAK1 sequence; (C) The expression of miR-421 in TNBC cell line; (D) Luciferase assay of cells co-transfected with the miR-421 mimics and the circ-AHNAK1 wild type or mutant luciferase reporter; (E) GFP-MS2-RIP assay detects enrichment of miR-421after MS2bs-circAHNAK1-WT, MS2bs-circAHNAK1-Mut or control transfection, respectively; (F) Effect of miR-421 mimics transfection on proliferation of circAHNAK1 overexpressing cells by CCK-8; (G) Effect of miR-421 mimics transfection on circAHNAK1 overexpressing cells by clone formation assay; (H) Quantitative clone formation by ImageJ software; (I) Transwell invasion assay assessed the impact on cell invasion;(J) ImageJ software quantifies the number of invading cells;(K)Wound healing assay for detecting changes in cell migration ability; (L) ImageJ software quantifies the extent of wound closure; (M) Xenograft model to evaluate tumor proliferation in vivo; (N) Comparison of tumor weight; (O)Representative images of luciferase signaling of lung metastasis in vivo; (P) Representative images of HE staining of lung metastatic nodule sections; (Q) Quantification of the number of lung metastatic nodules.
circAHNAK1 acts as a ceRNA to regulate RASA1. (A)Predicting the binding site of miR-421 in the RASA1-3′UTR region by TargetScan;(B) Luciferase assay after transfection with miR-421 mimics or inhibitor (C) Detection of RASA1 expression after miR-421 transfection by qRT-PCR; (D) Detection of RASA1 expression after transfection by immunofluorescence; (E)Detection of RASA1 expression after transfection by western blots. (F)Ago2-RIP assay showed enrichment of circAHNAK1, RASA1 and miR-421 on Ago2; (G) Ago2-RIP assay showed the effect of circAHNAK1 overexpression on RASA1 enrichment; (H) qRT-PCR detected RASA1 expression after transfection of circAHNAK1 and/or miR-421; (I)Western blots detected RASA1 expression after transfection of circAHNAK1 and/or miR-421;
RASA1 is down-regulated and associated with poor prognosis of TNBC. (A) qRT-PCR detected mRNA expression of RASA1 in breast cancer cell lines;(B)Western blots detected RASA1 expression in breast cancer cell lines;(C) Representative IHC images of high and low RASA1 expression in TNBC tissues;(D, E)The effect of RASA1 expression on OS and DFS in patients with TNBC.
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Research Paper Volume 11, Issue 23 pp 11054-11072
EGFR-specific CAR-T cells trigger cell lysis in EGFR-positive TNBC
Relevance score: 12.57629Yan Liu, Yehui Zhou, Kuo-Hsiang Huang, Ying Li, Xujie Fang, Li An, Feifei Wang, Qingfei Chen, Yunchao Zhang, Aihua Shi, Shuang Yu, Jingzhong Zhang
Keywords: triple-negative breast cancer, human epidermal growth factor receptor, chimeric antigen receptor engineered T cells
Published in Aging on December 4, 2019
EGFR expression in breast cancer cell lines. EGFR expression in TNBC cell lines (HS578T, MDA-MB-468, and MDA-MB-231) and MCF-7 cells detected by (A) real-time RT PCR, (B) Western blot, and (C) flow cytometry. Error bars represent means ± SEM. T-tests were used for statistical analysis; ***p < 0.001.
Characterization of T lymphocytes from PBMCs. (A–B) T cell phenotypes and subsets were examined by flow cytometry after labeling with anti-CD3-PE-Cy7, anti-CD4-PE, and anti-CD8-APC-Cy7.
Generation, isolation, and characterization of EGFR-specific CAR T lymphocytes. (A) Schematic illustration of Con-CAR, EGFR-CAR-1, and EGFR-CAR-2. (B) Expression of exogenous CD3ζin non-transduced T cells, con-CAR T cells, EGFR-CAR-1 T cells, and EGFR-CAR-2 T cells was measured using Western blots; β-actin was used as an endogenous control. (C) GFP and EGFR-GFP antigens were detected by Western blot. (D) Transduced T cells were stained with GFP and EGFR-GFP antigen and then detected by flow cytometry.
Cytokine release and cytotoxicity assay. Cytokine release in target cells in response to effector non-transduced T cells, con-CAR-T cells, EGFR-CAR-1 T cells, and EGFR-CAR-2 T cells. Effector cells were co-cultured with target cells (HS578T, MDA-MB-468, MDA-MB-231, and MCF-7) at an E:T ratio of 10:1 for 24h. (A) IFN-γ, (B) IL-4, and (C) IL-2 levels were assayed in the co-culture supernatants. Cytotoxicity was measured in each group using a standard LDH release assay. Effector cells were co-cultured with (D) HS578T, (E) MDA-MB-468, (F) MDA-MB-231, and (G) MCF-7 target cells at E:T ratios of 5:1, 10:1, or 20:1 for 24h.
TNBC cell lysis assay. (A) HS578T, (B) MDA-MB-468, and (C) MDA-MB-231 cells were labeled with YOYO-3 (red). Non-transduced T cells, con-CAR-T cells, EGFR-CAR-1 T cells, and EGFR-CAR-2 T effector cells were co-cultured with target cells at an E:T ratio of 10:1 for 24h.
EGFR-specific CAR-T cells inhibited EGFR-expressing TNBC tumor growth in CLDX mouse model. Compared to con-CAR-T cells, EGFR-CAR-1 and EGFR-CAR-2 T cells decreased the weights and volumes of tumors induced by (A, B) HS578, (D, E) MDA-MB-468, and (G, H) MDA-MB-231 TNBC cells, but did not affect body weight (C, F, I). Error bars represent means ± SEM. T-tests were used for statistical analysis; *p < 0.05, ** p < 0.01, ***p < 0.001.
EGFR-CAR-T cells inhibited high-EGFR-expressing TNBC tumor growth in PDX mouse model. ER, PR, HER2, and EGFR expression in (A) clinical breast cancer samples and (B) breast cancer tumors in PDX mice were assessed in immunohistochemical assays. Compared to con-CAR-T cells, EGFR-CAR-1 and EGFR-CAR-2 T cells decreased breast cancer (C) tumor weights and (D) tumor volumes but did not affect (E) body weights. Error bars represent means ± SEM. T-tests were used for statistical analysis; *p < 0.05, **p < 0.01.
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Research Paper Volume 11, Issue 16 pp 6286-6311
Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis
Relevance score: 14.071408Yunhai Li, Dejuan Yang, Ping Chen, Xuedong Yin, Jiazheng Sun, Hongzhong Li, Guosheng Ren
Keywords: network meta-analysis, triple-negative breast cancer, neoadjuvant chemotherapy, pathological complete response
Published in Aging on August 24, 2019
A PRISMA flow chart of the literature search and study selection in this meta-analysis.
Network diagram of eligible comparisons included in the network meta-analysis for pathological complete response (pCR). The node size is proportional to the total number of patients in the regimen. The width of each line is proportional to the number of studies comparing the two regimens linked by the line.
Forest plots of pair-wise meta-analyses for pathological complete response (pCR). (A) Standard chemotherapeutic agents vs. P-containing regimens. (B) Standard chemotherapeutic agents vs. B-containing regimens. (C) B-containing regimens vs. BP-containing regimens. (D) Standard chemotherapeutic agents vs. PPi-containing regimens. (E) Standard chemotherapeutic agents vs. Ca-containing regimens. (F) Standard chemotherapeutic agents vs. Za-containing regimens.
Bayesian network meta-analysis for pathological complete response (pCR). (A) The league table of comparisons. Data are presented as odds radio (OR) and 95% confidence intervals (CI). An OR>1 favors the column-defining treatment, and an OR<1 favors the row-defining treatment. (B) Heatmap of the rank probability of the twelve regimens for pCR. Rank 1 represents the best treatment and rank 12 represents the worst. Rank probabilities sum to one, both within a rank over treatments and within a treatment over ranks.
Bayesian network meta-analysis for grade 3–4 hematological adverse events. (A) The league table for comparisons of anemia. (B) The league table for comparisons of neutropenia. (C) The league table for comparisons of thrombocytopenia. Data are presented as odds radio (OR) and 95% confidence intervals (CI). An OR>1 favors the row-defining treatment, and OR<1 favors the column-defining treatment.
Stochastic multi-criteria acceptability analysis for benefit-risk. (A) Rank probability of regimens based on synthesizing pCR and anemia. (B) Rank probability of regimens based on synthesizing pCR and neutropenia. (C) Rank probability of regimens based on synthesizing pCR and thrombocytopenia. (D) Rank probability of regimens based on synthesizing pCR and the three serious adverse events. Rank 1 represents the best treatment and rank N represents the worst. The proportion corresponds to the probability of each regimen to be at a specific rank.