Disruption of crosstalk between LX-2 and liver cancer stem-like cells from MHCC97H cells by DFOG via inhibiting FOXM1

Liu

et al. 2020

Journal of Oncology

Self Cite

Background. Whether DNA methyltransferase 1 (DNMT1)/miR-34a/FoxM1 signaling promotes the stemness of liver cancer stem cells (LCSCs) remains unclear. This study aimed to assess whether methylation-based silencing of miR-34a by DNMT1 contributes to stemness features via FoxM1 upregulation in LCSCs. Methods. The CD133+ subgroup of MHCC97H cells sorted by MACS was used as LCSCs. DNMT1, BMI1, SOX2, and OCT4 mRNA levels, and miR-34a amounts were determined by qRT-PCR. DNMT1, CD44, and FoxM1 proteins were analyzed by immunoblot. Sphere and colony formation abilities were detected by respective assays. CD133+ cell percentages were assessed by flow cytometry. In vivo oncogenicity was evaluated using a tumor xenograft model in mice. The effects of DNMT1/miR-34a signaling on the stemness of LCSCs were examined by knockdown or overexpression of DNMT1 and/or transfection of miR-34a mimic or inhibitor using lentivirus-delivery systems. FoxM1 association with miR-34a was detected by a reporter assay. Results. We here showed that LCSCs exhibited elevated DNMT1 activity and expression, lower miR-34a expression with higher promoter methylation, and stronger stemness, compared with the parental liver cancer cells. DNMT1 knockdown repressed DNMT1, increased miR-34a amounts by promoter demethylation, and reduced stemness in LCSCs, whereas DNMT1 overexpression had the opposite effects in liver cancer cells. Transfection with miR-34a mimic repressed the stemness of LCSCs, while miR-34a inhibitor significantly downregulated miR-34a and enhanced stemness, without affecting DNMT1 in liver cancer cells. MiR-34a mimic rescued the effects of DNMT1 overexpression on the stemness of LCSCs, without affecting DNMT1 expression. Finally, FOXM1 was identified as a direct target by miR-34a in LCSCs. Conclusions. We revealed that aberrant activation of DNMT1 causes miR-34a promoter methylation and suppression, leading to FoxM1 upregulation by disinhibition and promotion of LCSC stemness. These findings suggest that blockage of DNMT1/miR-34a-mediated FOXM1 upregulation might suppress liver cancer by targeting LCSCs.

Section: Foxm1 Is a Direct Mir-34a Target In Lcscs It Was Demonstratmentioning

confidence: 68%

The DNMT1/miR-34a/FOXM1 Axis Contributes to Stemness of Liver Cancer Cells

Liu

et al. 2020

Journal of Oncology

Self Cite

“…The investigation of the crosstalk between HSCs and CSCs resulted in the identification of the transcription factor Forkhead Box M1 (FOXM1) as a main player in HSC activation and maintenance of stemness in CSCs in vitro. FOXM1 inhibition in co-cultures of these two populations disrupted the crosstalk, whereas the overexpression of FOXM1 reversed the effects of the inhibition [220]. These lines of research highlight additional potential targets to interrupt the communication between HSCs and cancer (stem) cells, with the ultimate goal of targeting the CSC via multiple approaches.…”

Section: The Csc Niche In Hcc: Ectopic Lymphoid Structures and Hepatimentioning

confidence: 94%

The Cancer Stem Cell in Hepatocellular Carcinoma

Schulte

López-Gil

Sáinz

et al. 2020

Cancers

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.

Canadian Journal of Gastroenterology and Hepatology

“…FOXM1 ranks among the most diferentially expressed genes. In this study, we focus on FOXM1 because it is involved in cancer stemness and metastasis [27][28][29]. Dysfunction of FOXM1 occurs in several malignant cancers and is highly correlated with poor prognosis and enhanced metastasis [13][14][15].…”

Section: Discussionmentioning

confidence: 99%

Sequential Treatment with Activin and Hepatocyte Growth Factor Induces FOXM1 to Promote Colorectal Cancer Liver Metastasis

Peng

Deng

et al. 2022

Background. Cancer stem cells (CSCs) are involved in liver metastasis in colorectal cancer (CRC). Activin and hepatocyte growth factor (HGF) are important regulators of stem cell properties. This study was performed to explore the effect of activin and HGF on CRC invasion and metastasis. The key genes involved in the action of activin and HGF in CRC were identified. Methods. HCT116 CRC cells were sequentially treated with activin and HGF and examined for migration and invasion in vitro and liver metastasis in vivo. RNA sequencing was performed to identify differentially expressed genes in response to activin and HGF. Results. Sequential treatment with activin and HGF-enhanced CRC cell migration, invasion, and metastasis. CXCR4 and AFP expressions were increased by activin and HGF treatment. Knockdown of FOXM1 blocked liver metastasis from HCT116 cells pretreated with activin and HGF and suppressed CXCR4 and AFP expression. Activin alone increased the mRNA and protein expression of FOXM1. In contrast, HGF alone enhanced the phosphorylation of FOXM1, without altering the total protein level of FOXM1. SMAD2 was required for activin-mediated FOXM1 induction. FOXM1 transactivated CXCR4 by directly binding to the promoter of CXCR4. Additionally, CXCR4 regulated AFP expression through the NF-κB pathway. Conclusions. Sequential treatment with activin and HGF accelerates CRC invasion and liver metastasis, which involves the upregulation and activation of FOXM1 and induction of CXCR4 and AFP.