STAT3 inhibitor in combination with irradiation significantly inhibits cell viability, cell migration, invasion and tumorsphere growth of human medulloblastoma cells.
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ABSTRACT:
SUBMITTER: Pan L
PROVIDER: S-EPMC8489919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of the persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named LY5, to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, bcl-XL, survivin, and micro-RNA-21. LY5 also inhibited the induction of STAT3 phosphorylation by interleukin-6 (IL-6), insulin-like growth factor (IGF)-1, IGF-2, and leukemia inhibitory factor in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-? (IFN-?) and EGF, respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-? and EGF, respectively. A combination of LY5 with cisplatin or x-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling.
| S-EPMC4319011 | biostudies-literature
Project description:Medulloblastoma (MB) is the most common pediatric brain malignancy and is divided into four molecularly distinct subgroups: WNT, Sonic Hedgehog (SHHp53mut and SHHp53wt), Group 3, and Group 4. Previous reports suggest that SHH MB features a unique tumor microenvironment compared with other MB groups. To better understand how SHH MB tumor cells interact with and potentially modify their microenvironment, we performed cytokine array analysis of culture media from freshly isolated MB patient tumor cells, spontaneous SHH MB mouse tumor cells and mouse and human MB cell lines. We found that the SHH MB cells produced elevated levels of IGFBP2 compared to non-SHH MBs. We confirmed these results using ELISA, western blotting, and immunofluorescence staining. IGFBP2 is a pleiotropic member of the IGFBP super-family with secreted and intracellular functions that can modulate tumor cell proliferation, metastasis, and drug resistance, but has been understudied in medulloblastoma. We found that IGFBP2 is required for SHH MB cell proliferation, colony formation, and cell migration, through promoting STAT3 activation and upregulation of epithelial to mesenchymal transition markers; indeed, ectopic STAT3 expression fully compensated for IGFBP2 knockdown in wound healing assays. Taken together, our findings reveal novel roles for IGFBP2 in SHH medulloblastoma growth and metastasis, which is associated with very poor prognosis, and they indicate an IGFBP2-STAT3 axis that could represent a novel therapeutic target in medulloblastoma.
| S-EPMC10082504 | biostudies-literature
Project description:Gastric cancer (GC) is a globally occurring malignancy that is characterized by a high mortality rate due to a high tendency to metastasize and poor prognoses. Sorcin, as known as SRI, a soluble resistance-related calcium-binding protein, plays a significant role in multidrug resistance. Sorcin is related to the migration and invasion of cancer cells. However, the mechanism remains unclear. Here, we used immunohistochemistry to confirm that the expression of sorcin in cancer tissues is higher than that in the adjacent normal tissues. The wound healing and transwell results indicate that sorcin can induce migration and invasion of GC cells. To explore the role of sorcin in GC metastasis, isobaric tags for relative and absolutely quantitation (iTRAQ) were used to examine cells with and without sorcin knockdown to identify the differentially expressed proteins (DEPs). The results were evaluated via RT-PCR and western blot to confirm the ITRAQ data. Inhibition of sorcin expression can down- regulate the expression of CTSZ, MMP2, MMP9 and p-STAT3 followed by suppression of tumor growth and metastasis. Together, we concluded that sorcin has a oncogenic activity via inducing tumor growth and metastasis, leading to development of therapeutic treatments for GC.
| S-EPMC5732804 | biostudies-literature
Project description:Objective:TMEM119 is a member of transmembrane proteins family, which is abnormally expressed in human cancers and associated with tumorigenesis. In this study, we focused on the expression of TMEM119 and its role in cell invasion and migration in gastric cancer. Methods:Real-time polymerase chain reaction, Western blotting, and immunohistochemistry were performed to examine the expression of TMEM119 in gastric cancer tissues and cell lines. After transfection with TMEM119 siRNA or recombined TMEM119-expressing vector, the invasion and migration ability of MKN45 and SGC-7901 cells was measured by transwell assay. The expression of TMEM119, p-STAT3, STAT3, VEGF, MMP2, and MMP9 proteins in SGC-7901 and MKN45 cells treated with TMEM119 siRNA, TMEM119-expressing vector, or AG490 was measured by Western blotting. Results:We found that higher TMEM119 expression was found in gastric cancer tissues and cell lines and was associated with lower survival rate. TMEM119 knockdown inhibited SGC-7901 cell invasion and migration, along with the expression of p-STAT3, VEGF, MMP2, and MMP9. TMEM119 overexpression promoted MKN45 cell invasion and migration, along with the expression of p-STAT3, VEGF, MMP2, and MMP9. Additionally, AG490 treatment significantly corrected TMEM119-induced MKN45 cell migration and invasion and expression of p-STAT3, VEGF, MMP9, and MMP2 proteins. Conclusion:The results indicated that TMEM119 promotes gastric cancer cell migration and invasion through activation of STAT3 signaling pathway, and TMEM119 may therefore act as a novel therapeutic target for gastric cancer.
| S-EPMC6145364 | biostudies-literature
Project description:Melanoma is the deadliest form of commonly encountered skin cancer, and has fast propagating and highly invasive characteristics. Pim-3, a highly expressed oncogene in melanoma, is a highly conserved serine/threonine kinase with various biological activities, such as proliferation-accelerating and anti-apoptosis effects on cancer progression. However, whether Pim-3 regulates melanoma metastasis has not been determined. Here, we constructed a Pim-3-silencing short hairpin RNA (sh-Pim-3), a TLR7-stimulating ssRNA and a dual-function vector containing a sh-Pim-3 and a ssRNA, and transfected them into the B16F10 melanoma cell line to investigate the effects of Pim-3 on migration and invasion in melanoma. We found that sh-Pim-3 inhibited B16F10 cell migration and invasion in vitro. In a tumor-bearing mouse model, sh-Pim-3 significantly downregulated pulmonary metastasis of B16F10 melanoma cell in vivo. Mechanistically, sh-Pim-3 inhibited metastasis by regulating the expression of genes related to epithelial-mesenchymal transition (EMT). Further study revealed that by promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), Pim-3 induced the expression of Slug, Snail, and ZEB1, which enhanced EMT-related changes and induced melanoma migration and invasion. Our study suggests that Pim-3 is a potential effective target for melanoma therapy.
| S-EPMC5790343 | biostudies-literature
Project description:Thyroid cancer is one of the most common malignant tumors, and the mortality rate associated with thyroid cancer has been increasing annually. Curcumin has been reported to exert an antitumor effect on papillary thyroid cancer (PTC), and the identification of additional mechanisms underlying the anticancer effect of curcumin on PTC requires further investigation. The present study aimed to explore the effects of curcumin on the viability, migration and invasion of PTC cells. TPC-1 cells were incubated with different concentrations of curcumin, and then, cell viability, migration and invasion, and wound healing were examined by CCK-8, Transwell and wound healing assays, respectively. Subsequently, microRNA (miR)-301a-3p mimics, miR-301a-3p inhibitors and signal transducer and activator of transcription (STAT)3 overexpression vector were transfected into TPC-1 cells, and cell viability, migration, and invasion were reassessed in these transfected cells. Matrix metallopeptidase (MMP)-2, MMP-9, epithelial-mesenchymal transition (EMT)-related markers, and Janus kinase (JAK)/STAT signaling pathway components were assessed by western blot analysis. Curcumin significantly inhibited cell viability, migration and invasion and downregulated MMP-2, MMP-9 and EMT marker expression. Additionally, curcumin decreased STAT3 expression by upregulating miR-301a-3p expression, and the inhibition of miR-301a-3p and the overexpression of STAT3 reversed the effects of curcumin on cell viability, migration and invasion, and MMP-2, MMP-9 and EMT marker expression in TPC-1 cells. Furthermore, curcumin suppressed the JAK/STAT signaling pathway through the miR-301a-3p/STAT3 axis. The data of the present study indicated that curcumin could inhibit the viability, migration and invasion of TPC-1 cells by regulating the miR-301a-3p/STAT3 axis. These findings may provide a possible strategy for the clinical treatment of PTC.
| S-EPMC8237388 | biostudies-literature
Project description:Background:Colorectal cancer (CRC) is one of the most lethal malignancies. Tripartite Motif Containing 14 (TRIM14) is a member of TRIM family proteins, which are involved in the pathogenesis of various cancers. This study aimed to investigate TRIM14 expression in CRC tissues, and its effects on the migration and invasion of CRC cell lines. Methods:TRIM14 mRNA expression was detected by real-time PCR analysis. Cell migration and invasion were measured by Transwell assays. Protein expression was assessed by western blot analysis. Results:The expression of TRIM14 was significantly higher in CRC tissues than in matched non-cancerous tissues. TRIM14 knockdown by specific short hairpin RNA (shRNA) attenuated CRC cell migration and invasion, whereas TRIM14 overexpression caused reverse effect. Moreover, TRIM14 positively regulated the protein levels of sphingosine kinase 1 (SPHK1) and phosphorylated STAT3 (p-STAT3), as well as the mRNA and protein expression of matrix metalloproteinase 2, MMP9 and vascular endothelial growth factor, which are transcriptional targets of the STAT3 signaling pathway. Importantly, the blockage of the SPHK1/STAT3 signaling pathway by SKI-II or AG490 could reverse the TRIM14-promoted CRC cell migration and invasion. Conclusions:Our results reveal a critical role for TRIM14 in promoting migration and invasion of CRC cells, and suggest TRIM14 may serve as a potential molecular target to prevent CRC metastasis.
| S-EPMC6288942 | biostudies-literature
Project description:Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial-mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression.
| S-EPMC9917887 | biostudies-literature
Project description:BackgroundRecently, many microRNAs have been found to be involved in the cancer progression including miR-125a. However, the underlying mechanisms of miR-125a in gastric cancer (GC) remain to be completely elucidated.ObjectiveThe study was to investigate the functional role of miR-125a and the expression relevance of signal transducer and activator of transcription 3 (STAT3) and hyaluronan synthase 1 (HAS1).MethodCCK-8 assay, scratch wound healing and transwell assay were conducted to identify the functional role of miR-125a in GC. In addition, using bioinformatics analysis, the target regulation relationship was found in STAT3 and miR-125a. To confirm the relationship, luciferase reporter assay was performed. More importantly, quantitative polymerase chain reaction and western blot assay were carried out to determine the association among miR-125a, STAT3 and HAS1 in GC cells.ResultsOverexpressed miR-125a inhibited the migration and invasion of GC cells through scratch wound healing and transwell assay, and its knockdown displayed adverse effects, but the viability of GC cells did not show significant difference using CCK-8 assay. In addition, we identified that the knockdown of STAT3 or HAS1 remarkably suppressed the migration and invasion abilities of GC cells. Using bioinformatics analysis, miRTar, in particular, indicated that the 3'-untranslated region of STAT3 binds to miR-125a with a high score. Subsequently, we also verified that STAT3 was a target of miR-125a via luciferase reporter assay. Furthermore, we found that upregulated miR-125a expression could conspicuously constrain STAT3 expression at both protein and mRNA levels in MKN45 and NCI-N87 cells using quantitative polymerase chain reaction and Western blot assay, but no significant difference had been found in SGC 7901 cells. To further identify the regulatory relationship between miR-125a and STAT3, downregulation of miR-125a in MKN45 and NCI-N87 cells was carried out, which showed that the protein and mRNA expression levels of STAT3 were declined in two cell lines. Finally, we observed that upregulated miR-125a could lead to the decrease of HAS1 at protein and mRNA levels, whereas its knockdown revealed opposite effects. Meanwhile, we noticed that overexpression of STAT3 could induce the escalation of HAS1 at protein and mRNA expression levels and its knockdown exhibited the adverse outcomes.ConclusionThese findings indicated that miR-125a may control the HAS1 expression in GC progression by targeting STAT3, which is likely to facilitate a better understanding of the regulation mechanisms of miR-125a in GC.
| S-EPMC6309784 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) comprises ∼20% of all breast cancers and is the most aggressive mammary cancer subtype. Devoid of the estrogen and progesterone receptors, along with the receptor tyrosine kinase ERB2 (HER2), that define most mammary cancers, there are no targeted therapies for patients with TNBC. This, combined with a high metastatic rate and a lower 5-year survival rate than for other breast cancer phenotypes, means there is significant unmet need for new therapeutic strategies. Herein, the anti-neoplastic effects of the electrophilic fatty acid nitroalkene derivative, 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA), were investigated in multiple preclinical models of TNBC. NO2-OA reduced TNBC cell growth and viability in vitro, attenuated TNFα-induced TNBC cell migration and invasion, and inhibited the tumor growth of MDA-MB-231 TNBC cell xenografts in the mammary fat pads of female nude mice. The up-regulation of these aggressive tumor cell growth, migration, and invasion phenotypes is mediated in part by the constitutive activation of pro-inflammatory nuclear factor κB (NF-κB) signaling in TNBC. NO2-OA inhibited TNFα-induced NF-κB transcriptional activity in human TNBC cells and suppressed downstream NF-κB target gene expression, including the metastasis-related proteins intercellular adhesion molecule-1 and urokinase-type plasminogen activator. The mechanisms accounting for NF-κB signaling inhibition by NO2-OA in TNBC cells were multifaceted, as NO2-OA (a) inhibited the inhibitor of NF-κB subunit kinase β phosphorylation and downstream inhibitor of NF-κB degradation, (b) alkylated the NF-κB RelA protein to prevent DNA binding, and (c) promoted RelA polyubiquitination and proteasomal degradation. Comparisons with non-tumorigenic human breast epithelial MCF-10A and MCF7 cells revealed that NO2-OA more selectively inhibited TNBC function. This was attributed to more facile mechanisms for maintaining redox homeostasis in normal breast epithelium, including a more favorable thiol/disulfide balance, greater extents of multidrug resistance protein-1 (MRP1) expression, and greater MRP1-mediated efflux of NO2-OA-glutathione conjugates. These observations reveal that electrophilic fatty acid nitroalkenes react with more alkylation-sensitive targets in TNBC cells to inhibit growth and viability.
| S-EPMC5787792 | biostudies-literature