Overexpression of TMEFF1 in Endometrial Carcinoma and the Mechanism Underlying its Promotion of Malignant Behavior in Cancer Cells.
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ABSTRACT:
SUBMITTER: Nie X
PROVIDER: S-EPMC8408118 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:BMPER has been reported to be associated with the biological behavior of a few malignant tumors, but the mechanism is still unclear. We aimed to detect BMPER expression in ovarian epithelial tumor tissues and its effects on their biological behaviors, as well as to elucidate the possible mechanism. Methods:BMPER expression in ovarian epithelial tumor tissues was detected by immunohistochemistry. BMPER expression in ovarian cancer cell lines was inhibited via RNA interference. Changes in the malignant behaviors of ovarian cancer cells were detected by MTT, wound healing, Transwell, and flow cytometry assays. Changes in proteins in the MAPK and autophagy-related signaling pathways were detected by Western blot analysis. Results:The expression of BMPER was significantly upregulated in ovarian epithelial malignant tumors and was related to increased lymph node metastasis and lower survival rate. High BMPER expression is an independent risk factor for poor prognosis in patients. Inhibition of BMPER inhibited the proliferation, invasion, and migration of ovarian cancer cells and promoted apoptosis. In addition, BMPER downregulation decreased the expression of PCNA, Bcl-2, MMP2, and MMP9 and increased the expression of Bax. Moreover, the levels of p-ERK, p-MEK, and the autophagy-related protein p-mTOR were decreased, and Beclin 1 levels and the LC3II/I ratio were increased. Conclusions:Our findings indicated that BMPER is closely related to poor prognosis in ovarian cancer. BMPER plays a role in promoting the malignant biological behavior of tumor cells through the MAPK and autophagy-related signaling pathways.
| S-EPMC7136775 | biostudies-literature
Project description:BackgroundEmerging evidence shows that abnormal expression of long non-coding RNA is involved in the occurrence and development of various tumors. LncRNA MONC is abnormally expressed in head and neck squamous cell carcinoma, lung cancer, colorectal cancer, and acute megakaryocytic leukemia, but the biological function and potential regulatory mechanism of MONC in endometrial cancer stem cells (ECSCs) and endometrial cancer cells (ECCs) have not been studied. In this study, we aimed to explore the tumor suppressive effect and mechanism of MONC in regulating ECSCs and ECCs.MethodsWe used qRT-PCR to detect the expression of MONC, miR-636 and GLCE in normal human endometrial tissues and endometrial carcinoma (EC) tissues. Luciferase assay was used to verify the binding sites between MONC and miR-636 and between miR-636 and GLCE. Double fluorescence in situ hybridization was used to locate MONC and miR-636 in cells. ECSCs were obtained by flow cytometry sorting assay. Sphere formation assay, CCK-8 assay, transwell invasion assay, cell cycle analysis and apoptosis assay were used to detect the effects of MONC/miR-636/GLCE axis on the malignant biological behavior of ECSCs and ECCs. The effect of MONC on the epithelial-to-mesenchymal transition (EMT) process was detected using western blot. Finally, we conducted in vivo verification through Tumor xenografts in BALB/C nude mice.ResultsIn this study, we found MONC is low expression in endometrial carcinoma (EC) and patients in the MONC high-expression group had a better prognosis. MONC and miR-636 are relatively co-localized in the cytoplasm. MONC directly inhibits the malignant biological behavior of ECSCs and ECCs by directly inhibiting miR-636. Simultaneously, miR-636 may indirectly reduce the expression of MONC. Down-regulation of miR-636 may promote GLCE expression by targeting the 3'-untranslated region (UTR) of the downstream gene GLCE, thereby inhibiting the progression of ECSCs. MONC combined with miR-636 inhibited tumor epithelial-to-mesenchymal transition (EMT) process. In addition, we verified the tumor suppressive effect of MONC in nude mice, miR-636 can rescue the tumor suppressive effect of overexpressing MONC.ConclusionsIn conclusion, this study showed that MONC inhibits the malignant phenotypes of ECSCs and ECCs by regulating the miR-636/GLCE axis. Thus the MONC/miR-636/GLCE axis may provide novel treatment avenues for human EC.
| S-EPMC8243592 | biostudies-literature
Project description:Imatinib mesylate (Imatinib), clinically employed for chronic myeloid leukemia and gastrointestinal stromal tumors, is a selective inhibitor of the tyrosine kinases, c-abl, c-kit and PDGFRs. Due to the frequent expression of these genes in breast cancer cells, the clinical efficacy of Imatinib has recently been investigated in patients with advanced and metastatic breast cancer. Here, we have studied the effects of Imatinib on human MA-11 breast carcinoma cells, expressing both c-abl and PDGFRbeta, in vitro and in mouse xenografts.The effects of Imatinib mesylate on the human MA-11 breast carcinoma cell line were studied in vitro and in xenografts.Daily intraperitoneal treatment with 60 mg/kg Imatinib for 9 days of athymic nude mice pre-implanted subcutaneously with MA-11 cells did not result in an anti-tumor effect, but rather increased the take rate of 3 × 10(4) cells from 30.8 to 84.6% and caused the appearance of large abdominal masses in 30% of mice. To investigate the mechanism(s) of the observed effects of Imatinib on MA-11 tumors, we exposed the cells in vitro to Imatinib for 9 days. The surviving population, expanded in culture, showed increased motility and over-expressed a set of genes associated with aggressive behavior. Also, several genes belonging to the Wnt and the MAPK pathway were differentially expressed. In promoter activation assays, Imatinib increased the promoter activity driven by both Wnt and MAPK/ERK-1/2.Our data suggest caution in the clinical use of Imatinib in breast cancer patients; the comparison of Imatinib-surviving breast cancer cells with parental cells may help define the regulatory pathways involved in the increased malignancy of residual tumor cells that survive therapy, ultimately providing important therapeutic targets.
| S-EPMC3273303 | biostudies-literature
Project description:Endometriosis is an estrogen-dependent disease. Studies have shown that miR-139-5p is significantly upregulated in endometriosis lesions, but its specific role and molecule mechanism in endometriosis has not yet been reported. The malignant biological behavior of ectopic endometrial stromal cells (ESCs) is similar to that of malignant cancer cells. BBC3 (BCL2 binding component 3) is a known apoptosis inducer and it serves key roles in the regulation of cell behavior. However, the role of BBC3 in ectopic ESCs remains unknown. The present study aimed to investigate the role of miR-139-5p in the progression of endometriosis and to determine its underlying molecular mechanism of action. Ectopic, non-ectopic and normal endometrial stromal cells (ESCs) were extracted from endometrial samples, and reverse transcription-quantitative PCR was performed to determine microRNA (miR)-139-5p and Bcl-2 binding component 3 (BBC3) mRNA expression levels in endometrial tissue samples and ESCs. The target gene of miR-139-5p was predicted using TargetScan software and verified using a dual luciferase reporter assay. Western blotting was performed to determine BBC3 protein expression levels. Flow cytometry analysis, and MTT and Transwell assays were performed to assess cell apoptosis, viability, and migration and invasion of the cells transfected with inhibitor control, miR-139-5p inhibitor, miR-139-5p inhibitor + control-small interfering (si)RNA or miR-139-5p inhibitor + BBC3-siRNA, respectively. The results demonstrated that miR-139-5p expression levels were upregulated in ectopic endometrial samples and ESCs compared with the respective control groups. Furthermore, it was verified that BBC3 was a direct target of miR-139-5p, and both BBC3 mRNA and protein expression levels were downregulated in ectopic endometrial samples and ESCs. Both transfection with the miR-139-5p inhibitor and BBC3-small interfering (si)RNA markedly downregulated miR-139-5p and BBC3 expression levels in ectopic ESCs, respectively. miR-139-5p inhibitor-induced upregulated BBC3 expression was reversed following transfection with BBC3-siRNA. Furthermore, the miR-139-5p inhibitor significantly decreased viability, migration and invasion, while inducing apoptosis in ectopic ESCs compared with the inhibitor control group. Notably, the aforementioned effects were reversed by knocking down BBC3 expression. In conclusion, the results of the present study suggested that miR-139-5p may play a key role in the progression of endometriosis by regulating the viability of ESCs and directly targeting BBC3.
| S-EPMC8438670 | biostudies-literature
Project description:Activin A receptor type 1C (ALK7) and its ligand nodal growth differentiation factor (NODAL) serve numerous roles in cancer cells, including regulating cancer invasion, migration and apoptosis. NODAL promotes breast cancer cell apoptosis by activating ALK7; however, ALK7 and NODAL expression in endometrial cancer (EC), as well as their effects and underlying mechanisms in EC cells, are not completely understood. The present study aimed to characterize the expression of NODAL and ALK7 in EC, as well as the underlying mechanisms. The expression levels of ALK7 and NODAL were detected via reverse transcription-quantitative PCR and western blotting. Cell transfection was performed to overexpress NODAL or interfere ALK7. Cell proliferation, invasion and migration were detected via Cell Counting Kit-8, Transwell and wound healing assays, respectively. Flow cytometry was performed to detect cell apoptosis and western blotting was conducted to detect the expression levels of apoptosis-related proteins. NODAL and ALK7 expression levels were significantly decreased in EC cell lines compared with normal endometrial cells. NODAL overexpression inhibited EC cell proliferation, invasion and migration, and promoted EC cell apoptosis compared with the overexpression-negative control (Ov-NC) group. Moreover, NODAL overexpression significantly increased ALK7 expression levels in EC cells compared with the Ov-NC group. ALK7 reversed NODAL overexpression-mediated inhibition of EC cell proliferation, invasion and migration, and promotion of EC cell apoptosis. The present study indicated that NODAL inhibited EC cell proliferation, invasion and migration, and promoted EC cell apoptosis by activating ALK7.
| S-EPMC7938447 | biostudies-literature
Project description:DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.
| S-EPMC7844562 | biostudies-literature
Project description:BackgroundAs the most common malignant tumor of primary renal tumor, renal cell carcinoma (RCC) is the highly invasive disease with high mortality. AKT is a serine/threonine kinase that play a critical role in the phosphoinositide 3-kinase (PI3K) signaling pathway, and it is an attractive target for RCC treatment. The aim of present study was to investigate the effect of AKT silence on malignant behavior of renal cell carcinoma cells.MethodsAKT expression was quantified by immunohistochemistry in tumor tissues and normal tissues. The human RCC cell lines Caki-2 cell were chosen for this study. The optimal silencing siRNA was subsequently selected by RT-qPCR and western blot. The effect of AKT silence on RCC cells was investigated by CCK8 assay, transwell assay, scratch test and flow cytometry. The AKT1 expression in human renal cell carcinoma tissue was detected by immunohistochemical staining.ResultsThe AKT in Caki-2 cells was silenced successfully. The results shown AKT silence could inhibit cell proliferation, invasion, and, migration. In addition, AKT silence could promote Caki-2 cell apoptosis with prevention of RCC cells move from G1 phase to S phase. Immunohistochemical staining revealed significant difference of expression of AKT1 in RCC tissues and normal renal tissues. Taken together, AKT family members might involve in malignant growth of RCC, and might be a potential therapeutic target.ConclusionOur data show that AKT silence inhibited cell proliferation, invasion, and, migration of Caki-2 cell, and promoted Caki-2 cell apoptosis. Moreover, AKT silence prevented RCC cells move from G1 phase to S phase. Therefore, AKT may act as an effective therapeutic target for RCC.
| S-EPMC9396790 | biostudies-literature
Project description:The tyrosine-kinase receptor that is specified by the KIT locus is demarcated by KITLG. This multifaceted factor is instrumental during in-utero germ and neural cell maturation and hematopoiesis, ostensibly reflecting its role in facilitating cell migration. Concurrently, KITLG is prone to a mutation in germ cell tumors, entailing a presumed connection to tumorigenesis. Despite this, the intricacies of its function in breast cancer and the relevant mechanisms remain elusive. Multiple independent databases depict a consistently low expression of KITLG within tissues affected by triple-negative breast cancers (TNBC), a trend strongly coupled with reduced survival rates. Interestingly, non-triple-negative breast cancers exhibit a markedly high expression of KITLG compared to the norm. An initial analysis of the GEO database speculates that KITLG may serve as an oncogene suppressor in TNBC, hinting at varied roles for KITLG isoforms within this disease context. In conclusion, our preliminary analysis offers valuable insights into the role and expression pattern of KITLG in TNBC. We provide evidence supporting its consideration as a promising new prognostic marker, thereby potentially enriching therapeutic strategies for TNBC. Indeed, given the limited advances in molecularly targeted therapy for TNBC, a significant need exists for a more precise therapeutic approach and a comprehensive understanding of its inherent mechanisms of action.
| S-EPMC10777047 | biostudies-literature
Project description:Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family, which is characterized by a conserved RING finger, B-box, and coiled-coil domains, function as important regulators for carcinogenesis. In this study, we tested whether TRIM44 (11p13) acts as a cancer-promoting gene through overexpression in gastric cancer. We analyzed seven gastric cancer cell lines and 112 primary tumors, which were curatively resected in our hospital between 2001 and 2003. Expression of the TRIM44 protein was detected in gastric cancer cell lines (2/7 cell lines; 29%) and primary tumor samples of gastric cancer (29/112 cases; 25%). Knockdown of TRIM44 expression using several specific siRNAs inhibited the proliferation, migration, and invasion of TRIM44-overexpressing cells. Overexpression of the TRIM44 protein was significantly correlated with an advanced type of macroscopic appearance, lymphatic invasion, and higher recurrence rate. TRIM44-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P = 0.0038, log-rank test) in both intensity and proportion expression-dependent manner. TRIM44 positivity was independently associated with worse outcome in multivariate analysis (P = 0.0233, hazard ratio 3.37 [1.18-9.64]). These findings suggest that TRIM44 plays a crucial role in tumor cell proliferation through its overexpression, and highlight its usefulness as a predictor and potential therapeutic target in gastric cancer.
| S-EPMC7659272 | biostudies-literature
Project description:YEATS domain containing 4 (YEATS4) has functions of chromatin modification and transcriptional regulation and is in a gene-amplified region (12q13) in various human cancers. In this study, we tested whether YEATS4 acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). We analyzed 5 GC cell lines and 135 primary tumor samples of GC, which were curatively resected in our hospital. Overexpression of the YEATS4 protein was frequently detected in GC cell lines (5/5 cell lines, 100%) and primary GC tumor tissues (32/135 cases, 23.7%). Knockdown of YEATS4 inhibited proliferation, migration and invasion of GC cells through NOTCH2 down-regulation in a TP53 mutation-independent manner, and induced apoptosis in wild-type TP53 GC cells. Moreover, knockdown of YEATS4 improved chemosensitivity for CDDP and L-OHP. Overexpression of YEATS4 protein significantly correlated with more aggressive lymphatic invasion, larger tumor size, deeper tumor depth, positive lymph node metastasis and recurrence. Patients with YEATS4-overexpressing tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that YEATS4 was independently associated with poor outcomes. These findings suggest that YEATS4 plays a pivotal role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
| S-EPMC6325477 | biostudies-literature