Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. Upon binding to its extracellular matrix (ECM) ligand, type I collagen, ITGA2 activates stemness-associated signaling pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, a small-molecule inhibitor of the ITGA2-collagen interaction, significantly sensitizes oral squamous cell carcinoma (OSCC) to cisplatin in xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy.
© 2025. The Author(s).

Fructus Viticis Total Flavonoids (FVTF) is a novel candidate preparation that possesses anticancer activity. However, the role and mechanism of FVTF-inhibiting human hepatocellular carcinoma (HCC) cell stem properties is unclear.
Liquid chromatography (LC) in conjugation with mass spectrometer (MS) was used to identify the compounds of FVTF. Tumorsphere and soft agar colony formation ability, cancer stem marker expression levels, CD133+ cell percentage, and a xenograft model were utilized to investigate the impact of FVTF on HCC cells stemness. PCR array and qRT-PCR were conducted to identify differentially expressed cancer stem-related genes and miRNAs between FVTF-treated and untreated HCC cells, respectively. Pyrosequencing was conducted to assess the DNA methylation level of the miR-34a-5p promoter. A luciferase reporter assay was performed to verify whether FoxM1 serves as a direct target of miR-34a-5p. Additionally, immunohistochemistry of an HCC tissue microarray was carried out to assess the expression levels of DNMT1, FoxM1, and miR-34a-5p.
A total of 26 compounds, including 10 flavones, in FVTF were identified. FVTF significantly reduced the ability of tumorsphere and soft agar colony formation, the levels of CD44 protein and BMI1, OCT4 and SOX2 mRNAs in HCC cells, and in vivo tumor initiation ability of HCC cells. Mechanistically, FVTF inhibited HCC cell stem properties via targeting DNMT1/miR-34a-5p/FoxM1 axis. Clinically, DNMT1 expression was inversely correlated with miR-34a-5p expression, whereas a positive correlation was noted between DNMT1 and FoxM1 expression levels, and high DNMT1 levels, low miR-34a-5p levels, and high FoxM1 levels were associated with cancer recurrence. Furthermore, a combination of DNMT1, miR-34a-5p and FoxM1 served as an independent prognostic indicator influencing both DFS and OS in patients with HCC.
FVTF inhibits HCC cell stem properties by targeting DNMT1/miR-34a-5p/FoxM1 axis, which is associated with HCC recurrence and prognosis, and FVTF is a prospective treatment drug for human HCC.
© 2025. The Author(s).

Abstract Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. When bound to its ECM ligand, type I collagen, ITGA2 activates several stemness-related pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, which inhibits the ITGA2–collagen interaction, showed a synergistic anti-tumor effect when combined with cisplatin in both in vitro and xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy.

Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. When bound to its ECM ligand, type I collagen, ITGA2 activates several stemness-related pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, which inhibits the ITGA2–collagen interaction, showed a synergistic anti-tumor effect when combined with cisplatin in both in vitro and xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy. Highlights 1) KLF7 as a key molecule in maintaining oral cancer stemness. 2) ITGA2as a key downstream gene regulated by KLF7 in the maintenance of stemness. 3) ITGA2 interacts with extracellular matrix type I collagen, activating stemness-related pathways and promoting YAP1 nuclear translocation to sustain OCSCs. 4) ITGA2 as a novel anti-CSC target, providing a new strategy to overcome OSCC drug resistance.

Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program. Phosphoenolpyruvate carboxylase 1 (PCK1), a gluconeogenic metabolic enzyme, is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis. The oncogenesis and progression of tumors are closely related to cancer stem cells. It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma. Herein, the results showed that PCK1 inhibited the self-renewal property of hepatoma cells, reduced the mRNA level of cancer stem cell markers, and inhibited tumorigenesis. Moreover, PCK1 increased the sensitivity of hepatocellular carcinoma cells to sorafenib. Furthermore, we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation. Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib. Thus, combined treatment with verteporfin and sorafenib may be a potential anti-tumor strategy in hepatocellular carcinoma.
© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.