FoxM1 promotes epithelial–mesenchymal transition, invasion, and migration of tongue squamous cell carcinoma cells through a c-Met/AKT-dependent positive feedback loop
“…FOXM1 is a key transcription factor in the regulation of cell physiology, and has been shown to modulate the expression of genes associated with the cell cycle and with genome stability [40][41][42]. Previous studies found that FOXM1 dysregulation can cause abnormal cell proliferation, thereby leading to carcinogenesis; its overexpression has been observed in many types of cancer including lung, liver, breast, brain, and oral cancers [43][44][45][46]. Other than serving as a cancer-specific diagnostic marker, FOXM1 is also a key anticancer target [47,48].…”
Daphne genkwa, a Chinese medicinal herb, is used frequently in Southeast Asian countries to treat diseases; the flavonoid hydroxygenkwanin (HGK) is extracted from its flower buds. The bioactivity of HGK, particularly as an anti-liver cancer agent, has not been explored. In this study, human hepatocellular carcinoma (HCC) cell lines and an animal xenograft model were employed to investigate both the activity of HGK against liver cancer and its cellular signaling mechanisms. HCC cells treated with HGK were subjected to cell function assays. Whole transcriptome sequencing was used to identify genes whose expression was influenced by HGK, and the flavonoid's cancer suppression mechanisms were further investigated through gain-and loss-of-function assays. Finally, in vitro findings were tested in a mouse xenograft model. The data showed that HGK induced the expression of the microRNA miR-320a, which in turn inhibited the expression of the transcription factor 'forkhead box protein M1' (FOXM1) and downstream FOXM1-regulated proteins related to epithelial-mesenchymal transition, thereby leading to the suppression of liver cancer cell growth and invasion. Significant inhibition of tumor growth was also observed in HGK-treated mice. Hence, the present study demonstrated the activity of HGK against liver cancer and validated its potential use as a therapeutic agent.
“…FOXM1 is a key transcription factor in the regulation of cell physiology, and has been shown to modulate the expression of genes associated with the cell cycle and with genome stability [40][41][42]. Previous studies found that FOXM1 dysregulation can cause abnormal cell proliferation, thereby leading to carcinogenesis; its overexpression has been observed in many types of cancer including lung, liver, breast, brain, and oral cancers [43][44][45][46]. Other than serving as a cancer-specific diagnostic marker, FOXM1 is also a key anticancer target [47,48].…”
Daphne genkwa, a Chinese medicinal herb, is used frequently in Southeast Asian countries to treat diseases; the flavonoid hydroxygenkwanin (HGK) is extracted from its flower buds. The bioactivity of HGK, particularly as an anti-liver cancer agent, has not been explored. In this study, human hepatocellular carcinoma (HCC) cell lines and an animal xenograft model were employed to investigate both the activity of HGK against liver cancer and its cellular signaling mechanisms. HCC cells treated with HGK were subjected to cell function assays. Whole transcriptome sequencing was used to identify genes whose expression was influenced by HGK, and the flavonoid's cancer suppression mechanisms were further investigated through gain-and loss-of-function assays. Finally, in vitro findings were tested in a mouse xenograft model. The data showed that HGK induced the expression of the microRNA miR-320a, which in turn inhibited the expression of the transcription factor 'forkhead box protein M1' (FOXM1) and downstream FOXM1-regulated proteins related to epithelial-mesenchymal transition, thereby leading to the suppression of liver cancer cell growth and invasion. Significant inhibition of tumor growth was also observed in HGK-treated mice. Hence, the present study demonstrated the activity of HGK against liver cancer and validated its potential use as a therapeutic agent.
“…AURKA has also been shown to negatively regulate FOXO1 at the transcriptional level, indicating that FOXM1 can indirectly regulate FOXO expression via AURKA to sustain its expression and activity in cancer cells [ 294 ]. Likewise, Akt and FOXM1, both upstream inhibitors of FOXO3, also positively regulate cell migration in a positive feedback loop manner to promote tongue squamous cell carcinoma cell migration [ 295 ]. FOXC1 (also known as FKHL7) is another forkhead protein closely related to metastasis and FOXO function.…”
Section: Deregulation Of Foxos In Cancer and Metastasismentioning
Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.
“… 16 Moreover, expression of FOXM1 promotes EMT, invasion, and migration of a variety of tumor types. 17 , 28 , 29 , 30 Here, we additionally showed that downregulation of hsa_circ_0061140 suppressed FOXM1 expression but inhibits miR-370-rescued FoxM1 expression inhibition after hsa_circ_0061140 silence. In vivo experiments further confirmed that hsa_circ_0061140 knockdown led to the suppression of ovarian cancer growth by inhibiting FOXM1 expression through sponging miR-370.…”
Section: Discussionmentioning
confidence: 51%
“…FOXM1 was previously shown to confer proliferation and invasion advantages to a variety of tumors, including non-small cell lung cancer (NSCLC), 13 esophageal squamous cell carcinoma, 14 gastric cancer, 15 and breast cancer. 16 Upregulation of FOXM1 promotes the EMT, invasion, and migration of tongue squamous cell carcinoma, 17 supporting a role in hsa_circ_0061140-mediated ovarian cancer proliferation and invasion. Figure 2 Knockdown of hsa_circ_0061140 Suppresses Ovarian Cancer Cell Proliferation and Invasion (A and B) Expression of hsa_circ_0061140 in SKOV3 (A) and A2780 (B) cells detected via real-time qPCR after transfection with hsa_circ_0061140 interference vector (sicircRNA) or negative control (NC) for 48 hr.…”
Circular RNAs (circRNAs) are a class of noncoding RNAs that regulate gene expression at the posttranscriptional level. The specific functions of circRNAs in ovarian cancer are yet to be established. Previous sequencing analyses have revealed an abnormal expression of hsa_circ_0061140 in ovarian cancer. The main aim of the present study is to establish the specific role of hsa_circ_0061140 in ovarian cancer. circRNA expression in ovarian cancer cells was detected via real-time qPCR. The effects on specific cellular characteristics (proliferation, migration, and the EMT) and subcellular localization of hsa_circ_0061140 were assessed via RNA fluorescence in situ hybridization, knockdown, and luciferase reporter assays in the SKOV3 and A2780 cell lines. Tumorigenesis was induced in nude mice to assess the effects of hsa_circ_0061140 on ovarian cancer growth in vivo. Our results showed that hsa_circ_0061140 was upregulated in ovarian cancer cell lines. Knockdown of hsa_circ_0061140 suppressed cell proliferation and migration, both in vivo and in vitro, by inhibiting FOXM1 expression through sponging miR-370. Overexpression of FOXM1 or suppression of miR-370 rescued hsa_circ_0061140 silencing-induced inhibition of cell proliferation, migration, and the EMT. The associations among hsa_circ_0061140, miR-370, and FOXM1 were confirmed via bioinformatic prediction and fluorescein reporter experiments. Thus, hsa_circ_0061140 appeared to function as a competing endogenous RNA of miR-370 that promoted cell growth and metastasis in ovarian cancer through regulation of the miR-370/FOXM1 pathway mediating EMT.
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