| OBJECTIVE:To explore the molecular mechanism of the effect of pre-metastasis microenvironment of potential metastatic organs on circulating tumor cells in hepatocellular carcinoma during the metastasis and colonization of distal organs.Background:Hepatocellular carcinoma(HCC)is highly lethal,often progresses rapidly and has limited options for advanced patients.At the same time,HCC has a high postoperative recurrence rate.Due to the high variability of liver cancer cells in the process of metastasis and recurrence,there is a lack of timely and accurate monitoring methods and prevention schemes in clinical practice,and clinical surgeons often do nothing about it.Circulating tumor cells(CTCs),especially interstitial tumor cells,are important determinants of cancer metastasis,which cause most recurrences and deaths of hepatocellular carcinoma.According to the"seed-soil" theory of cancer metastasis and recurrence,the pre-metastatic microenvironment(PMN)of potential metastases has a huge impact on cancer cells,including chemotaxis of cancer cells,and changes in biological characteristics of cancer cells.However,the potential mechanism of microenvironmental colonization of liver cancer CTCs before metastasis is not clear,and there is room and significance for further exploration.Methods:A retrospective analysis of 36 patients with liver-occupying lesions from Zhujiang Hospital affiliated to Southern Medical University from July 2015 to January 2017.All patients collected circulating blood samples and used the CanPatrol TM system.The CTCs of patients were detected and classified,and the correlation between the phenotypic CTCs and the clinical characteristics of patients was analyzed in combination with the patient follow-up information.In vitro experiments,the cell phenotypes of commonly used human liver cancer cell lines were analyzed and identified,and a shRNA lentiviral vector targeting Prrx1 was constructed to generate stable interstitial phenotypes of Prrx1 liver cancer cells.Assess the biological changes such as stemness,migration ability,and drug resistance of mesenchymal phenotype hepatoma cell lines with low expression of Prrx1 under the influence of SDF-1/CXCR4 signaling pathway,and further explore the mechanisms involved in the JAK2-STAT3 signaling pathway.A nude mouse model of HCC lung metastasis was constructed,and our hypothesis was verified in in vivo experiments and clinical specimens.To explore the clinical application prospects of STAT3 tyrosine phosphorylation inhibitor C188-9 and specific blocking of CXCR4 antibody.Results:The number of mesenchymal CTCs in blood was closely associated with tumour recurrence or metastasis.Pre-metastatic niche-derived SDF-1 could downregulate Prrx1,which induced the stemness,drug resistance,and increased expression of CXCR4 in HCC cells through the STAT3 pathway in vitro.In vivo,mice bearing tumours of Prrx1 low-expressing cells had significantly shorter survival.In xenograft tumours and clinical samples,loss of Prrx1 was negatively correlated with increased expression of CXCR4 in lung metastatic sites compared with that in the primary foci.Conclusions:These findings demonstrate that decreased expression of Prrx1 stimulates SDF-1/CXCR4 signalling and contributes to organ colonisation with blood CTCs in HCC.STAT3 inhibition and specific blockade of CXCR4 have clinical potential as therapeutics for eliminating organ metastasis in advanced HCC.Conclusion:mesenchymal CTCs in HCC patients are closely related to HCC recurrence.In the process of hepatocellular carcinoma CTCs distant organ metastasis and colonization,activated SDF-1/CXCR4 axis on CTCs reduces the expression of Prrx1 in the cell itself,and promotes the colonization of CTCs in the blood through the STAT3 signaling pathway.Inhibition of STAT3 phosphorylation and specific block of CXCR4 have clinical potential as a therapeutic approach to eliminate HCC organ metastasis. |
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