ENC1 Facilitates Colorectal Carcinoma Tumorigenesis and Metastasis via JAK2/STAT5/AKT Axis-Mediated Epithelial Mesenchymal Transition and Stemness.
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ABSTRACT:
SUBMITTER: Cui Y
PROVIDER: S-EPMC8010667 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionHepatoblastoma (HB) is a malignant liver tumor predominantly found in children and tumor metastasis is one of the main causes of poor prognosis in affected patients. The precise molecular mechanisms responsible for HB metastasis remain incompletely understood. However, there is evidence suggesting a connection between the dysregulation of microRNAs (miRNAs) and the progression of tumor metastasis in HB.MethodsThe study utilized weighted gene co-expression network analysis (WGCNA) to analyze a miRNA microarray dataset of HB. The expression of miR-181b-5p in HB tissues and cells was detected using quantitative real-time PCR. The impact of miR-181b-5p on the metastatic capacity of HB was evaluated through scratch and Transwell assays. The effects of exogenously expressing miR-181b on the metastatic phenotypes of HB cells were evaluated in vivo. Furthermore, a luciferase reporter assay was performed to validate a potential target of miR-181b-5p in HB.ResultsWe found that miR-181b-5p was highly expressed in HB tissues and HB cell lines. Overexpression of miR-181b enhanced scratch healing, cell migration, and invasion abilities in vitro, as well as enhancing HB lung metastasis potential in vivo. Dual-luciferase reporter assays showed that Suppressor Of Cytokine Signaling 2 (SOCS2) was a direct target of miR-181b. The overexpression of miR-181b resulted in the suppression of SOCS2 expression, subsequently activating the epithelial-mesenchymal transition and JAK2/STAT5 signaling pathways. The rescue experiment showed that SOCS2 overexpression attenuated the effects of miR-181b on HB cells.ConclusionOur study showed that miR-181b promotes HB metastasis by targeting SOCS2 and may be a potential therapeutic target for HB.
| S-EPMC10639105 | biostudies-literature
Project description:Background: At the time of diagnosis, colorectal cancer (CRC) patients are usually in an advanced stage of disease, which is accompanied by metastasis. Long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. However, the contributions of lncRNA LINC01272 to CRC remain elusive. Methods: Bioinformatics and the survminer R package were used to predict intermolecular correlations and prognostic indicators. Quantitative real-time PCR was used to examine molecular expression. In vitro experiments, including migration assays, invasion assays, and wound healing assays, were used to investigate the effects of LINC01272, ITGB2 and miR-876 on CRC cell migration and invasion abilities. Furthermore, a dual-luciferase reporter gene assay was performed to explore the potential mechanism by which LINC01272 contributes to CRC. Results: We found that LINC01272 was highly expressed in multiple cancers and closely related to core epithelial-mesenchymal transition (EMT) factors and that high levels of LINC01272 are associated with a poor prognosis in CRC patients. qRT-PCR revealed that LINC01272 was highly expressed and negatively associated with miR-876 in CRC. Additionally, LINC01272 or ITGB2 silencing reduced, while miR-876 overexpression promoted, the invasiveness and metastatic capacity of CRC cells in vitro. Moreover, LINC01272 potentially targeted miR-876, and miR-876 potentially targeted ITGB2. Conclusion: LINC01272 was highly expressed in CRC and predicted a poor prognosis. LINC01272 promoted EMT and metastasis by regulating miR-876/ITGB2 to act as an oncogene in CRC. LINC01272 may be a promising prognostic biomarker and therapeutic target for the treatment of CRC patients in the future.
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Project description:Colorectal cancer (CRC) is a major source of morbidity and mortality, characterized by intratumoral heterogeneity and the presence of cancer stem cells (CSCs). Bufalin has potent activity against many tumors, but studies of its effect on CRC stemness are limited. We explored bufalin's function and mechanism using CRC patient-derived organoids (PDOs) and cell lines. In CRC cells, bufalin prevented nuclear translocation of β-catenin and down-regulated CSC markers (CD44, CD133, LGR5), pluripotency factors, and epithelial-mesenchymal transition (EMT) markers (N-Cadherin, Slug, ZEB1). Functionally, bufalin inhibited CRC spheroid formation, aldehyde dehydrogenase activity, migration, and invasion. Network analysis identified a C-Kit/Slug signaling axis accounting for bufalin's anti-stemness activity. Bufalin treatment significantly downregulated C-Kit, as predicted. Furthermore, overexpression of C-Kit induced Slug expression, spheroid formation, and bufalin resistance. Similarly, overexpression of Slug resulted in increased expression of C-Kit and identical functional effects, demonstrating a pro-stemness feedback loop. For further study, we established PDOs from diagnostic colonoscopy. Bufalin differentially inhibited PDO growth and proliferation, induced apoptosis, restored E-cadherin, and downregulated CSC markers CD133 and C-Myc, dependent on C-Kit/Slug. These findings suggest that the C-Kit/Slug axis plays a pivotal role in regulating CRC stemness, and reveal that targeting this axis can inhibit CRC growth and progression.
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Project description:Epithelial-mesenchymal transition (EMT) is an important process in embryonic development, fibrosis, and cancer metastasis. During cancer progression, the activation of EMT permits cancer cells to acquire migratory, invasive, and stem-like properties. A growing body of evidence supports the critical link between EMT and cancer stemness. However, contradictory results have indicated that the inhibition of EMT also promotes cancer stemness, and that mesenchymal-epithelial transition, the reverse process of EMT, is associated with the tumor-initiating ability required for metastatic colonization. The concept of 'intermediate-state EMT' provides a possible explanation for this conflicting evidence. In addition, recent studies have indicated that the appearance of 'hybrid' epithelial-mesenchymal cells is favorable for the establishment of metastasis. In summary, dynamic changes or plasticity between the epithelial and the mesenchymal states rather than a fixed phenotype is more likely to occur in tumors in the clinical setting. Further studies aimed at validating and consolidating the concept of intermediate-state EMT and hybrid tumors are needed for the establishment of a comprehensive profile of cancer metastasis.
| S-EPMC5496497 | biostudies-other
Project description:BackgroundOvarian cancer is one of the most widespread malignant diseases of the female reproductive system worldwide. The plurality of ovarian cancer is diagnosed with metastasis in the abdominal cavity. Epithelial-mesenchymal transition (EMT) exerts a vital role in tumor cell metastasis. However, it remains unclear whether long non-coding RNA (lncRNA) are implicated in EMT and influence ovarian cancer cell invasion and metastasis. This study was designed to investigate the impacts of lncRNA AC005224.4 on ovarian cancer.MethodsLncRNA AC005224.4, miR-140-3p, and snail family transcriptional repressor 2 ( SNAI2 ) expression levels in ovarian cancer and normal ovarian tissues were determined using real-time quantitative polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) and Transwell (migration and invasion) assays were conducted to measure SKOV3 and CAOV-3 cell proliferation and metastasis. E-cadherin, N-cadherin, Snail, and Vimentin contents were detected using Western blot. Nude mouse xenograft assay was utilized to validate AC005224.4 effects in vivo . Dual-luciferase reporter gene assay confirmed the targeted relationship between miR-140-3p and AC005224.4 or SNAI2 .ResultsAC005224.4 and SNAI2 upregulation and miR-140-3p downregulation were observed in ovarian cancer tissues and cells. Silencing of AC005224.4 observably moderated SKOV3 and CAOV-3 cell proliferation, migration, invasion, and EMT process in vitro and impaired the tumorigenesis in vivo . miR-140-3p was a target of AC005224.4 and its reduced expression level was mediated by AC005224.4. miR-140-3p mimics decreased the proliferation, migration, and invasion of ovarian cancer cells. SNAI2 was identified as a novel target of miR-140-3p and its expression level was promoted by either AC005224.4 overexpression or miR-140-3p knockdown. Overexpression of SNAI2 also facilitated ovarian cancer cell viability and metastasis.ConclusionAC005224.4 was confirmed as an oncogene via sponging miR-140-3p and promoted SNAI2 expression, contributing to better understanding of ovarian cancer pathogenesis and shedding light on exploiting the novel lncRNA-directed therapy against ovarian cancer.
| S-EPMC10228486 | biostudies-literature
Project description:Epithelial cell adhesion molecule (EpCAM) is known to be highly expressed in a variety of epithelial carcinomas, and it is involved in cell adhesion and proliferation. However, its expression profile and biological function in nasopharyngeal carcinoma (NPC) remains unclear. In this study, higher expression of EpCAM was found in NPC samples compared with non-cancer nasopharyngeal mucosa by qRT-PCR. Additionally, immunohistochemistry (IHC) analysis of NPC specimens from 64 cases showed that high EpCAM expression was associated with metastasis and shorter survival. Multivariate survival analysis identified high EpCAM expression as an independent prognostic factor. Ectopic EpCAM expression in NPC cells promoted epithelial-mesenchymal transition (EMT), induced a cancer stem cell (CSC)-like phenotype, and enhanced metastasis in vitro and in vivo without an effect on cell proliferation. Notably, EpCAM overexpression reduced PTEN expression and increased the level of AKT, mTOR, p70S6K and 4EBP1 phosphorylation. Correspondingly, an AKT inhibitor and rapamycin blocked the effect of EpCAM on NPC cell invasion and stem-like phenotypes, and siRNA targeting PTEN rescued the oncogenic activities in EpCAM knockdown NPC cells. Our data demonstrate that EpCAM regulates EMT, stemness and metastasis of NPC cells via the PTEN/AKT/mTOR pathway.
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Project description:Breast cancer is one of the most frightful causes of death among females worldwide. Accumulating evidence attached the importance of microRNAs negative regulation to tumorigenesis in breast cancer, suggesting novel cancer therapies targeting microRNAs modulation. Recent studies demonstrated that isoliquiritigenin could inhibit breast cancer cells proliferation and migration, but the underlying mechanism is still limited. In this study, the anti-cancer effects as well as the detailed mechanisms of isoliquiritigenin were explored. The results proved that isoliquiritigenin could negatively regulate breast cancer growth through the induction of apoptosis. We also verified the anti-cancer effect of isoliquiritigenin on migration and invasion, and identified highly expressed miR-374a as one of the main microRNAs down-regulated by isoliquiritigenin treatment in breast cancer. Further study displayed that isoliquiritigenin increased PTEN expression through the decrease of miR-374a expression to inhibit the aberrant Akt signaling. Our findings suggest isoliquiritigenin as a novel anti-cancer candidate significantly regulating miR-374a/PTEN/Akt axis in microRNA-based breast cancer therapies.
| S-EPMC5567123 | biostudies-literature
Project description:Metastasis of hepatoblastoma (HB) is a key factor that impairs the prognosis and treatment of children. The suppressor of cytokine signaling 2 (SOCS2) is a classical negative feedback protein that regulates cytokine signal transduction and has been known to be downregulated in several tumor, but the molecular mechanisms of its involvement in HB metastasis are unknown. We found that SOCS2 was a gene down-regulated in hepatoblastoma and associated with HB metastasis through bioinformatics. The qRT-PCR, Western blot and IHC showed that SOCS2 was significantly lower in HB tissues. Clinicopathological correlation analysis revealed that low expression of SOCS2 was significantly correlated with tumor metastasis (P = 0.046) and vascular invasion (P = 0.028), associated with poor prognosis. Overexpression of SOCS2 inhibited the migration and invasion of hepatoblastoma cells, while knockdown of SOCS2 expression promoted these malignant phenotypes. In vivo studies revealed overexpression of SOCS2 inhibited the formation of lung metastasis. Up-regulation of SOCS2 in HB cell inhibited EMT and JAK2/STAT5. Conversely, down-regulation of SOCS2 promoted EMT and JAK2/STAT5. The addition of the JAK2 inhibitor Fedratinib partially reversed the effects of si-SOCS2 on HB cells. SOCS2 may inhibit the migration and invasion of HB cells by inhibiting the JAK2/STAT5 signaling pathway. These results may provide guiding significance for the clinical treatment of HB.
| S-EPMC10710468 | biostudies-literature
Project description:Rationale: Metastasis is the leading cause of disease-related death among patients with nasopharyngeal carcinoma (NPC). Mounting evidence suggest that epithelial-mesenchymal transition (EMT) is crucial for cancer cells to acquire metastatic ability. In this study, we aim to clarify the extent to which EMT is involved in various cancer properties and identify novel markers for predicting the prognosis of NPC patients. Methods: Two cellular models derived from the same NPC cell line with distinct metastasis ability were used for microarray analysis to identify key transcriptional factors that drive metastasis. Cell migration and invasion were analyzed by wound healing and Transwell analysis. Lung metatasis was determined by tail vein injection assay. Cancer stemness was analyzed using colony formation and xenograft assay. The EMT extent was evaluated using immunoblotting, RT-qPCR and immunofluorescence of EMT markers. The value of OVOL2 in prognosis was determined by immunohistochemistry in NPC biopsies. Results: OVOL2 was the most significantly down-regulated EMT transcription factor (EMT-TF) in cellular models of NPC metatasis. Low levels of OVOL2 were associated with poor overall survival of NPC patients and the reduced expression is partly due to promoter methylation and epithelial dedifferentiation. Knockout of OVOL2 in epithelial-like NPC cells partially activates EMT program and significantly promotes cancer stemness and metastatic phenotypes. Conversely, ectopically expression of OVOL2 in mesenchymal-like cells leads to a partial transition to an epithelial phenotype and reduced malignancy. Reversing EMT by depleting ZEB1, a major target of OVOL2, does not eliminate the stemness advantage of OVOL2-deficient cells but does reduce their invasion capacity. A comparison of subpopulations at different stages of EMT revealed that the extent of EMT is positively correlated with metastasis and drug resistance; however, only the intermediate EMT state is associated with cancer stemness. Conclusion: Distinct from other canonical EMT-TFs, OVOL2 only exhibits modest effect on EMT but has a strong impact on both metastasis and tumorigenesis. Therefore, OVOL2 could serve as a prognostic indicator for cancer patients.
| S-EPMC5928881 | biostudies-literature
Project description:BackgroundCancer stem cells (CSCs) are responsible for tumour initiation, metastasis and recurrence. However, the mechanism of CSC formation, maintenance and expansion in colorectal cancer (CRC) remains poorly characterised.MethodsThe role of COP9 signalosome subunit 6 (CSN6) in regulating cancer stemness was evaluated by organoid formation and limited dilution analysis. The role of CSN6-TRIM21-OCT1-ALDH1A1 axis in CSC formation was evaluated in vitro and in vivo. The association of CSN6, TRIM21 and ALDH1A1 expression was validated by a tissue microarray with 267 CRC patients.ResultsThe results showed that CSN6 is critical for sphere formation and maintaining the growth of patient-derived organoids (PDOs). We characterised the role of CSN6 in regulating cancer stemness, which involves the TRIM21 E3 ubiquitin ligase, transcription factor POU class 2 homeobox 1 (OCT1) and cancer stem cell marker aldehyde dehydrogenase 1 A1 (ALDH1A1). Our data showed that CSN6 facilitates ubiquitin-mediated degradation of TRIM21, which in turn decreases TRIM21-mediated OCT1 ubiquitination and subsequently stabilises OCT1. Consequently, OCT1 stabilisation leads to ALDH1A1expression and promotes cancer stemness. We further showed that the protein expression levels of CSN6, TRIM21 and ALDH1A1 can serve as prognostic markers for human CRC.ConclusionsIn conclusion, we validate a pathway for cancer stemness regulation involving ALDH1A1 levels through the CSN6-TRIM21 axis, which may be utilised as CRC molecular markers and be targeted for therapeutic intervention in cancers.
| S-EPMC7250844 | biostudies-literature