Arecoline promotes proliferation and migration of human HepG2 cells through activation of the PI3K/AKT/mTOR pathway

Hai, Xie; Ren, Jianmin; Liao, Xueming; Chen, Haishao; Xie, Xianlong; Dai, Huijun; Pan, Linghui

doi:10.1186/s41065-022-00241-0

Cited by 10 publications

(7 citation statements)

References 44 publications

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“…However, when TNF-α and IL-6 in epithelial cells are activated by arecoline, it inhibits cell movement but not proliferation (Figures 1 and 3). These findings suggest that low-dose arecoline may influence other factors associated with cell movement and proliferation, such as Wnt signaling [43] and microRNAs [44]. Even at low doses, accumulated arecoline still induces DNA damage in cells and triggers DNA repair processes [40].…”

Section: Discussionmentioning

confidence: 95%

Arecoline Induces ROS Accumulation, Transcription of Proinflammatory Factors, and Expression of KRT6 in Oral Epithelial Cells

Wang,

Shen,

Chen

et al. 2024

Biomedicines

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Areca nut is a major contributor to the high prevalence of oral cancer in Asia. The precise mechanisms by which areca nut stimulates mucosal cells and contributes to the progression of oral cancer urgently require clarification. The current study aimed to assess the effects of arecoline on the normal human gingival epithelium cell line S-G. Cell viability, levels of reactive oxygen species (ROS), protein expression, cellular morphology, and gene expression were evaluated using the MTT test, flow cytometry, Western blot analysis, optical or confocal microscopy, and RT-qPCR. Keratin (KRT6) analysis involved matched normal and cancer tissues from clinical head and neck specimens. The results demonstrated that 12.5 µg/mL of arecoline induced ROS production, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNA expression in S-G cells. This activation of the MAPK/ERK pathway increased KRT6 expression while limiting cell migration. In head and neck cancer tissues, KRT6B gene expression exceeded that of normal tissues. This study confirms that arecoline induces ROS accumulation in normal cells, leading to the secretion of proinflammatory factors and KRT6 expression. This impedes oral mucosal healing, thereby promoting the progression of oral cancer.

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Section: Discussionmentioning

confidence: 95%

Arecoline Induces ROS Accumulation, Transcription of Proinflammatory Factors, and Expression of KRT6 in Oral Epithelial Cells

Wang,

Shen,

Chen

et al. 2024

Biomedicines

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“…In hepatocytes, arecoline N -oxide exhibited higher cytotoxicity and caused more DNA damage than did arecoline [ 24 ]. A study conducted using human hepatoma cells revealed that low concentrations of arecoline induced cell proliferation and migration by activating the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway [ 68 ]; unfortunately, these findings were not validated in studies using human, animal, or cellular models. Notably, an epidemiological study also indicated that BQ use was not associated with gastric or colorectal cancer [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Roles of Arecoline and Arecoline N-Oxide in Oral Cancer and Strategies to Block Carcinogenesis

2023

Cells

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Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline N-oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with N-acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial–mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.

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“…Xie et al. [ 44 ] reported that miR-21-3p upregulated the expression of PI3K-AKT pathway factors, CDK1, CCND1 but decreased RAF1 expression in hepatocellular cancer cells. And Zhang et al.…”

Section: Discussionmentioning

confidence: 99%

Screening microRNAs as potential prognostic biomarkers for lung adenocarcinoma

Dai,

Li,

Yang

et al. 2023

Annals of Medicine

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Objective To screen and identify microRNAs (miRNAs) associated with the prognosis of lung adenocarcinoma (LUAD) using clinical samples and construct a prediction model for the prognosis of LUAD. Methods 160 patient samples were used to screen and identify miRNAs associated with the prognosis of LUAD. Differentially expressed miRNAs were analyzed using gene chip technology. The selected miRNAs were validated using samples from the validation sample group. Cox proportional hazards regression was used to construct the model and Kaplan-Meier was used to plot survival curves. Model power was assessed by testing the prognosis of the constructed model using real-time polymerase chain reaction (RT-PCR) data. Results The data showed that miR-1260b, miR-21-3p and miR-92a-3p were highly expressed in the early recurrence and metastasis group, while miR-2467-3p, miR-4659a-3p, miR-4514, miR-1471 and miR-3621 were lowly expressed. It was further confirmed that miR-21-3p was significantly highly expressed in the early recurrence and metastasis group ( p = 0.02). Receiver operating characteristic (ROC) curve results showed cut-off point value of 0.0172, sensitivity of 88.2% and specificity of 100%. The predictive results of the constructed model were in good agreement with the actual prognosis of patients by using the validation sample test (Kappa = 0.426, p < 0.001), with a model sensitivity of 74.4%, a specificity of 68.3%, and an accuracy of 71.3%. Conclusion miRNAs associated with the prognosis of patients with stage I LUAD were screened and validated, and a risk model for predicting the prognosis of patients was constructed. This model has good consistency with the actual prognosis of patients.

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Arecoline promotes proliferation and migration of human HepG2 cells through activation of the PI3K/AKT/mTOR pathway

Cited by 10 publications

References 44 publications

Arecoline Induces ROS Accumulation, Transcription of Proinflammatory Factors, and Expression of KRT6 in Oral Epithelial Cells

Arecoline Induces ROS Accumulation, Transcription of Proinflammatory Factors, and Expression of KRT6 in Oral Epithelial Cells

Systematic Review of Roles of Arecoline and Arecoline N-Oxide in Oral Cancer and Strategies to Block Carcinogenesis

Screening microRNAs as potential prognostic biomarkers for lung adenocarcinoma

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