scholarly journals SYT8 promotes pancreatic cancer progression via the TNNI2/ERRα/SIRT1 signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhiping Fu ◽  
Xing Liang ◽  
Ligang Shi ◽  
Liang Tang ◽  
Danlei Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Tumor Metastasis ◽  
Molecular Mechanisms ◽  
Hormone Secretion ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Orphan Nuclear Receptor

AbstractPancreatic cancer is a highly lethal malignancy due to failures of early detection and high metastasis in patients. While certain genetic mutations in tumors are associated with severity, the molecular mechanisms responsible for cancer progression are still poorly understood. Synaptotagmin-8 (SYT8) is a membrane protein that regulates hormone secretion and neurotransmission, and its expression is positively regulated by the promoter of the insulin gene in pancreatic islet cells. In this study, we identified a previously unknown role of SYT8 in altering tumor characteristics in pancreatic cancer. SYT8 levels were upregulated in patient tumors and contributed towards increased cell proliferation, migration, and invasion in vitro and in vivo. Increased SYT8 expression also promoted tumor metastasis in an in vivo tumor metastasis model. Furthermore, we showed that SYT8-mediated increase in tumorigenicity was regulated by SIRT1, a protein deacetylase previously known to alter cell metabolism in pancreatic lesions. SIRT1 expression was altered by orphan nuclear receptor ERRα and troponin-1 (TNNI2), resulting in cell proliferation and migration in an SYT8-dependent manner. Together, we identified SYT8 to be a central regulator of tumor progression involving signaling via the SIRT1, ERRα, and TNNI2 axis. This knowledge may provide the basis for the development of therapeutic strategies to restrict tumor metastasis in pancreatic cancer.

scholarly journals Positive feedback between lncRNA FLVCR1-AS1 and KLF10 may inhibit pancreatic cancer progression via the PTEN/AKT pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jiewei Lin ◽  
Shuyu Zhai ◽  
Siyi Zou ◽  
Zhiwei Xu ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Molecular Mechanisms ◽  
Tumor Tissues ◽  
And Migration

Abstract Background FLVCR1-AS1 is a key regulator of cancer progression. However, the biological functions and underlying molecular mechanisms of pancreatic cancer (PC) remain unknown. Methods FLVCR1-AS1 expression levels in 77 PC tissues and matched non-tumor tissues were analyzed by qRT-PCR. Moreover, the role of FLVCR1-AS1 in PC cell proliferation, cell cycle, and migration was verified via functional in vitro and in vivo experiments. Further, the potential competitive endogenous RNA (ceRNA) network between FLVCR1-AS1 and KLF10, as well as FLVCR1-AS1 transcription levels, were investigated. Results FLVCR1-AS1 expression was low in both PC tissues and PC cell lines, and FLVCR1-AS1 downregulation was associated with a worse prognosis in patients with PC. Functional experiments demonstrated that FLVCR1-AS1 overexpression significantly suppressed PC cell proliferation, cell cycle, and migration both in vitro and in vivo. Mechanistic investigations revealed that FLVCR1-AS1 acts as a ceRNA to sequester miR-513c-5p or miR-514b-5p from the sponging KLF10 mRNA, thereby relieving their suppressive effects on KLF10 expression. Additionally, FLVCR1-AS1 was shown to be a direct transcriptional target of KLF10. Conclusions Our research suggests that FLVCR1-AS1 plays a tumor-suppressive role in PC by inhibiting proliferation, cell cycle, and migration through a positive feedback loop with KLF10, thereby providing a novel therapeutic strategy for PC treatment.

scholarly journals 3BDO Inhibits proliferation, epithelial–mesenchymal transition (EMT) and stemness via suppressing survivin in human glioblastoma cells

2021 ◽  
Author(s):  
zhaotao wang ◽  
yongping Li ◽  
minyi liu ◽  
danmin chen ◽  
yunxiang ji ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Xenograft Mouse Model

Abstract BackgroundGlioblastoma (GBM) is a tumor of the central nervous system carries an extremely poor prognosis. Unfortunately, it also is the most frequently encountered tumor in this region. These tumors arise from glioblastoma stem cells (GSCs), which are glioma cells that are known to possess high degrees of stemness. GBM invades through the process of EMT, which features loss of cell differentiation and polarity. Survivin is a type of apoptotic inhibitor that has been characterized in several malignancies such as glioma. Normal tissues rarely express survivin. On the other hand, 3-benzyl-5-((2-nitrophenoxy) methyl) dihydrofuran-2(3H)-one (3BDO) represents an autophagy inhibitor and activates the mTOR pathway. It has been reported that 3BDO shows anti-cancer activities in lung carcinoma. However, the effects of 3BDO on GBM reminds unknown. Therefore, the purpose of this study was to explore the role and molecular mechanisms that 3BDO mediates in GBM.MethodCCK-8 experiments and clone formation assay were performed to detect the cell proliferation. Transwell assay was conducted to examined cell migration and invasion. Western blotting and immunofluorescence staining was used to analyze protein expression levels. Xenograft mouse model was used to evaluate the effect of 3BDO in vivo.ResultsWe found that 3BDO inhibited U87 and U251 cell proliferation in a dose-dependent manner. Additonally, 3BDO decreased the sphere formation and stemness markers (sox2, nestin and CD133) in GSCs. 3BDO also inhibited migration, invasion and suppressed EMT markers (N-cadherin, vimentin and snail) in GBM cells. Moreover, we found that 3BDO downregulated survivin expression of survivin both in GBM cells (U87, U251) and GSCs. Furthermore, overexpression of survivin reduced the therapeutic effects of 3BDO on GBM cell EMT, invasion, migration and proliferation, as well as decreased stemness in GSCs. Finally, we demonstrated that 3BDO inhibited tumor growth in a tumor xenograft mouse model constructed using U87 cells. Similar to the in vitro findings, 3BDO diminished suvivin expression, stemness and levels of EMT makers in vivo.Conclusionsour results demonstrated that 3BDO repressed GBM via downregulating survivin-mediated stemness and EMT both in vitro and in vivo.

Curcumin Inhibits Pancreatic Cancer Progression via Down-Regulation of miR-21-5p

2020 ◽  
Vol 18 (3) ◽  
pp. 236-240
Author(s):  
Li Junjian ◽  
Xu Qigang ◽  
Tao Chonglin
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
B Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Promote Cell Proliferation ◽  
Pancreatic Cancer Cells

In this study, we investigated the role of curcumin in pancreatic cancer through the regulation of miR-21-5p. We first evaluated the expression of miR-21-5p in pancreatic cancer cells (ASPC-1) treated with different concentrations of curcumin. The results showed that curcumin effectively inhibited the expression of miR-21-5p in ASPC-1 cells in a dose-dependent manner. B cell translocation gene 2 was identified as a target gene of miR-21-5p. MiR-21-5p mimics could promote cell proliferation, migration, and invasion of ASPC-1, as well as decrease the expression of B cell translocation gene 2. Curcumin treatment inhibited cell proliferation, migration and invasion of ASPC-1, as well as increased the expression of B cell translocation gene 2. MiR-21-5p could reverse the inhibitory activities of curcumin on ASPC-1 cell proliferation, migration, and invasion. In conclusion, curcumin is capable of inhibiting the proliferation, migration and invasion of pancreatic cancer cells via down-regulating miR-21-5p-mediated B cell translocation gene 2.

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 Circ_0001686 Promotes Prostate Cancer Progression by Up-Regulating SMAD3/TGFBR2 via miR-411-5p

2020 ◽  
Author(s):  
Qiliang Cai ◽  
Jiancheng Pan ◽  
Enli Liang ◽  
Dingrong Zhang ◽  
Cheng Fang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Nude Mouse Model

Abstract Background: Prostate cancer (PCa) is one of the most common malignancies in men. Circular RNAs (circRNAs) are known to be the important regulators in cancer progression. However, the role of circRNAs in PCa is yet to be investigated. Therefore, this study focuses on investigating the effect and the underlying molecular mechanisms of hsa_circ_0001686 (circ_0001686) in PCa. Methods: Sample tissues were collected from the PCa patients to carry out the microarray expression profile of the human circRNAs. In addition, the expression levels of circ_0001686, has_miR-411-5p (miR-411-5p), SMAD3, and TGFBR2 were also detected by qRT-RCR. Next, transfection experiments were employed to measure the effect of circ_0001686 on cell proliferation, migration, and invasion in the PCa cell lines (CWR22RV1and LNCaP). These effects were analyzed using MTT, colony formation, transwell, and scratch wound assays, respectively. The si-circ_0001686 was used as a negative control. Starbase and TargetScan databases were used to predict the putative binding sites among circ_0001686, miR-411-5p, and SMAD3/TGFBR2. The dual-luciferase reporter assays were performed to verify these interactions. Furthermore, the levels of SMAD3 and TGFBR2 in CWR22RV1 and LNCaP cells were measured by western blot. Finally, in vivo experiments in the nude mouse model were carried out to strengthen the in vitro findings. Results: The expression of circ_0001686 was markedly up-regulated while the expression of miR-411-5p was down-regulated in PCa cells. Moreover, circ_0001686 promoted cell proliferation, migration, and invasion. Molecular mechanism exploration revealed that circ_0001686 acts as a sponge of miR-411-5p which affects the downstream target gene SMAD3, and TGFBR2. Both the in vitro and in vivo studies verified that miR-411-5p inhibits cancer growth and metastasis in PCa.Conclusions: The circ_0001686 sequesters miR-411-5p to increase the expression of SMAD3/TGFBR2 which consequently promotes the proliferation, invasion, and migration in PCa cells.

scholarly journals Total Flavonoids of Litchi Seed Attenuate Prostate Cancer Progression Via Inhibiting AKT/mTOR and NF-kB Signaling Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Chang ◽  
Dan Zhu ◽  
Yanjiang Chen ◽  
Weiquan Zhang ◽  
Xi Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Induced Apoptosis

Litchi seeds have been traditionally used in Chinese herbal formula for urologic neoplasms including prostate cancer (PCa). However, the effective components of Litchi seeds and the mechanisms of their actions on PCa cell growth and metastasis remain unclear. In this study, we investigated the effects and molecular mechanisms of the Total Flavonoid of Litchi Seed (TFLS) in PCa PC3 and DU145 cell lines. We found that TFLS significantly inhibited the PCa cell proliferation, induced apoptosis, and prevented cell migration and invasion. Furthermore, we observed that TFLS upregulated the expression of epithelial biomarker E-cadherin and downregulated mesenchymal biomarker Vimentin. TFLS also increased the expression of cleaved-PRAP and Bax, and decreased the expression of Bcl-2 in both PC3 and DU145 cells. Besides, TFLS inhibited AKT signaling pathway by reducing the phosphorylation of AKT and activities of downstream signal transducers including mTOR, IκBα and NF-kB. Finally, TFLS treated mice exhibited a significant decrease in tumor size without toxicity in major organs in vivo. These results indicated that TFLS could suppress PCa cell growth in vivo and inhibit PCa cell proliferation and metastasis in vitro through induction of apoptosis and phenotypic reversal of EMT, which may be achieved by inhibiting the AKT/mTOR and NF-κB signaling pathways. Taken together, our data provide new insights into the role of TFLS as a novel potent anti-cancer agent for the treatment of PCa.

scholarly journals Mechanisms of circular RNA circ_0066147 on pancreatic cancer progression

2021 ◽  
Vol 16 (1) ◽  
pp. 495-510
Author(s):  
Jie Zhang ◽  
Zhang Zhang
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Cell Behaviors ◽  
E2f Transcription Factor

Abstract Background The purpose of the study was to explore the precise parts of circ_0066147 (circular RNA [circRNA] scm-like with four mbt domains 1, circSFMBT1) in pancreatic cancer (PC) progression. Methods Ribonuclease R assay was used to confirm the stability of circ_0066147. circ_0066147, miR-326 and E2F transcription factor 2 (E2F2) expression levels was detected by quantitative reverse-transcription polymerase chain reaction or Western blot. Cell proliferation, apoptosis, migration and invasion abilities were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, flow cytometry, wound-healing and transwell assays, respectively. Targeted relationships among circ_0066147, miR-326 and E2F2 were verified by the dual-luciferase reporter or RNA pull-down assay. Results circ_0066147 expression was upregulated in PC tissues and cells. circ_0066147 knockdown inhibited PC cell proliferation, migration, invasion and enhanced apoptosis in vitro, as well as weakened tumor growth in vivo. Mechanistically, circ_0066147 directly targeted miR-326 and circ_0066147 modulated E2F2 expression by miR-326. miR-326 mediated the regulation of circ_0066147 in PC cell behaviors in vitro. Furthermore, E2F2 was a functional target of miR-326 in modulating PC cell behaviors in vitro. Conclusion circ_0066147 regulated PC malignant progression in part depending on the miR-326/E2F2 axis, illuminating circ_0066147 was a potential prognostic marker and therapeutic target for PC management.

scholarly journals TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
You Shuai ◽  
Zhonghua Ma ◽  
Weitao Liu ◽  
Tao Yu ◽  
Changsheng Yan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Mechanistic Model ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Reporter Assays

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

scholarly journals Wnt5a Signaling in Normal and Cancer Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Yan Zhou ◽  
Thomas J. Kipps ◽  
Suping Zhang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Target Cells ◽  
Dependent Manner ◽  
Self Renewal ◽  
Surface Receptors ◽  
Canonical Wnt

Wnt5a is involved in activating several noncanonical Wnt signaling pathways, which can inhibit or activate canonical Wnt/β-catenin signaling pathway in a receptor context-dependent manner. Wnt5a signaling is critical for regulating normal developmental processes, including stem cell self-renewal, proliferation, differentiation, migration, adhesion, and polarity. Moreover, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a signaling in regulating normal and cancer stem cell self-renewal, cancer cell proliferation, migration, and invasion. In this article, we review recent findings regarding the molecular mechanisms and roles of Wnt5a signaling in stem cells in embryogenesis and in the normal or neoplastic breast or ovary, highlighting that Wnt5a may have different effects on target cells depending on the surface receptors expressed by the target cell.

scholarly journals Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

2021 ◽  
Author(s):  
Xuyang Lv ◽  
Jiangchuan Sun ◽  
Linfeng Hu ◽  
Ying Qian ◽  
Chunlei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

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