Genetic Variation in MicroRNA-423 Promotes Proliferation, Migration, Invasion, and Chemoresistance in Breast Cancer Cells.
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SUBMITTER: Morales-Pison S
PROVIDER: S-EPMC8745459 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The dysregulated circular RNAs (circRNAs) are linked to progression and chemoresistance in colorectal cancer (CRC). However, the role of circRNA protein tyrosine kinase 2 (circPTK2) in CRC progression and chemoresistance is uncertain. The circPTK2, microRNA (miR)-136-5p, m6A 'reader' protein YTH domain family protein 1 (YTHDF1), β-catenin and cyclin D1 abundances were examined via quantitative reverse transcription PCR or Western blotting. The progression was investigated by cell counting kit-8 (CCK-8), colony formation, transwell and xenograft analysis. The resistance to 5-fluorouracil (5-FU) and oxaliplatin was analyzed via detecting cell viability and apoptosis using CCK-8 analysis and flow cytometry. The binding relationship was examined through dual-luciferase reporter, RNA immunoprecipitation and pull-down analysis. In our study, circPTK2 abundance was enhanced in CRC and associated with liver metastasis, clinical stage and chemoresistance. CircPTK2 knockdown constrained cell proliferation, migration, invasion, resistance to 5-FU and oxaliplatin, and the Wnt/β-catenin signaling. MiR-136-5p was bound with circPTK2 and downregulated in CRC. MiR-136-5p knockdown attenuated the influence of circPTK2 silence on CRC progression and chemoresistance. YTHDF1 was targeted via miR-136-5p and upregulated in CRC samples and cells. MiR-136-5p targeted YTHDF1 to restrain CRC progression and chemoresistance. In addition, we confirmed that circPTK2 silence reduced xenograft tumor growth. In conclusion, circPTK2 interference suppressed CRC proliferation, migration, invasion and chemoresistance via regulating miR-136-5p and YTHDF1.Abbreviations: circRNAs: circular RNAs; CRC: colorectal cancer; circPTK2: circRNA protein tyrosine kinase 2; miR: microRNA; YTHDF1: YTH domain family protein 1; CCK-8: cell counting kit-8; 5-FU: 5-fluorouracil; RIP: RNA immunoprecipitation.
| S-EPMC8805883 | biostudies-literature
Project description:BackgroundRadiotherapy, chemotherapy, and surgery have made crucial strides in glioblastoma treatment, yet they often fail; thus, new treatment and new detection methods are needed. Aberrant expression of Nanos3 has been functionally associated with various cancers. Here, we sought to identify the clinical significance and potential mechanisms of Nanos3 in human glioblastoma.MethodsNanos3 expression was studied in nude mouse glioblastoma tissues and glioblastoma cell lines by immunohistochemistry, Western blot, and RT-PCR. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing assay was performed to generate the Nanos3 knockdown glioblastoma cell lines. The effects of Nanos3 on glioblastoma cells proliferation, migration, invasion, chemoresistance, germ cell characteristics, and tumor formation were analyzed by CCK8, transwell, cell survival experiments and alkaline phosphatase staining in vitro and in nude mouse models in vivo. Correlation between the expression of stemness proteins and the expression of Nanos3 was evaluated by Western blot.ResultsWe found that Nanos3 was strongly expressed in both glioblastoma cell lines and tissues. Western blot and sequencing assays showed that the Nanos3 knockdown glioblastoma cell lines were established successfully, and we discovered that Nanos3 deletion reduced the proliferation, migration, and invasion of glioblastoma cells in vitro (P < 0.05). Nanos3 knockdown enhanced the sensitivity of glioblastoma cells to doxorubicin (DOX) and temozolomide (TMZ) (P < 0.05), and Nanos3+/- glioblastoma cell lines did not show the characteristics of the germline cells. In addition, Nanos3 deletion inhibited subcutaneous xenograft tumor growth in vivo (P < 0.001). Moreover, the oncogenesis germline protein levels of CD133, Oct4, Ki67, and Dazl decreased significantly in glioblastoma cells following Nanos3 knockdown.ConclusionsBoth in vitro and in vivo assays suggest that Nanos3, which is a cancer-germline gene, initiates the tumorigenesis of glioblastoma via acquiring the oncogenesis germline traits. These data demonstrate that ectopic germline traits are necessary for glioblastoma growth.
| S-EPMC7249350 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) have a closed-loop structure and are associated with various cellular biological processes, including carcinogenesis and cancer development. However, our knowledge of circRNAs in gastric cancer (GC) remains limited. Thus, this study aimed to investigate the role and underlying molecular mechanisms of hsa_circ_0023642 in GC.Materials and methodsBioinformatic analysis revealed that hsa_circ_0023642 was upregulated in GC. Chromogenic in situ hybridization (CISH) chips was used to explore the relationship between the expression of hsa_circ_0023642 and the malignant degree, clinical stage, and prognosis of patients with GC. The role of hsa_circ_0023642 in GC was assessed in vitro, and biotin-coupled RNA pull-down was conducted to evaluate the interaction in between hsa_circ_0023642 and miR-223.ResultsThe current study showed that hsa_circ_0023642 was upregulated in GC and presented a high positive correlation with the malignant progression of GC. In addition, in vitro experiments showed that the silencing of hsa_circ_0023642 in GC cell lines MKN-45 and SGC-7901 significantly reduced the proliferation, invasion, and migration of GC cells. We confirmed that hsa_circ_0023642 could serve as a sponge of miR-223, subsequently promoting GC progression.ConclusionThis study shows that the upregulation of hsa_circ_0023642 affects the malignant progression, clinical stage, and prognosis of GC which provides a new molecular target for the therapy of GC.
| S-EPMC7595887 | biostudies-literature
Project description:Objective:Breast cancer has become the most common malignancy among women worldwide; therefore, novel diagnostic and prognostic markers and therapeutic targets are urgently required. NF-?B signaling plays a pivotal role in enhancing breast cancer malignant phenotypes, especially cancer invasion and metastasis, which is the main cause of death in cancer patients. TNIP2, an important inhibitor of the NF-?B pathway, is known to involve a negative feedback loop of the NF-?B signaling cascade and to regulate tumor aggressiveness in various cancer types. However, the mRNA level of TNIP2 is barely altered in breast cancer; thus, the mechanism that regulates TNIP2 in breast cancer still needs to be elucidated. Methods:We analyzed the expression and prognosis of miR-423 in a TCGA BRCA miRNA cohort and in clinical specimens. We detected the invasive capacity through a Matrigel-coated Transwell penetration assay, a three-dimensional (3D) spheroid invasion assay and a wound healing assay. Then, we applied luciferase assays, real-time PCR assays and Western blotting to further study the mechanism. Results:In this study, analysis of the TCGA BRCA miRNA cohort and clinical specimens demonstrated that miR-423 was upregulated in human breast cancers and was positively correlated with clinical stage, poor overall survival and metastasis classification. Moreover, the invasiveness of breast cancer cells was enhanced by ectopic expression of miR-423 and inhibited by miR-423 downregulation. Mechanistically, upregulation of miR-423 led to activation of the NF-?B signaling pathway and elevated expression of snail and twist, while repression of miR-423 inhibited this pathway. Furthermore, the results indicated that TNIP2 is a target gene of miR-423, and suppression of TNIP2 resulted in increased invasiveness in miR-423-silenced cells. Conclusion:Our results suggest that miR-423 is a crucial factor that enhances breast cancer cell invasion through the NF-?B signaling pathway and shed light on miR-423 as a promising prognostic and therapeutic marker for metastatic breast cancer.
| S-EPMC7297514 | biostudies-literature
Project description:MicroRNAs (miRNAs/miRs) are highly conserved single-stranded small non-coding RNAs, which are involved in the physiological and pathological processes of breast cancer, and affect the prognosis of patients with breast cancer. The present study used the Gene Expression Omnibus (GEO)2R tool to detect miR-100 expression in breast cancer tissues obtained from GEO breast cancer-related datasets. Bioinformatics analysis revealed that miR-100 expression was downregulated in different stages, grades and lymph node metastasis stages of breast cancer, and patients with high miR-100 expression had a more favorable prognosis. Based on these analyses, Cell Counting Kit-8, wound healing and Transwell assays were performed, and the results demonstrated that overexpression of miR-100 inhibited the proliferation, migration and invasion of breast cancer cells. To verify the tumor-suppressive effect of miR-100 in breast cancer, the LinkedOmics and PITA databases were used to assess the association between miR-100 and forkhead box A1 (FOXA1). The results demonstrated that miR-100 had binding sites within the FOXA1 gene, and FOXA1 expression was negatively associated with miR-100 expression in breast cancer tissues. Similarly, a negative association was observed between miR-100 and FOXA1 expression, using the StarBase V3.0 database. The association between miR-100 and FOXA1 was further verified via reverse transcription-quantitative PCR and western blot analyses, and the dual-luciferase reporter assay. The results demonstrated that miR-100 targeted the 3'-untranslated region of FOXA1 in breast cancer cells. Furthermore, rescue experiments were performed to confirm whether miR-100 exerts its antitumor effects by regulating FOXA1. The results demonstrated that overexpression of FOXA1 promoted the proliferation, migration and invasion of breast cancer cells; thus, the antitumor effects of miR-100 in breast cancer were reversed following overexpression of FOXA1. Taken together, the results of the present study suggest that miR-100 inhibits the proliferation, migration and invasion of breast cancer cells by targeting FOXA1 expression. These results may provide a novel insight and an experimental basis for identifying effective therapeutic targets of high specificity for breast cancer.
| S-EPMC8503813 | biostudies-literature
Project description:Breast cancer is the most common malignant tumor in women, and its incidence is increasing each year. To effectively treat breast cancer, it is important to identify genes involved in its occurrence and development and to exploit them as potential drug therapy targets. Here, we found that potassium channel subfamily K member 6 (KCNK6) is significantly overexpressed in breast cancer, however, its function in tumors has not been reported. We further verified that KCNK6 expression is upregulated in breast cancer biopsies. Moreover, overexpressed KCNK6 was found to enhance the proliferation, invasion, and migration ability of breast cancer cells. These effects may occur by weakening cell adhesion and reducing cell hardness, thus affecting the malignant phenotype of breast cancer cells. Our study confirmed, for the first time, that increased KCNK6 expression in breast cancer cells may promote their proliferation, invasion, and migration. Moreover, considering that ion channels serve as therapeutic targets for many small molecular drugs in clinical treatment, targeting KCNK6 may represent a novel strategy for breast cancer therapies. Hence, the results of this study provide a theoretical basis for KCNK6 to become a potential molecular target for breast cancer treatment in the future.
| S-EPMC8237943 | biostudies-literature
Project description:Background/Aims:The effects of microRNA-423 on proliferation and drug resistance of breast cancer cells were explored, the downstream target genes of miR-423 and the targeted regulatory relationship between them were studied. Methods:RT-qPCR was used to detect the expression of miR-423 in breast cancer tissues and cell lines, and the transfection efficiency of miR-423 inhibitory vector miR-423-inhibitor was constructed and verified. CCK-8 and colony formation assays were used to examine the effect of miR-423 on tumor cell proliferation. Target gene prediction and screening and luciferase reporter assay were used to verify downstream target genes of miR-432. The mRNA and protein expression of miR-423target gene ZFP36 was detected by RT-qPCR and Western blotting. Results:The expression of miR-423 was significantly higher than that in normal tissues. Compared to the non-malignant mammary epithelial cell line MCF-10A, the expression of miR-423 was significantly raised in MCR-7 and MCF-7/ADR cells. ZFP36 was a downstream target gene of miR-423 and negatively correlated with the expression of miR-423 in breast cancer. The knockdown of miR-423 can significantly enhance the cytotoxicity of the drug, increase the apoptotic rate of MCF-7/ADR cells. miR-423 was capable of activating the Wnt/?-catenin signaling pathway leading to chemoresistance and proliferation, whereas overexpression of ZFP36 reduced drug resistance and proliferation. Conclusion:miR-423 acted as an oncogene to promote tumor cell proliferation and migration. ZFP36 was a downstream target gene of miR-423, and miR-423 inhibited the expression of ZFP36 via Wnt/?-catenin signaling pathway of breast cancer cells.
| S-EPMC6986407 | biostudies-literature
Project description:ObjectivesmiRNAs play crucial roles in human tumourigenesis. This study was performed to measure expression and function of miR-762 in breast cancer.Materials and methodsExpression of miR-762 in breast tissues and cell lines (SK-BR-3, DA-MB-435s, MCF-7 and MDA-MB-231, HBL-100) was measured by using real-time RT-PCR. We restored expression of miR-762 in MCF-7 cells to measure its functional roles. Luciferase assays were performed to reveal the target gene of miR-762.ResultsExpression of miR-762 was high in both breast cancer cell lines and specimens, and its overexpression increased breast cancer cell proliferation and invasion. Interferon regulatory factor 7 (IRF7) is a direct target of miR-762 and overexpression of miR-762 reduced expression of IRF7. Moreover, IRF7 was repressed, its levels inversely correlated to miR-762 expression. IRF7 rescued miR-762-induced cell invasion and proliferation.ConclusionsThese results demonstrate that miR-762 tumour effect was achieved by targeting IRF7 in human breast cancer specimens.
| S-EPMC6496530 | biostudies-literature
Project description:Colorectal cancer (CRC), one of the most common cancer types, causes a large number of cancer?related mortalities annually worldwide. Dysregulated microRNAs (miRNAs/miR) are closely associated with the malignant progression of CRC. Therefore, the present study aimed to investigate the expression and regulatory role of miR?592 in CRC. It was found that miR?592 expression was significantly elevated in CRC tissues and cell lines, and was associated with the prognosis of patients. Cellular phenotype assays demonstrated that miR?592 could promote CRC cell proliferation, migration and invasion. Bioinformatics analysis demonstrated that miR?592 mainly participated in the positive regulation of transcription, as well as the regulation of cell motility. Moreover, miR?592 targets were enriched in several signaling pathways, such as the 'mTOR' and 'FoxO' signaling pathways. In addition, secreted protein acidic and rich in cysteine (SPARC) was identified as a target of miR?592 in CRC. The present results suggested that miR?592 acts as an oncogene in CRC, in part, by directly inhibiting SPARC expression. Collectively, the present study provides a novel potential therapeutic strategy for CRC.
| S-EPMC7893699 | biostudies-literature
Project description:microRNAs (miRNAs) have emerged as major regulators of the initiation and progression of human cancers, including breast cancer. The aim of this study is to determine the expression pattern of miR-96 in breast cancer and to investigate its biological role during tumorigenesis. We showed that miR-96 was significantly upregulated in breast cancer. We then investigated its function and found that miR-96 significantly promoted cell proliferation, migration and invasion in vitro and enhanced tumor growth in vivo. Furthermore, we explored the molecular mechanisms by which miR-96 contributes to breast cancer progression and identified PTPN9 (protein tyrosine phosphatase, non-receptor type 9) as a direct target gene of miR-96. Finally, we showed that PTPN9 had opposite effects to those of miR-96 on breast cancer cells, suggesting that miR-96 may promote breast tumorigenesis by silencing PTPN9. Taken together, this study highlights an important role for miR-96 in the regulation of PTPN9 in breast cancer cells and may provide insight into the molecular mechanisms of breast carcinogenesis.
| S-EPMC5114647 | biostudies-literature