IBSP, a potential recurrence biomarker, promotes the progression of colorectal cancer via Fyn/β-catenin signaling pathway.
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ABSTRACT:
SUBMITTER: Chen Y
PROVIDER: S-EPMC8209559 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Accumulating literatures have indicated that long non-coding RNAs (lncRNAs) are crucial molecules in tumor progression in various human cancers, including colorectal cancer (CRC). However, the clinical significance and regulatory mechanism of a vast majority of lncRNAs in CRC remain to be determined. The current study aimed to explore the function and molecular mechanism of lncRNA AC010789.1 in CRC progression. AC010789.1 found to be overexpressed in CRC tissues and cells. High expression of AC010789.1 was associated with lymph node metastasis and poor prognosis. Moreover, AC010789.1 silencing inhibited proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro as well as tumorigenesis and metastasis in vivo. Mechanistically, we demonstrated that repression of AC010789.1 promoted miR-432-3p expression, and miR-432-3p directly binds to ZEB1. We then proved the anti-tumor role of miR-432-3p in CRC, showing that the inhibitory effect of AC010789.1 knockdown on CRC cells was achieved by the upregulation of miR-432-3p but downregulation of ZEB1. We also established that silencing AC010789.1 suppressed the Wnt/β-catenin signaling pathway. However, this inhibitory effect was partially counteracted by inhibition of miR-432-3p. In summary, these results reveal that silencing AC010789.1 suppresses CRC progression via miR-432-3p-mediated ZEB1 downregulation and suppression of the Wnt/β-catenin signaling pathway, highlighting a potentially promising strategy for CRC treatment.
| S-EPMC7593606 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) extensively interact with cancer cells and other stroma cells in the tumor microenvironment. However, the role of MSCs in colorectal cancer (CRC) progression and metastasis is controversial. This study was designed to identify the role of inflammation-activated-MSCs in CRC development. Our results show that tumor necrosis factor (TNF)-?-preactivated-hMSCs significantly promote the progression of colon cancer cells by enhancing cell proliferation, epithelial-mesenchymal transition, migration, and invasion. TNF-?-primed-hMSCs secrete high level of CCL5, which interacts with its receptor CCR1 expressed in colon cancer cells. Interestingly, the stimulation of colon cancer cell progression by TNF-?-primed hMSCs is associated with the upregulation of ?-catenin signaling pathway. Blocking ?-catenin pathway significantly decreases the TNF-?-primed-conditioned medium or CCL5-mediated cancer cell progression by decreasing the enhancement of Slug, suggesting that the CCL5/?-catenin/Slug pathway plays a critical role in hMSC-mediated cancer progression. Furthermore, in vivo model in nude mice confirms the ability of hMSCs to promote the proliferation and progression of colon cancer cells, and the upregulation of CCl5/?-catenin/Slug pathway. Taken together, the present study has demonstrated a novel pathway involving CCl5/CCR1/?-catenin/Slug, via which hMSCs promotes CRC development.
| S-EPMC5520690 | biostudies-other
Project description:BackgroundThe expression of forkhead box protein H1 (FOXH1) is frequently upregulated in various cancers. However, the molecular mechanisms underlying the association between FOXH1 expression and lung cancer progression still remain poorly understood. Thus, the main objective of this study is to explore the role of FOXH1 in lung cancer.MethodsThe Cancer Genome Atlas dataset was used to investigate FOXH1 expression in lung cancer tissues, and the Kaplan-Meier plotter dataset was used to determine the role of FOXH1 in patient prognosis. A549 and PC9 cells were transfected with short hairpin RNA targeting FOXH1 mRNA. The Cell Counting Kit-8, colony formation, soft agar, wound healing, transwell invasion and flow cytometry assays were performed to evaluate proliferation, migration and invasion of lung cancer cells. Tumorigenicity was examined in a BALB/c nude mice model. Western blot analysis was performed to assess the molecular mechanisms, and β-catenin activity was measured by a luciferase reporter system assay.ResultsHigher expression level of FOXH1 was observed in tumor tissue than in normal tissue, and this was associated with poor overall survival. Knockdown of FOXH1 significantly inhibited lung cancer cell proliferation, migration, invasion, and cycle. In addition, the mouse xenograft model showed that knockdown of FOXH1 suppressed tumor growth in vivo. Further experiments revealed that FOXH1 depletion inhibited the epithelial-mesenchymal transition of lung cancer cells by downregulating the expression of mesenchymal markers (Snail, Slug, matrix metalloproteinase-2, N-cadherin, and Vimentin) and upregulating the expression of an epithelial marker (E-cadherin). Moreover, knockdown of FOXH1 significantly downregulated the activity of β-catenin and its downstream targets, p-GSK-3β and cyclin D1.ConclusionFOXH1 exerts oncogenic functions in lung cancer through regulation of the Wnt/β-catenin signaling pathway. FOXH1 might be a potential therapeutic target for patients with certain types of lung cancer.
| S-EPMC8180118 | biostudies-literature
Project description:Aberrant activation of Wnt/β‑catenin signaling is observed in >90% of colorectal cancer cases. microRNAs (miRNAs) regulate the expression of key genes in Wnt/β‑catenin signaling. As a result, abnormal expression of miRNAs regulates the activation of Wnt/β‑catenin signaling in several types of cancer. In the current study, it was demonstrated that miR‑501‑3p was overexpressed in colorectal tumor tissues compared to the adjacent normal tissues. Downregulation of miR‑501‑3p inhibited cell proliferation and sphere formation, while it induced cell cycle arrest at the G1 phase in colorectal cancer cells. Bioinformatics analysis results predicted that adenomatous polyposis coli (APC), a negative regulator of Wnt/β‑catenin signaling, was a potential target gene of miR‑501‑3p. Inhibition of miR‑501‑3p increased APC expression in colorectal cancer cells. Additionally, β‑catenin was destabilized following miR‑501‑3p inhibition; immunofluorescence analysis revealed that β‑catenin translocated from nucleus to cytoplasm. In addition, cyclin D1 and c‑Myc, two well‑characterized target genes of Wnt/β‑catenin signaling, were downregulated following miR‑501‑3p inhibition. Transfection of APC small interfering RNA re‑activated β‑catenin and stimulated the expression of cyclin D1 and c‑Myc. Furthermore, silencing of APC reversed the miR‑501‑3p inhibitor‑induced cell cycle disruption, and the inhibition of cell proliferation and sphere formation in colorectal cancer cells. In conclusion, the present study identified miR‑501‑3p as a novel regulator of Wnt/β‑catenin signaling in colorectal cancer cells via targeting APC, suggesting that miR‑501‑3p may act as a novel oncogenic miRNA in colorectal cancer.
| S-EPMC6685591 | biostudies-literature
Project description:Aberrant regulation of the Wnt/β-catenin signaling pathway is one of the major causes of colorectal cancer (CRC). Loss-of-function mutations in APC are commonly found in CRC, leading to inappropriate activation of canonical Wnt signaling. Conversely, gain-of-function mutations in KRAS and BRAF genes are detected in up to 60% of CRCs. Whereas KRAS/mitogen-activated protein kinase (MAPK) and canonical Wnt/β-catenin pathways are critical for intestinal tumorigenesis, mechanisms integrating these two important signaling pathways during CRC development are unknown. Results herein demonstrate that transformation of normal intestinal epithelial cells (IECs) by oncogenic forms of KRAS, BRAF or MEK1 was associated with a marked increase in β-catenin/TCF4 and c-MYC promoter transcriptional activities and mRNA levels of c-Myc, Axin2 and Lef1. Notably, expression of a dominant-negative mutant of T-Cell Factor 4 (ΔNTCF4) severely attenuated IEC transformation induced by oncogenic MEK1 and markedly reduced their tumorigenic and metastatic potential in immunocompromised mice. Interestingly, the Frizzled co-receptor LRP6 was phosphorylated in a MEK-dependent manner in transformed IECs and in human CRC cell lines. Expression of LRP6 mutant in which serine/threonine residues in each particular ProlineProlineProlineSerine/ThreonineProline motif were mutated to alanines (LRP6-5A) significantly reduced β-catenin/TCF4 transcriptional activity. Accordingly, MEK inhibition in human CRC cells significantly diminished β-catenin/TCF4 transcriptional activity and c-MYC mRNA and protein levels without affecting β-catenin expression or stability. Lastly, LRP6 phosphorylation was also increased in human colorectal tumors, including adenomas, in comparison with healthy adjacent normal tissues. Our data indicate that oncogenic activation of KRAS/BRAF/MEK signaling stimulates the canonical Wnt/β-catenin pathway, which in turn promotes intestinal tumor growth and invasion. Moreover, LRP6 phosphorylation by ERK1/2 may provide a unique point of convergence between KRAS/MAPK and Wnt/β-catenin signalings during oncogenesis.
| S-EPMC4687460 | biostudies-literature
Project description:BACKGROUND:Studies have shown that cancer susceptibility candidate 11 (CASC11), a newly discovered long non-coding RNA (lncRNA), was aberrantly overexpressed in hepatic carcinoma, gastric cancer and colorectal cancer. However, its effects on cervical cancer has been kept unknown up to now. The present study was aimed to investigate the relationship between lncRNA CASC11 and cervical cancer and further explore the mechanism of CASC11 effect on cervical cancer progression. MATERIALS:Quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expressions of CASC11 in cancerous and adjacent normal tissues of patients with cervical cancer as well as in cell lines. The proliferation, migration, invasion and apoptosis were assayed after transfecting the cell with si-CASC11 or pcDNA3.1-CASC11. TOP/FOP-Flash luciferase reporter assay and western blot were used to analysis the activation of Wnt/?-catenin signaling pathway. Si-CASC11-transfected HeLa cells were subcutaneously inoculated into male athymic (nude) mice to investigate the effect of CASC11 on the tumor formation. RESULTS:We discovered that CASC11, the expression of which was positively associated with the tumor size and the FIGO staging and negatively related to the patients' survival rate, was up-regulated in the cervical cancer tissues and cell lines. Silencing CASC11 inhibited the proliferation, migration as well as invasion and promoted the cell apoptosis. Conversely, overexpression of CASC11 facilitated the cancer cell's proliferation, migration and invasion ability and suppressed the apoptosis. Further study showed that CASC11 promoted the migration and invasion of cervical cancer cells by activating Wnt/?-catenin signaling pathway and silencing CASC11 inhibited the tumor growth in vivo. CONCLUSION:Our study demonstrated that CASC11 promoted the cervical cancer progression by activating Wnt/?-catenin signaling pathway for the first time, which provides a new target or a potential diagnostic biomarker of the treatment for cervical cancer.
| S-EPMC6599525 | biostudies-literature
Project description:BackgroundKIF18B was identified as a potential oncogene by analysis of The Cancer Genome Atlas database.Materials and methodsWe assessed KIF18B expression and explored its clinical significance in cervical cancer tissues. We have also evaluated the effects of KIF18B on cervical cancer cell proliferation, migration, and invasion both in vitro and in vivo.ResultsOur results show that KIF18B is overexpressed in cervical cancer tissues and is associated with a large primary tumor size, an advanced FIGO stage, and an advanced tumor grade. Knockdown of KIF18B induces cell cycle G1-phase arrest and inhibits the proliferation, migration, and invasion of cervical cancer cells, whereas its overexpression promotes proliferation, migration, and invasion in these cells. Moreover, silencing of KIF18B reduces expression of CyclinD1, β-catenin, C-myc, and p-GSK3β expression.ConclusionThese data suggest that KIF18B can serve as a novel oncogene that promotes the tumorigenicity of cervical cancer cells by activating Wnt/β-catenin signaling pathway.
| S-EPMC5880519 | biostudies-literature
Project description:BackgroundWnt2 is overexpressed and able to promote tumorigenesis in many types of cancer. However, its expression and role in lung cancer has not been well clarified yet. In this study, we aims to investigate the expression pattern, clinical significance and the underlying molecular mechanism of Wnt2 in non-small lung cancer (NSCLC).MethodsImmunohistochemical staining and ELISA assays were applied to detect Wnt2 level in tumor tissue and serum. EDU incorporation assays and colony formation assays were used to evaluate the growth-promoting effect of Wnt2 in vitro. Then we performed western blot and immunofluorescence assays to detect the activation of WNT signaling pathway. Finally mice engrafted with NSCLC tumor cells were used to assess the role of Wnt2 in vivo.ResultsImmunohistochemical staining consisting of 264 NSCLC tumor tissues showed that a high level of Wnt2 was associated with a poor overall survival (OS) and relapse-free survival (RFS) of NSCLC patients (P = 0.002 and 0.0005, respectively). Multivariate analysis presented that Wnt2 level in tumor tissue was an independent prognostic factor (P = 0.049 for OS and P = 0.002 for RFS, respectively). Furthermore, ELISA assays for 181 individuals (116 NSCLC and 65 controls) revealed that serum Wnt2 levels in adenocarcinoma was significantly higher than that in healthy volunteers (P < 0.0001). In vitro H460 cell line stably overexpressing Wnt2 showed enhanced growth activity than the control cells whereas knockdown of Wnt2 by siRNA in H1299 cells resulted in decreased growth activity. Additionally, Wnt2 level in tumor tissues was significantly associated with Ki-67 level (rs: 0.316; P < 0.0001). Immunofluorescence and Western blot assays detected the translocation of β-catenin from cytoplasm into nucleus, which indicated that Wnt2 probably promotes proliferation by activating WNT/β-catenin pathway. In vivo H460 cells expressing exogenous Wnt2 showed increased growth-promoting effect in Balb/c nude mice than control cells.ConclusionsThe present study for the first time suggested that Wnt2 was both a prognostic and a diagnostic biomarker for NSCLC. Tumor-derived Wnt2 can promote growth activity of NSCLC cells through activating WNT/β-catenin signaling pathway.
| S-EPMC4449433 | biostudies-literature
Project description:Purpose: This study aims to explore the FHL1 expression level in colorectal cancer (CRC) patients, analyze its association with patient survival and investigate the role of FHL1 in CRC. Methods: We used secondary sequencing to profile mRNA expression in CRC tissue and corresponding adjacent normal tissue from four CRC patients. We focus on FHL1 and analyzed the association between its expression level and clinical indicators. Furthermore, we explored the functional role of FHL1 in colorectal cancer tumorigenesis by transfecting cells with siRNA or overexpression plasmids. Results: Hierarchical clustering revealed significantly differentially expressed mRNAs. FHL1 expression was significantly lower in CRC tissue than in adjacent normal tissue as well as in CRC cell lines relative to NCM460. Low FHL1 expression in CRC tissue correlated with poor patient survival. Our data demonstrated that overexpression of FHL1 inhibited the proliferation, colony formation potential, and expression of CdK4 and Cyclin D1, whereas ablating FHL1 promoted their proliferation and colony formation potential, suggesting that FHL1 acts as a tumor suppressor in CRC. Moreover, we showed that FHL1 inhibited the proliferation of colorectal cancer cells by negatively regulating the Wnt/β-catenin signaling pathway. Conclusion: FHL1 is a potential tumor suppressor gene in colorectal cancer, and regulation of the FHL1-Wnt/β-catenin pathway may be part of its antitumor mechanism.
| S-EPMC8317513 | biostudies-literature
Project description:5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.
| S-EPMC7578039 | biostudies-literature