Explore the vast range of titles available.

Background tRNA-derived fragments (tRFs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of tRFs to colorectal cancer (CRC) remain largely unknown. Methods tRF3008A (a tRFRNA derived from tRNA Val ) was identified by RNA sequencing and validated by quantitative reverse transcription PCR. The role of tRF3008A in CRC progression was assessed both in vitro and in vivo, and its downstream target genes were identified and validated in CRC cells. RNA pull-down with mass spectrometry and AGO-RIP were used to confirm the interaction of tRF3008A and AGO proteins. The clinical implications of tRF3008A were assessed in CRC tissues and blood samples. Results The expression of tRF3008A was reduced in colorectal cancer, and its reduction was significantly correlated with advanced and metastatic disease in CRC. Patients with low tRF3008A expression showed significantly shorter DFS, and multivariate analysis identified tRF3008A as an independent prognostic biomarker in CRC. Functionally, tRF3008A inhibits the proliferation and migration of CRC in vivo and in vitro by repressing endogenous FOXK1, a positive regulator of the Wnt/β-catenin pathway. Mechanistically, tRF3008A binds to AGO proteins as a guide to destabilize oncogenic FOXK1 transcript. Conclusions tRF3008A suppresses the metastasis and progression of colorectal cancer by destabilizing FOXK1 in an AGO-dependent manner.

Background/Aims: Metastasis is the primary cause of colorectal cancer (CRC)-related death. However, the molecular mechanisms underlying metastasis in CRC remain unclear. Methods: We evaluated mRNA and protein expression levels by quantitative real-time reverse transcription PCR, western blotting, immunofluorescence, tissue microarrays, and immunohistochemistry assays. We also assessed the migration and invasion abilities of CRC cells in vitro by wound healing assays, invasion and migration assays, western blot analysis, and immunofluorescence. Tumor metastasis was evaluated in nude mice in vivo. Results: A positive correlation was observed between the expression patterns of Forkhead box k1 (FOXK1) and Snail in CRC. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Snail directly bound to and activated the human FOXK1 gene promoter. Moreover, the Snail-FOXK1 axis promote epithelial mesenchymal transition (EMT)-mediated CRC cell invasion and metastasis. FOXK1 and Snail expression levels were correlated with tumor progression and served as significant predictors of overall survival in patients with CRC. Furthermore, overexpression of FOXK1 induced the EMT by upregulating the expression of cysteine-rich angiogenic inducer 61 (Cyr61). Luciferase assays showed that Cyr61 was a direct transcriptional target of FOXK1. Down regulation of Cyr61 decreased FOXK1-enhanced “CRC cell” migration, invasion, and metastasis. Additionally, FOXK1 expression was positively correlated with Cyr61 expression and was associated with poor prognosis. Conclusions: The Snail/FOXK1/Cyr61 signaling axis regulates the EMT and metastasis of CRC.

Background: MiR-646 has been reported to be aberrantly expressed in human cancers. However, the underlying molecular mechanisms of action of miR-646 in gastric cancer (GC) have not yet been investigated. Methods: In vitro function of miR-646 in GC was evaluated using EdU assay, plate colony formation assay, and matrigel invasion assay. Real-time PCR or western blotting was performed to detect miR-646 and FOXK1 expressions. In vivo tumour growth and metastasis were conducted in nude mice. Results: MiR-646 expression was downregulated in GC tissues compared with adjacent normal tissues. Low miR-646 expression is associated with malignant progression. Transient transfection of GC cells with miR-646 inhibited their growth and migration. Moreover, miR-646 influenced the expression of epithelial–mesenchymal transition (EMT)-associated proteins. TGF- β 1 treatment significantly suppressed the expression of miR-646 and overexpression of this microRNA counteracted the influence of the TGF- β 1-induced EMT phenotype. In terms of the underlying mechanism, miR-646 directly targeted FOXK1. In vivo , it inhibited the FOXK1-mediated proliferation and EMT-induced metastasis. Consistently, inverse correlations were also observed between the expression of miR-646 and FOXK1 in human GC tissue samples. Furthermore, miR-646 regulated Akt/mTOR signalling after FOXK1. Conclusions: miR-646 inhibited GC cell proliferation and the EMT progression in GC cells by targeting FOXK1.

Background Ovarian cancer (OC) is a female malignant tumor with a high fatality rate. Long non-coding RNAs (lncRNAs) are deeply involved in OC progression. The aim of this study is to explore the specific mechanism of lncRNA prostate androgen-regulated transcript 1 (PART1) in OC. Methods Quantitative real time PCR was utilized to determine the expression levels of PART1, microRNA (miR)-503-5p and forkhead-box k1 (FOXK1) in OC tissues and/or cells. The cell viability, migration, and invasion in OC were evaluated by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-h-tetrazolium bromide assay, wound healing assay and transwell invasion assay, respectively. Flow cytometry was used to analyze the cell apoptosis. The xenograft tumor was conducted in nude mice to verify the effect of PART1 knockdown on OC in vivo. The target relationships among PART1, miR-503-5p and FOXK1 were predicted by StarBase, and verified by luciferase reporter assay. The level of FOXK1 was assessed by western blot. Results Increased expression of PART1 and FOXK1 was observed in OC tissues or cells, whereas miR-503-5p was downregulated. PART1 silencing or miR-503-5p overexpression repressed the cell viability, migration and invasion, and protomed apoptosis. Meanwhile, miR-503-5p was a target of PART1, and FOXK1 was a direct target gene of miR-503-5p. Both downregulation of miR-503-5p and upregulation of FOXK1 partly relieved the suppressive effects of PART1 knockdown on the oncogenicity of OC in vitro. Conclusion Decreased PART1 represses the cell viability, migration and invasion of OC via regulating the miR-503-5p/FOXK1 axis, which provided an underlying target for treating OC.

To determine whether FOXK1 induces CD8⁺ T cell exhaustion via histone lactylation in high-grade serous ovarian cancer (HGSOC). Cellular studies utilized qRT-PCR and Western blotting to compare FOXK1 expression in normal ovarian vs. cancer cells. Western blot assessed proteins linked to aerobic glycolysis, lipid metabolism, histone ubiquitination, and epithelial-mesenchymal transition (EMT). Cell migration/invasion were evaluated via scratch and Transwell assays. In vivo, a mouse ovarian cancer model was established. Lactate and lipid levels in supernatants/tissues were measured using Oil Red O and detection kits. TOX and glucose and lipid metabolism regulatory factors were analyzed by H&E staining and immunohistochemistry. The expression levels of immune related factors and the proportion of positive immune detection points in the supernatant of CD8+ T cell culture and tumor tissue were detected by ELISA kits and flow cytometry. Ovarian cancer cells showed elevated FOXK1, glycolysis proteins, lipid regulators, histone ubiquitination, EMT markers, lactate, and lipids compared to normal cells. Tumor tissues exhibited higher glycolysis proteins, lipid regulators, ubiquitination, and lipids than non-cancerous tissue. FOXK1 knockdown in SKOV3 cells reduced lactate, lipids, glucose uptake, glycolysis/lipid proteins, and inhibited proliferation/migration/invasion, while enhancing CD8 + T cell proliferation, immune checkpoint positivity, and immune factors, with decreased apoptosis. In mice, FOXK1 knockdown reduced tumor volume, TOX, glycolipid regulators, ubiquitination, and lipids, but increased immune factors and checkpoint-positive cells in tissues. FOXK1 regulates glycolipid metabolism and TOX histone lactylation, driving CD8 + T cell exhaustion, suggesting novel immunotherapy targets.

Aberrantly expressed miRNAs play a vital role in the development of some cancers, such as human osteosarcoma (OS). However, the detailed molecular mechanisms underlying miR-186-5p-involved osteosarcoma are unclear. qRT-PCR and western blot analysis were employed to measure the expressions of miR-186-5p and forkhead box k1 (FOXK1). CCK-8 assay evaluated the effect of miR-186-5p and FOXK1 on cell proliferation. Transwell assay confirmed cell migration and invasion. Eventually, the dual-luciferase reporter assay validated 3'-untranslated region (3'-UTR) of FOXK1 as a direct target of miR-186-5p. Down-regulation of miR-186-5p was identified in OS tissues and cell lines, and negatively correlated with distant metastasis, Enneking stage and poor 5-year prognosis as well as the expression of forkhead box k1 (FOXK1) protein. Further assays demonstrated that miR-186-5p overexpression had inhibitory effects on in-vitro cell proliferation, cell cycle, and in-vivo tumor growth. miR-186-5p overexpression also inhibited the epithelial-tomesenchymal transition (EMT), migration and invasion of OS cells. Importantly, miR-186-5p directly targeted FOXK1 3'-UTR and negatively regulated its expression. Silencing of FOXK1 expression enhanced the inhibitory effects of miR-186-5p on OS cell proliferation, migration and invasion. These findings highlighted miR-186-5p as a tumor suppressor in the regulation of progression and metastatic potential of OS, and may benefit the development of therapies targeting miR-186-5p in patients with OS.

Forkhead box K1 (FOXK1) is members of the FOX transcription factor family. Previous work has found out that FOXK1 promotes cell proliferation, migration and invasion in several cancers, such as gastric cancer, glioma cancer and lung cancer; however, the exact role of FOXK1 in breast cancer is still poorly known. Here, the association between FOXK1 expression and the clinicopathological characteristics of patients with breast cancer was identified. To further decipher the functional roles of FOXK1, it was overexpressed or knocked down in MCF-7, MDA-MB-231 and MCF-10A cells. Cell Counting Kit-8, colony formation and cell cycle assays were performed to examine the proliferation of breast cancer cells. Moreover, wound-healing and Transwell invasion analyses were carried out to explore the effect of FOXK1 on breast cancer cell migration and invasion. Our findings discovered that FOXK1 promotes cell proliferation, migration and invasion in breast cancer. In addition, consistent with the previous report, FOXK1 also facilitates EMT in breast cancer. TargetScan was used to predict up-stream of FOXK1, indicating that miR-365-3p could regulate FOXK1 expression in breast cancer. The findings of the present study demonstrated that miR-365-3p-FOXK1 axis plays a key role in breast cancer.

Background Spinal cord injury (SCI) causes severe energy metabolism dysfunction, hindering neuronal survival and recovery. Adipose tissue-derived stromal cells (ADSCs) have neuroprotective potential, but their role in regulating neuronal energy metabolism and the underlying mechanisms remain unclear. This study aimed to investigate whether ADSCs are capable of restoring neuronal glycolysis through the FOXK1-HK2 signaling pathway, thereby replenishing the energy supply and facilitating tissue regeneration. Methods We employed rat and cell models of SCI to observe the effects of ADSCs on glycolytic metabolism and apoptosis. Transcriptome sequencing identified glycolysis-related differentially expressed genes. Lactate detection and Seahorse assays were used to quantify glycolytic activity. Dual-luciferase reporter assays verified the FOXK1-HK2 regulatory relationship. Cut&Run assay provided direct evidence of FOXK1 binding to the HK2 promoter. Behavioral tests, histopathological staining and immunofluorescence were used to evaluate in vivo functional recovery and tissue repair. FOXK1 knockdown confirmed its role in the ADSC-mediated pathway. Results We found that ADSCs exerted multiple protective and regulatory effects on neurons and motor function. Specifically, they strongly inhibited neuronal oxidative stress, protected mitochondria, and promoted neuronal metabolic reprogramming. Additionally, ADSCs increased glycolytic activity and lactate production, which further contributed to promoting neuronal survival and the recovery of hindlimb motor function. Blocking TGF-β1 signaling abrogated ADSC-induced activation of the FOXK1-HK2 axis and subsequent enhancement of glycolysis, confirming TGF-β1 as a critical paracrine mediator. Through interaction with HK2, FOXK1 plays a critical role in modulating glycolysis. Dual-luciferase reporter and Cut&Run assays confirmed that FOXK1 regulates the HK2 promoter, thereby increasing its transcriptional activity. The inhibition of FOXK1 expression resulted in suppressed HK2 expression, reduced glycolytic flux, and weakened the neuroprotective effects of ADSCs on SCI. Conclusions ADSCs are considered a potential option for SCI treatment, and their therapeutic effects are closely related to the FOXK1/HK2 axis, which mediates ADSCs’ regulation of neuronal glycolytic metabolism to exert protective and reparative functions. Graphical Abstract

In human gastric cancer (GC), the upregulation of FOXK1 and vimentin is frequently observed in cancer cells and correlates with increased malignancy. We report that FOXK1 synergizes with vimentin to promote GC invasion and metastasis via the induction of epithelial-mesenchymal transition (EMT). We showed that higher expression levels of FOXK1 were significantly associated with GC development. FOXK1 can physically interact with and stabilize vimentin. Moreover, a positive correlation between the expression of FOXK1 and vimentin was found in GC cells. Higher expression levels of these two proteins were significantly associated with differentiation, lymph node metastasis, AJCC stage, and poorer prognosis. Furthermore, the coexpression of FOXK1 and vimentin enhances cell metastasis through the induction of EMT in GC cells. However, the siRNA-mediated repression of vimentin in FOXK1-overexpressing cells reversed the EMT-like phenotype and reduced GC cell migration and invasion in vitro and in vivo. Altogether, our findings suggest that the vimentin-FOXK1 axis provides new insights into the molecular mechanisms underlying EMT regulation during GC progression and metastasis.

Ovarian cancer (OC) is a female malignant tumor with a high fatality rate. Long non-coding RNAs (lncRNAs) are deeply involved in OC progression. The aim of this study is to explore the specific mechanism of lncRNA prostate androgen-regulated transcript 1 (PART1) in OC. Quantitative real time PCR was utilized to determine the expression levels of PART1, microRNA (miR)-503-5p and forkhead-box k1 (FOXK1) in OC tissues and/or cells. The cell viability, migration, and invasion in OC were evaluated by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-h-tetrazolium bromide assay, wound healing assay and transwell invasion assay, respectively. Flow cytometry was used to analyze the cell apoptosis. The xenograft tumor was conducted in nude mice to verify the effect of PART1 knockdown on OC in vivo. The target relationships among PART1, miR-503-5p and FOXK1 were predicted by StarBase, and verified by luciferase reporter assay. The level of FOXK1 was assessed by western blot. Increased expression of PART1 and FOXK1 was observed in OC tissues or cells, whereas miR-503-5p was downregulated. PART1 silencing or miR-503-5p overexpression repressed the cell viability, migration and invasion, and protomed apoptosis. Meanwhile, miR-503-5p was a target of PART1, and FOXK1 was a direct target gene of miR-503-5p. Both downregulation of miR-503-5p and upregulation of FOXK1 partly relieved the suppressive effects of PART1 knockdown on the oncogenicity of OC in vitro. Decreased PART1 represses the cell viability, migration and invasion of OC via regulating the miR-503-5p/FOXK1 axis, which provided an underlying target for treating OC.