| BackgroundOral squamous cell carcinoma(OSCC)is one of the most common malignant neoplasm with a high morbidity and mortality profile.Although the current level of diagnosis and surgical,radiotherapy and chemotherapy treatment methods have made some progress,but most of the tumors are not found until the middle and advanced stage,and the 5-year survival rate is still less than 50%.Therefore,early detection and intervention can greatly improve the quality of life and survival rate of patients.Hepatocyte growth factor(HGF)is a multifunctional cytokine that can regulate cell movement,proliferation and morphogenesis.Binding with specific transmembrane receptor c-Met,HGF can trigger a series of enzymatic reactions of signal transduction proteins and participate in human embryonic development,organ development,tissue repair,wound healing and the occurrence and development of cancer.Recent studies have found that HGF/c-Met signaling pathway plays a two-way regulatory role in the development of tumor: abnormally activated HGF/c-Met signaling pathway promotes tumor progression,but when normal tissues express HGF,it can inhibit the malignant transformation of tissues.Studies have confirmed that abnormal activation of HGF /c-Met signaling pathway in OSCC can promote tumor proliferation,invasion and metastasis.However,the role of HGF in the malignant transformation of oral mucosa is still unclear.ObjectiveThe purpose of this study is to investigate the function of HGF in the development of OSCC by detecting the expression of HGF in human OSCC tissues and constructing the tongue cancer model of HGF-Tg mice.Material and Methods1.According to the inclusion criteria,53 cases of human OSCC samples and 21 cases of paracancerous tissue samples were collected,and complete patient personal information and clinicopathological parameters(age,gender,tumor size,location,distant metastasis,lymph node metastasis,TNM stage,tumor differentiation,survival time,etc.)were recorded.2.The expression of HGF in OSCC and paracancerous tissues was detected by immunohistochemistry,and the correlation between HGF expression and clinicopathological parameters and prognosis was analyzed.3.The experimental group was drinking water contained 4NQO continually for16 weeks,while the control group contained no 4NQO,only the same volume of propylene glycol.Mice were sacrificed after 16,20,24 weeks,or when the body weight loss≥1/3.The death time of naturally dead mice was recorded throughout the experiment,and the remaining surviving mice were executed at the 28 th week.All mice were carefully inspected daily and weighed weekly.The blood,tongue,esophagus,liver,kidney and spleen were taken.The weight of liver,kidney and spleen were recorded.The expression of HGF,c-Met and PCNA in tongue lesions was analyzed by immunohistochemistry.The apoptosis of tongue lesions was analyzed by TUNEL,and the liver and kidney functions(AST,ALT,ALP,TBIL,BUN,CREA)were detected.Results1.The positive expression rate of HGF in OSCC and paracancerous tissues was92.5%(49/53)and 81%(17/21),respectively,and HGF level in OSCC was higher than that in adjacent non-tumor tissues and normal tissues.2.HGF expression was closely correlated with tumor size and TNM stage(P<0.05),but not with age,gender,tumor location,differentiation and lymph node metastasis(P>0.05).There was no significant difference in survival rate and survival time between HGF high-expression group and HGF low-expression group(P > 0.05).3.In 4NQO group,the expressions of HGF and c-Met in tongue dysplasia and tumor tissues of Wt mice were significantly higher than those in normal epithelial tissues;HGF and c-Met in tongue lesions of HGF-Tg mice were higher than those in Wt mice(P<0.05).4.At the 16 th,20th and 24 th week,the weight of HGF-Tg mice was significantly higher than that of Wt mice in 4NQO group(P<0.05);the incidence of tongue tumor,tumor number and tumor volume were lower than those of Wt mice(P< 0.05);the survival rate was higher than that of Wt mice(P=0.033).Histopathological analysis showed that HGF-Tg mice were less sensitive to 4NQO-induced oral tumorigenesis.5.At the 16 th,20th and 24 th week,PCNA positive rate of HGF-Tg mice in4 NQO group was lower than that of Wt mice(P<0.05).From the 16 th to 20 th week,the percentage of TUNEL positive cells of Wt mice was significantly higher than that of HGF-Tg mice(P<0.05);from the 20 th to 24 th week,the percentage of TUNEL positive cells in Wt group was significantly lower than that in the HGF-Tg group(P<0.05).6.In 4NQO group,the tumor number of esophageal of Wt mice was higher than that of HGF-Tg mice at the 20 th week(P<0.05),and there was no significant difference between the two kinds of mice at the 24 th week.Histopathological analysis showed that the degree of esophageal lesions of HGF-Tg mice was significantly lighter.7.At the 16 th,20th week,the liver index of Wt mice in 4NQO group was lower than that of control group,while HGF-Tg in 4NQO group had no difference with control group,but higher than that of Wt mice in 4NQO group(P<0.05).At 24 th week,liver index of Wt mice in 4NQO group was lower than that of control group,but HGF-Tg in 4NQO group was higher than that of control group,which was significantly higher than that of Wt mice(P<0.01).8.Liver function: compared with Wt mice,AST decreased(P>0.05),ALT increased(P>0.05),AST/ALT decreased(P<0.05),TBIL decreased(P>0.05)of HGF-Tg in 4NQO group at 16 th week.There was no difference in ALP between the two groups.At the 20 th week,AST,ALT,AST/ALT,TBIL and ALP were lower in HGF-Tg mice in 4NQO group(P<0.05).At the 24 th week,AST was higher(P>0.05),ALT was lower(P>0.05),AST/ALT was higher(P<0.05),TBIL was higher(P>0.05),ALP was lower(P>0.05)in HGF-Tg mice in 4NQO group.In conclusion,the degree of liver injury in HGF-Tg mice is lighter than that of Wt mice in 4NQO group.9.At the 16 th week,the renal index of HGF-Tg mice was significantly higher than that of Wt mice in 4NQO group(P<0.01).At the 20 th week,the renal index of the two groups was higher than that of control group,but there was no significant difference between the two groups(P>0.05).At the 24 th week,the kidney quality of Wt and HGF-Tg mice decreased seriously,and there was congestion on the tissue surface.The kidney index of the two kinds of mice was lower than that of the control group.The kidney index of HGF-Tg mice was higher than that of Wt mice in 4NQO group,but there was no statistical difference.10.Renal function: at the 16 th week,BUN of Wt and HGF-Tg mice in 4NQO group was lower than that in control group,while that of Wt mice was higher than that of HGF-Tg in 4NQO group with no statistical difference(P>0.05);there was no significant difference in CREA between the two groups,and that of Wt mice was lower than that of HGF-Tg mice in 4NQO group,with no statistical difference(P>0.05).At the 20 th week,BUN and CREA of Wt mice in 4NQO group were significantly higher than those in control group,but there was no significant difference between HGF-Tg mice in 4NQO group and control group;BUN and CREA in Wt mice were significantly higher than those of HGF-Tg group in 4NQO group with statistical difference(P<0.05).At the 24 th week,BUN and CREA in Wt and HGF-Tg mice in 4NQO group were significantly higher than those in control group;BUN of Wt mice was higher than that of HGF-Tg mice in 4NQO group,but there was no significant difference(P>0.05),and there was no significant difference in CREA between Wt and HGF-Tg mice in 4NQO group.In conclusion,the degree of renal injury of HGF-Tg mice is lighter than that of Wt mice in 4NQO group.11.At the 16 th week,the spleen index of Wt and HGF-Tg mice in 4NQO group was higher than that in control group,and HGF-Tg mice was significantly higher than that of Wt mice in 4NQO group(P<0.01).At the 20 th week,the spleen index of Wt and HGF-Tg mice in 4NQO group was slightly higher than that of the control group,but there was no significant difference between Wt and HGF-Tg mice in 4NQO group(P>0.05).At the 24 th week,the spleen quality of Wt and HGF-Tg in 4NQO group decreased seriously,and the spleen index of Wt and HGF-Tg in 4NQO group was significantly lower than that of the control group.The spleen index of HGF-Tg mice was slightly higher than that of Wt mice in 4NQO group,but there was no statistical difference(P>0.05).ConclusionsThe expression of HGF in human OSCC tissue and 4NQO induced mouse tongue cancer tissue increased,and HGF expression was correlated with tumor size and TNM clinical stage,indicating that HGF is involved in the occurrence and development of OSCC.By comparing the tongue cancer model of HGF-Tg and Wt mice,it was found that the malignant transformation of tongue and esophageal mucosa induced by 4NQO was more slow when HGF was highly expressed in normal tissues,and the damage degree of liver,kidney and spleen function was lighter,which indicated that HGF could inhibit the tumorigenesis and protect liver,kidney and spleen organ in the carcinogenesis stage of squamous cell carcinoma. |
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