COL14A1 promotes self-renewal of human liver cancer stem cells through activation of ERK signaling

Objective:Liver cancer stem cells(CSCs)are the culprits of hepatocellular carcinoma metastasis and recurrence.Only by eliminating tumor stem cells can malignant tumors be fundamentally cured.This study aimed to identify the role and underlying mechanism of aberrant Collagen Type XIV Alpha 1 Chain(COL14A1)overexpression in liver CSCs,and improve understanding of the molecular basis of hepatocellular carcinoma metastasis and recurrence.Methods:First,quantitative real-time polymerase chain reaction was used to confirm aberrant high-expression of COL14A1 in liver CSCs.Next,interference experiments were performed to determine the key role of COL14A1.To explore the mechanism of COL14A1 overexpression in liver CSCs,putative microRNA(miRNAs)targeting COL14A1 were analyzed using the miRTarBase database.Next,quantitative real-time polymerase chain reaction,western blotting,and luciferase reporter assays were performed to verify the interaction between miR-7108-3p and COL14A1.Lastly,key target proteins of the COL14A1-extracellular-regulated signal kinase(ERK)signaling pathway were identified through western blotting analysis.This study was approved by the Ethics Committee of Shanghai Fourth People’s Hospital,Tongji University School of Medicine,China(approval No.2019tjdx17)on February 21,2019.Results:COL14A1 is abnormally highly expressed in liver CSCs,which is necessary for liver CSCs to maintain their self-renewal capability.Mechanistically,COL14A1 is post-transcriptionally regulated by miR-7108-3p in a negative manner.Low expression of miR-7108-3p increased translation of COL14A1,which subsequently activated ERK signaling,ultimately maintaining the self-renewal and stem cell-like properties of liver CSCs.Conclusion:COL14A1,which is negatively regulated by miR-7108-3p,was found to play a crucial role in maintaining the selfrenewal and stem cell-like properties of liver CSCs through activation of ERK signaling.