Hypoxia‐driven paracrine osteopontin/integrin αvβ3 signaling promotes pancreatic cancer cell epithelial–mesenchymal transition and cancer stem cell‐like properties by modulating forkhead box protein M1

Liu

et al. 2020

Journal of Oncology

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: Discussionmentioning

confidence: 99%

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

Liu

et al. 2020

Journal of Oncology

J Hepato Biliary Pancreat

“…For instance, Cao et al. reported that hypoxia‐driven paracrine osteopontin/integrin αvβ3 signaling promoted pancreatic cancer cell epithelial‐mesenchymal transition and cancer stem cell‐like properties by modulating FOXM1. Deng et al.…”

Section: Discussionmentioning

confidence: 99%

Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8

Gao

Zhang

et al. 2019

Background To investigate the potential anti-tumoral properties of propofol in pancreatic cancer and elucidate the underlying mechanisms. Methods The relative expression of ADAM metallopeptidase domain 8 (ADAM8) in response to hypoxia in Panc1 cells was analyzed by western blotting. The enzymatic activity was determined by fluorescence release from PEPDAB013 decomposition. Cell growth was measured via cell counting and cell viability was measured using CCK-8 kit. Cell migrative capacity was evaluated by transwell and adhesion assay. The relative abundance of angiogenesis-related markers including platelet-derived growth factor AA, angiogenin, endothelin-1 and vascular endothelial growth factor were determined by real-time polymerase chain reaction and western blotting. The antitumoral activity of propofol was investigated with Panc1derived xenograft mice model. Results ADAM8 was significantly induced by hypoxia and efficiently inhibited by co-treatment with propofol. Propofol suppressed proliferation and compromised viability of Panc1 cells. In addition, the migrative capacity was greatly inhibited by propofol dosage. Comprehensive profiling of angiogenesis-related markers demonstrated that propofol remarkably suppressed neovascularization response in Panc1 cells under hypoxia. We further uncovered that propofol administration via subcutaneous injection delayed xenograft tumor progression. Conclusion Propofol specifically inhibited ADAM8 expression and activation in response to hypoxia in pancreatic cancer, and held great value for therapeutic effects.

“…1,2 The molecular mechanism and therapeutic strategies of PC have been continuously studied. 3,4 Therefore, it is of great significance for us to determine the molecular mechanism of PC and find more novel biomarkers for PC to contribute to the developmental, preventive and therapeutic strategies for PC.…”

Section: Introductionmentioning

confidence: 99%

<p>KRT17 Functions as a Tumor Promoter and Regulates Proliferation, Migration and Invasion in Pancreatic Cancer via mTOR/S6k1 Pathway</p>

Li¹,

Ni²,

Tang³

et al. 2020

CMAR

Background: Pancreatic cancer (PC) is one of the most well-known malignancies with high mortality, but the underlying mechanism of PC remains unknown. Keratin17 (KRT17) expression has been reported in many malignancies, but its functions in PC are not clear. The aim of our study was to evaluate KRT17 expression and its potential role in PC. Methods: The online databases GEPIA and THPA were used to identify KRT17 expression in tissues. Quantitative real-time PCR (qRT-PCR) was used to determine KRT17 expression in cell lines. Ki67 and ROS levels were detected by immunofluorescence assay and a 2ʹ,7ʹdichlorodihydrofluorescein diacetate (DCFH-DA) probe. KRT17 downregulation was induced by the small interfering RNA (siRNA) technique. Proliferation function was evaluated by colony formation assay and RTCA. Migration and invasion were evaluated by transwell migration assay. A Western blot assay was used to detect protein levels. Results: KRT17 was overexpressed in PC tissues compared to that in normal tissues. The results showed that Ki67 and ROS levels were decreased in pancreatic cancer cells after transfection with siKRT17. After KRT17 downregulation in PC cell lines, cell viability functions, including proliferation, migration and invasion, and mTOR/S6K1 phosphorylation levels were attenuated. Conclusion: KRT17 knockdown significantly inhibited proliferation, migration and invasion in pancreatic cancer cells.