| Oral submucous fibrosis(OSF) is a kind of chronic,invisible,and betel nut chewing-related oral mucosal diseases,which can turn into oral squamous cell carcinoma(OSCC).It was observed clinically that the local recurrence rate and neck lymph node metastasis rate of such patients,with poor prognosis,are higher than those of OSCC non-originating from OSF.It indicates that there may be different biological behavior between OSCC originating from OSF and the other ones.However,there is little clinical and basic research regarding the biological behavior of OSCC originating from OSF.Wnt pathway is a class of highly conserved signal transduction pathway in the evolution of organism.It controls numerous processes of life activities,regulates cell proliferation and differentiation,and relates to occurrence and development of tumor.In recent years,the study on the relationship between Wnt pathway and cancer invasion and metastasis has been paid close attention to.But there is no study on Wnt pathway in OSCC originating from OSF.Objective:The purpose of this paper is to research the clinical feature and mechanisms on the biological behavior of OSCC originating from OSF.Using the existing clinical data,a comparative study about the clinical characteristics and biological behavior between OSCC originating from OSF and the other ones was made,so as to supplement and perfect the clinical research about the biological behavior of OSCC originating from OSF.The expressions of some key molecules of Wnt pathway in the tissues of OSCC originating from OSF were detected by immunohistochemistry SP method and Real-Time PCR,the expression changes of these molecules at mRNA level and protein level were observed,and then the possible role of Wnt signaling pathway in the mechanism of invasion and metastasis of OSCC originating from OSF was investigated.After the advantages and disadvantages on controlling the rate of recurrence and metastasis by different surgical methods were compared,the recommend surgery of OSCC originating from OSF was put forward,and the significance of mechanism research about the biological behavior of OSCC originating from OSF was validated clinically.Materials & Methods:The patients with OSCC after surgical treatment (Jan 2002～Dec 2008) in the Department of Oral and Maxillofacial Surgery,Xiangya Hospital,Central South University were studied.The clinical data of these patients were analyzed retrospectively.They were divided into the group of OSCC originating from OSF and the group of OSCC non-originating from OSF.Their case distribution,site,clinical characteristics,lymphatic metastasis and recurrence were compared and analyzed.The expressions ofβ-catenin,Wnt2,E-cadherin,TCF-4 and CD44v6 were detected in the carcinoma and adjacent tissues of 52 OSCCs originating from OSF and 48 OSCCs non-originating from OSF by immunohistochemistry SP method,respectively.Then the expressions ofβ-catenin mRNA,E-cadherin mRNA and TCF-4 mRNA in these tissues were detected by Real-Time PCR,respectively.45 cases of OSCC originating from OSF were selected.25 of these cases were treated by the methods including resection of expanding adjacent tissues, successive and vertical removal of primary tumor and neck lymphoid tissue,restoration of individual flap and so on.The clinical efficacy of these methods were compared with traditional surgical methods.The results were analyzed by statistical software SPSS 13.0.Results:1.The rates of recurrence and metastasis of OSCC originating from OSF(43.12%) are higher than those of OSCC non-originating from OSF (30.77%).The patients with OSCC originating from OSF have poor prognosis.2.Translocation expression ofβ-catenin1) In normal oral mucosa,the expression ofβ-catenin performs membrane positive(strong staining rate:93.33%).2) In the tissues of OSCC originating from OSF,the expression ofβ-catenin performed reduce or even disappearance of membrane staining (strong staining rate:7.69%);in the tissues of OSCC non-originating from OSF,the phenomenon of reduced membrane staining also existed (strong staining rate:20%);no statistically significant difference was found between the two groups(P＞0.05).There was no statistically significant difference about intracytoplasmic accumulation ofβ-catenin between OSCC originating from OSF group(61.5%) and OSCC non-originating from OSF(57.8%)(P＞0.05).The rate of nuclear translocation ofβ-catenin in OSCC originating from OSF was 59.6%, but the phenomenon of nuclear translocation ofβ-catenin in OSCC non-originating from OSF was not found.3) The strong membrane staining rate ofβ-catenin in adjacent tissues of OSCC originating from OSF(57.7%) was lower than that in OSCC non-originating from OSF(86.7%)(P＜0.01).4) The result of Real-Time PCR showed that there was no significant difference about the expression ofβ-catenin mRNA between OSCC originating from OSF(1.10) and OSCC non-originating from OSF(1.70)(P＞0.05);in the same way,no significant difference was found about the expression ofβ-catenin mRNA in adjacent tissues between OSCC originating from OSF(0.87) and OSCC non-originating from OSF(0.85)(P＞0.05).3.Abnormal expression of Wnt21) In normal oral mucosa,Wnt2 expressed as negative.2) The positive staining rate of Wnt2 in the tissues of OSCC originating from OSF(78.84%) was higher than that in OSCC non-originating from OSF(44%)(P＜0.01).The positive staining rate of Wnt2 in adjacent tissues of OSCC originating from OSF was 34.62%, but the staining rate of Wnt2 in adjacent tissues of OSCC non-originating from OSF was negative.3) There was a negative correlation between Wnt2 expression andβ-catenin membrane staining(r=-0.956,P=0.011).There was a positive correlation between Wnt2 expression and cytoplasmic accumulation ofβ-catenin.It Showed that the translocation ofβ-catenin related to the initiation of Wnt pathway.4.Expression of E-cadherin1) In normal oral mucosa,the expression of E-cadherin registered as membrane positive,and the strong staining rate was 93.33%.2) The strong staining rate of E-cadherin in OSCC originating from OSF(3.85%) was significantly lower than that in OSCC non-originating from OSF(53.33%)(P＜0.01).No significant difference about the strong staining rate of E-cadherin was found in the adjacent tissues between OSCC originating from OSF(57.69%) and OSCC non-originating from OSF(64.44%)(P＞0.05).3) There was a positive correlation between membrane E-cadherin and membrane expression ofβ-catenin(r=0.962,P=0.038).There was a negative correlation between Wnt2 and reduce or disappearance of E-cadherin(r=-0.919,P=0.027).The translocation ofβ-catenin accompanied by reduce of membrane E-cadherin.4) The result of Real-Time PCR showed that the expression levels of E-cadherin mRNA in the 4 groups such as Group OSCC originating from OSF were significantly lower than that in normal group(P＜0.01); there was no significant difference about the expression levels of E-cadherin mRNA among the other groups(P＞0.05).5.Expression of TCF-4 and CD44v61) In normal oral mucosa,the expression of TCF-4 was nucleus weakly positive,and the expression of CD44v6 performed membrane positive.2) The positive rate of TCF-4 in Group OSCC originating from OSF(69.23%) was significantly higher than that in Group OSCC non-originating from OSF(48.89%)(P＜0.05).The staining rate of TCF-4 in the adjacent tissues of OSCC originating(50%) from OSF was significantly higher than that of OSCC non-originating from OSF (22.22%)(P＜0.05).3) The positive rate of CD44v6 in Group OSCC originating from OSF(40%) was significantly lower than that in Group OSCC non-originating from OSF(82.7%)(P＜0.01).However,the staining rate of CD44v6 in the adjacent tissues showed no significant difference between OSCC originating from OSF(57.7%) and OSCC non-originating from OSF(48.89%)(P＞0.05).4) There was a positive correlation between the expression of CD44v6 and TCF-4(r=0.949,P=0.014).5) The result of Real-Time PCR showed that the expression of TCF-4 mRNA in Group OSCC non-originating from OSF was significantly higher than that in the other 4 groups(P＜0.01);the differences among the other groups were not statistically significant(P＞0.05).6.Compared with using traditional treatment means(40%),using the new methods(12%),including resection of expanding adjacent tissues,vertical removal of primary tumor and neck lymphoid tissue, restoration of individual flap and so on,the rates of recurrence and metastasis of OSCC originating from OSF could be reduced significantly.Conclusions:1.Clinically,OSCC originating from OSF has a more invasive and metastatic biological behavior.2.In OSCC originating from OSF,Wnt pathway is in the abnormal activation status.3.Upregulation of Wnt2 in OSCC originating from OSF causes the accumulation ofβ-catenin in the cytoplasm/nucleus,prompts Wnt/β-catenin pathway to activate.This pathway plays a key role in carcinogenesis of OSF and dissemination of cancer.4.The abnormal expressions of E-cadherin and CD44 resulting from the activation of Wnt signaling pathway could play an important role on the process of invasion and metastasis of OSCC originating from OSF.5.To expand the resection border of adjacent tissues and successive vertical resection of tongue-the floor of mouth-neck could obtain a satisfying treatment effect.It can be used as a recommend surgical method of OSCC originating from OSF.
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