scholarly journals HINT3 suppresses AKT/mTOR signaling activity during breast cancer tumorigenesis through transcriptionally activation of PTEN

2020 ◽  
Author(s):  
Qi Ju ◽  
Yaobang Liu ◽  
Bing Lian ◽  
Hong Li ◽  
Dahai Chai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Colony Growth ◽  
Mtor Signaling ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter

Abstract Background Histidine triad nucleotide-binding (HINT) protein belongs to the histidine triad proteins family. Recent studies have shown that HINT1 and HINT2 play pivotal roles in cancer growth. However, the function of HINT3 in cancers, including breast cancer (BRCA) remains to be determined. In the present study, we investigated the role of HINT3 in BRCA. Methods The clinical relevance of HINT3 in BRCA was analyzed using the datasets from The Cancer Genome Atlas. HINT3 was over-expressed and knocked down using lentivirus system. qRT-PCR and Western blot assays were performed to detect mRNA and protein expression. CCK-8 and colony formation assays were used to assess cell proliferation. Migration was analyzed using Transwell assay. Luciferase reporter activity assay was performed using pGL3.Basic/TK system. Xenogrfted tumorigenesis was performed to evaluate the effect of HINT3 on tumor development. Results HINT3 was down-regulated in BRCA tissues based on TCGA analysis and our qPCR analysis. TCGA database also showed that HINT3 transcript was much lower in BRCA tissues with higher stage. In vitro, HINT3 knockdown promoted the cell proliferation, colony growth and EDU cooperation in MCF7 and MDA-MB-231 cells. Oppositely, HINT3 overexpression suppressed the DNA synthesis and proliferation in both cells. In vivo, HINT3 ectopic expression blunted the xenografted tumorigenesis of MDA-MB-231 cells. Furthermore, HINT3 silencing or overexpression enhanced and inhibited the migration capacity of MCF7 and MDA-MB-231 cells, respectively. Lastly, HINT3 upregulated PTEN at transcription level, which resulted in inactivation of AKT/mTOR signaling in vitro and in vivo. Conclusions Taken together, HINT3 inhibits PTEN/AKT/mTOR signaling pathway and suppresses the proliferation, growth, migration and tumor development of BRCA cells.

scholarly journals CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuxiang Lin ◽  
Jie Zhang ◽  
Yan Li ◽  
Wenhui Guo ◽  
Lili Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Triple Negative Breast Cancer ◽  
Transcriptional Activation ◽  
Triple Negative ◽  
Pearson Correlation ◽  
Disease Free Survival ◽  
Luciferase Reporter

Abstract Background Cytidine nucleotide triphosphate synthase 1 (CTPS1) is a CTP synthase which play critical roles in DNA synthesis. However, its biological regulation and mechanism in triple-negative breast cancer (TNBC) has not been reported yet. Methods The expression of CTPS1 in TNBC tissues was determined by GEO, TCGA databases and immunohistochemistry (IHC). The effect of CTPS1 on TNBC cell proliferation, migration, invasion, apoptosis and tumorigenesis were explored in vivo and in vitro. In addition, the transcription factor Y-box binding protein 1 (YBX1) was identified by bioinformatics methods, dual luciferase reporter and chromatin immunoprecipitation (CHIP) assays. Pearson correlation analysis was utilized to assess the association between YBX1 and CTPS1 expression. Results CTPS1 expression was significantly upregulated in TNBC tissues and cell lines. Higher CTPS1 expression was correlated with a poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Silencing of CTPS1 dramatically inhibited the proliferation, migration, invasion ability and induced apoptosis of MDA-MB-231 and HCC1937 cells. Xenograft tumor model also indicated that CTPS1 knockdown remarkably reduced tumor growth in mice. Mechanically, YBX1 could bind to the promoter of CTPS1 to promote its transcription. Furthermore, the expression of YBX1 was positively correlated with CTPS1 in TNBC tissues. Rescue experiments confirmed that the enhanced cell proliferation and invasion ability induced by YBX1 overexpression could be reversed by CTPS1 knockdown. Conclusion Our data demonstrate that YBX1/CTPS1 axis plays an important role in the progression of TNBC. CTPS1 might be a promising prognosis biomarker and potential therapeutic target for patients with triple-negative breast cancer.

scholarly journals The Oncogenic Role of HIF-1α/miR-182-5p/ZFP36L1 Signaling Pathway in Nasopharyngeal Carcinoma

2021 ◽  
Author(s):  
Gang Wang ◽  
Fangzheng Zhou ◽  
Tong Ou ◽  
Haiyan Sun ◽  
Zhirui Shan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Transcriptional Activation ◽  
Tumor Development ◽  
Luciferase Reporter ◽  
Functional Study ◽  
Activation Effect

Abstract Background: Accumulating evidence indicates that dysregulation of human microRNAs could serve as diagnostic and prognostic biomarkers for nasopharyngeal carcinoma (NPC), whereas miR-182-5p has not been explored in NPC. Our study aims to elucidate the biological function of miR-182-5p in NPC in vitro and in vivo and the potential molecular mechanism involved. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine miR-182-5p expression in NPC primary tissues and cell lines. Immunohistochemistry (IHC) for ZFP36L1 was conducted in NPC samples. Western blot was used to evaluate protein expression in cell lines. A series of functional assays were carried out to evaluate the roles of miR-182-5p and ZFP36L1 in tumor development and progression of NPC. Bioinformatics tools and luciferase reporter assays were utilized to identify the potential mechanisms of action. Moreover, rescue experiments were applied to explore whether ZFP36L1 mediated the effects of miR-182-5p in NPC. Results: Up-regulation of miR-182-5p was significantly associated with tumor development and poor prognosis in patients with NPC. Functional study demonstrated that miR-182-5p overexpression enhanced, whereas suppression of miR-182-5p impeded NPC cell proliferation, migration, tumorigenesis and metastasis. Mechanistically, miR-182-5p interacted with ZFP36L1 at two sites in its 3’ un-translated region (UTR) and repressed ZFP36L1 expression in NPC. Consistently, an inverse correlation was observed between the expression levels of miR-182-5p and ZFP36L1 using clinical NPC tissues, and down-regulation of ZFP36L1 in NPC predicts poor survival. Furthermore, overexpression of miR-182-5p in NPC was attributable to the transcriptional activation effect induced by hypoxia-inducible factor 1α (HIF-1α). Conclusion: Our data suggest that miR-182-5p facilitates cell proliferation and migration in NPC through its ability to down-regulate ZFP36L1 expression, and that the HIF-1α/miR-182-5p/ZFP36L1 axis may serve as a novel therapeutic target in the management of NPC.

scholarly journals CTPS1 Promotes Malignant Progression of Triple-Negative Breast Cancer With Transcriptional Activation By YBX1

2021 ◽  
Author(s):  
Yuxiang Lin ◽  
Jie Zhang ◽  
Yan Li ◽  
Wenhui Guo ◽  
Lili Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Triple Negative Breast Cancer ◽  
Transcriptional Activation ◽  
Triple Negative ◽  
Pearson Correlation ◽  
Disease Free Survival ◽  
Luciferase Reporter

Abstract Background: Cytidine nucleotide triphosphate synthase 1 (CTPS1) is a CTP synthase which play critical roles in DNA synthesis. However, its biological regulation and mechanism in triple-negative breast cancer (TNBC) has never been reported yet.Methods: The expression of CTPS1 in TNBC tissues was determined by GEO, TCGA databases and immunohistochemistry (IHC). The effect of CTPS1 on TNBC cell proliferation, migration, invasion, apoptosis and tumorigenesis were explored in vivo and in vitro. In addition, the transcription factor Y-box binding protein 1 (YBX1) was identifed by bioinformatics methods, dual luciferase reporter and chromatin immunoprecipitation (CHIP) assays. Pearson correlation analysis was utilized to assess the association between YBX1 and CTPS1 expression. Results: CTPS1 expression was significantly upregulated in TNBC tissues and cell lines. Higher CTPS1 expression was correlated with a poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Silencing of CTPS1 dramatically inhibited the proliferation, migration, invasion ability and induced apoptosis of MDA-MB-231 and HCC1937 cells. Xenograft tumor model also indicated that CTPS1 knockdown remarkably reduced tumor growth in mice. Mechanically, YBX1 could bind to the promoter of CTPS1 to promote its transcription. Furthermore, the expression of YBX1 was positively correlated with CTPS1 in TNBC tissues. Rescue experiments confirmed that the enhanced cell proliferation and invasion ability induced by YBX1 overexpression could be reversed by CTPS1 knockdown. Conclusion: Our data demonstrate that YBX1/CTPS1 axis plays an important role in the progression of TNBC. CTPS1 might be a promising prognosis biomarker and potential therapeutic target for patients with triple-negative breast cancer.

scholarly journals Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Cui-Cui Zhao ◽  
Jing Chen ◽  
Li-Ying Zhang ◽  
Hong Liu ◽  
Chuan-Gui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
The Cancer Genome Atlas ◽  
Proliferation And Apoptosis

Abstract Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

scholarly journals MiR-664b-3p Inhibited Triple-Negative Breast Cancer Cell Growth Via Targeting BRIP1

2021 ◽  
Author(s):  
Qiu Jin ◽  
Bo Lin ◽  
Wenhui Zhao ◽  
Runyuan Ji
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Luciferase Reporter ◽  
Breast Cancer Cell Growth ◽  
Cell Functions

Abstract BackgroundMany studies indicate that microRNAs (miRNAs) play a crucial role in modulating the development and progression of triple-negative breast cancer (TNBC). However, miR-664b-3p affections on the TNBC functions and mechanisms are still unknown. The purpose of our study was to clarify the effects of miR-664b-3p in cellular TNBC development and progression.MethodsIn our study, the expressions of miR-664b-3p in cell lines and tissueswere tested by real-time PCR (RT-PCR), immunofluorescence, H&E and immunohistochemistry staining. CCK-8 assay, colony formation, EdU, flow cytometry apoptosis, wound scratch, Transwell assays were applied to explore the cell functions. The targeted relationship between miR-664b-3p and its target BRIP1 was determined by dual-luciferase reporter assay and rescue experiments. ResultsWe observed that miR-664b-3p was significantly decreased in TNBC cell lines. Overexpression of miR-664b-3p could observably inhibit cell proliferation, migration, invasion and induced apoptosis in vitro. Meanwhile, miR-664-3p suppressed TNBC tumor growth in vivo. Furthermore, luciferase reporter assays identified the interaction between 3’UTR of BRIP1 and miR-664b-3p. Moreover, we investigated the mechanisms underlying the effect of miR-664b-3p on cell functions, and the result showed that miR-664b-3p inhibited cell proliferation, invasion and accelerated apoptosis by targeting BRIP1.ConclusionFrom the above, our findings indicated that miR-664b-3p played a significant role in TNBC progression by targeting BRIP1, providing new therapeutic targets for diagnostic in TNBC.

scholarly journals CircNOL10 suppresses breast cancer progression by sponging miR-767-5p to regulate SOCS2/JAK/STAT signaling

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Fang Wang ◽  
Xiaochun Wang ◽  
Jingruo Li ◽  
Pengwei Lv ◽  
Mingli Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Cytokine Signaling

Abstract Background Circular RNAs (circRNAs) have caught increasing attentions and interests for their important involvement in cancer initiation and progression. This study aims to investigate the biological functions of circNOL10 and its potential molecular mechanisms in breast cancer (BC). Materials and methods qRT-PCR and western blot assays were performed to measure the expression of related genes. CCK-8, colony formation, flow cytomerty and transwell assays were used to assess cell proliferation, cell cycle, migration and invasion. RNA pull-down, luciferase reporter and RIP assays were applied to address the potential regulatory mechanism of circNOL10. Results CircNOL10 was down-regulated in BC tissues and cells. Low expression of circNOL10 was associated with larger tumor size, advanced TNM stage, lymph node metastasis and unfavorable prognosis. Overexpression of circNOL10 inhibited cell proliferation, migration, invasion and EMT in vitro and slowed xenograft tumor growth in vivo. Mechanistically, circNOL10 could act as a molecular sponge for miR-767-5p, leading to the up-regulation of suppressors of cytokine signaling 2 (SOCS2) and inactivation of JAK2/STAT5 pathway. Moreover, circNOL10-mediated suppression of malignant phenotypes was attenuated by miR-767-5p. Similar to circNOL10, enforced expression of SOCS2 also resulted in the suppression of cell proliferation and metastasis. Furthermore, knockdown of SOCS2 reversed the tumor-suppressive effect induced by circNOL10. Conclusions CircNOL10 repressed BC development via inactivation of JAK2/STAT5 signaling by regulating miR-767-5p/SOCS2 axis. Our findings offer the possibility of exploiting circNOL10 as a therapeutic and prognostic target for BC patients.

scholarly journals Circular RNA_PDHX Promotes the Proliferation and Invasion of Prostate Cancer by Sponging MiR-378a-3p

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuanshen Mao ◽  
Wenfeng Li ◽  
Bao Hua ◽  
Xin Gu ◽  
Weixin Pan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Specific Binding ◽  
Ectopic Expression ◽  
The Cancer Genome Atlas ◽  
Clinicopathological Parameters ◽  
Circular Rnas ◽  
Proliferation And Invasion

The dysregulation of circular RNAs (circRNAs) is implicated in the pathogenesis of prostate cancer (PCa). However, the underlying mechanisms by which hsa_circ_0003768 (circPDHX) contributes to PCa remain elusive. The differentially expressed circRNAs between PCa and normal tissues were identified by Gene Expression Omnibus dataset. The association of circPDHX and miR-378a-3p expression with the clinicopathological parameters and prognosis in patients with PCa was analyzed by fluorescence in situ hybridization and The Cancer Genome Atlas dataset. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell assays as well as a xenograft tumor model were used to assess the role of circPDHX in PCa cells. circPDHX-specific binding with miR-378a-3p was validated by bioinformatic analysis, luciferase gene reporter, and RNA immunoprecipitation assays. As a result, we found that increased expression of circPDHX was associated with Gleason score (P = 0.001) and pathogenic T stage (P = 0.01) and acted as an independent prognostic factor of poor survival (P = 0.036) in patients with PCa. Knockdown of circPDHX inhibited cell proliferation and invasion in vitro and in vivo, but ectopic expression of circPDHX reversed these effects. Furthermore, circPDHX could sponge miR-378a-3p to promote cell proliferation, but miR-378a-3p counteracted circPDHX-induced cell proliferation and insulin-like growth factor 1 receptor (IGF1R) expression in PCa cells. In conclusion, our findings demonstrated that circPDHX facilitated the proliferation and invasion of PCa cells by sponging miR-378a-3p.

scholarly journals Long Noncoding RNA SNHG1 Promotes TERT Expression by Sponging miR-18b-5p in Breast Cancer

2021 ◽  
Author(s):  
Yujuan Kang ◽  
Lin Wan ◽  
Qin Wang ◽  
Yanling Yin ◽  
Jiena Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Malignant Tumors ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Tert Expression

Abstract Background: Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) plays a positive role in the progression of human malignant tumors. However, the molecular mechanism of SNHG1 remains elusive in breast cancer. Methods: The Cancer Genome Atlas data were used to examine the differential expression of SNHG1 in tumor and normal tissues, as well as the relationship between SNHG1 expression and prognosis. Oncogenic role of SNHG1 in breast cancer was studied both in vitro and in vivo. Animal experiments along with colony counting kit-8, colony formation, wound healing, and Transwell invasion assays were used to verify that SNHG1 was an oncogene in breast cancer. Furthermore, reverse transcription-polymerase chain reaction, western blotting analysis, subcellular RNA fractionation, and dual-luciferase reporter assay were performed to prove the competing endogenous RNA (ceRNA) mechanism of SNHG1, miR-18b-5p, and telomerase reverse transcriptase (TERT). Finally, chromatin immunoprecipitation was performed to confirm that the transcription factor E2F1 could enhance SNHG1 transcription.Results: LncRNA SNHG1 was upregulated and had a positive relationship with poor prognosis according to bioinformatics analysis. Silencing SNHG1 inhibited tumorigenesis in breast cancer both in vitro and in vivo. Mechanistically, SNHG1 functioned as a ceRNA to promote TERT expression by sponging miR-18b-5p. Moreover, miR-18b-5p acted as a tumor repressor in breast cancer. Finally, E2F1, a transcription factor, enhanced SNHG1 transcription.Conclusions: Our results provide a comprehensive understanding of the oncogenic mechanism of lncRNA SNHG1 in breast cancer. Importantly, we identified a novel E2F1–SNHG1–miR-18b-5p–TERT axis, which may be a potential therapeutic target for breast cancer.

scholarly journals Let-7d Inhibits Growth and Metastasis in Breast Cancer by Targeting Jab1/Cops5

2018 ◽  
Vol 47 (5) ◽  
pp. 2126-2135 ◽  
Author(s):  
Yongchang Wei ◽  
Guohong Liu ◽  
Balu Wu ◽  
Yufen Yuan ◽  
Yunbao Pan
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tumor Development ◽  
Luciferase Reporter ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients ◽  
In Vivo Experiments ◽  
Cancer Tissues

Background/Aims: MicroRNAs (miRNAs) regulate the expressions of cancer-related genes, and are involved in the development and progression of various human cancers. Here, we performed further analyses to determine whether let-7d is functionally linked to Jab1 in breast cancer. Methods: In situ hybridization and immunohistochemical analyses were used to determine the level of let-7d and Jab1 in breast cancer clinical specimens and its correlation with clinicopathological data. Let-7d overexpressing breast cancer cell lines combined with mouse models bearing cell-derived xenografts were used to assess the functional role of let-7d both in vitro and in vivo. Results: In this study, we found that let-7d was downregulated in breast cancer tissues, coupled with the elevations of Jab1 protein expressions, compared with paired adjacent noncancerous breast tissues. Let-7d overexpression significantly suppressed the proliferation and invasion in MCF-7 and MDA-MB-231 cells. Dual luciferase reporter assay indicated that Jab1 was the direct target of let-7d. Stepwise studies from in vitro and in vivo experiments indicated that let-7d overexpression inhibited cell growth and decreased Jab1 expressions in breast cancer cells and nude mice tumor tissues. Statistical analyses demonstrated that breast cancer patients with low levels of let-7d or high levels of Jab1 had a significant correlation with worse prognosis. Conclusion: These findings provide novel insights into molecular mechanism of let-7d and Jab1 in tumor development and progression of breast cancer, and thus let-7d/Jab1 are novel potential therapeutic targets for breast cancer patients.

scholarly journals Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Chen Du ◽  
Caihong Lv ◽  
Yue Feng ◽  
Siwen Yu
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cell Lines ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion

Abstract Background Accumulating evidence supports that lysine-specific demethylase 5 (KDM5) family members act as oncogenic drivers. This study was performed to elucidate the potential effects of KDM5A on prostate cancer (PCa) progression via the miR-495/YTHDF2/m6A-MOB3B axis. Methods The expression of KDM5A, miR-495, YTHDF2 and MOB3B was validated in human PCa tissues and cell lines. Ectopic expression and knockdown experiments were developed in PCa cells to evaluate their effects on PCa cell proliferation, migration, invasion and apoptosis. Mechanistic insights into the interaction among KDM5A, miR-495, YTHDF2 and MOB3B were obtained after dual luciferase reporter, ChIP, and PAR-CLIP assays. Me-RIP assay was used to determine m6A modification level of MOB3B mRNA in PCa cells. Mouse xenograft models of PCa cells were also established to monitor the tumor growth. Results KDM5A was highly expressed in human PCa tissues and cell lines. Upregulated KDM5A stimulated PCa cell proliferation, migration and invasion, but reduced cell apoptosis. Mechanistically, KDM5A, as a H3K4me3 demethylase, bound to the miR-495 promoter, which led to inhibition of its transcription and expression. As a target of miR-495, YTHDF2 could inhibit MOB3B expression by recognizing m6A modification of MOB3B mRNA and inducing mRNA degradation. Furthermore, KDM5A was found to downregulate MOB3B expression, consequently augmenting PCa cell proliferation, migration and invasion in vitro and promoting tumor growth in vivo via the miR-495/YTHDF2 axis. Conclusion In summary, our study highlights the potential of histone demethylase KDM5A activity in enhancing PCa progression, and suggests KDM5A as a promising target for PCa treatment.

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