Expression Of WWOX, MDM2and P73Protein In Cutaneous Malignant Melanoma

Background and objectWW domain-containing oxidoreductase gene (WWOX) is a tumor suppressorgene located in the common chromosomal fragile site FRAl6D (16q23.3-24.1).WWOX is either down regulated or lost in a variety of carcinomas. p73is a newmember of p53tumor suppressor gene family. However, the role of p73in tumordevelopment is still controversial. Whether it is a tumor suppressor is unclear. Mousedouble minute2homolog (MDM2) is a recently identified tumor gene. MDM2protein functions as an E3ubiquitin ligase to target WWOX for proteasomaldegradation and therefore blocks the apoptosis pathway, which will promote tissuecancerization.In recent years, the incidence and mortality of cutaneous malignant melanoma(CMM) in China is rising clearly. Early diagnosis followed by extensive surgicalresection has the best outcome. However, there is very little effective treatment foraggressive CMM. To identify novel biomarkers for the early diagnosis and gene therapy in cutaneous malignant melanoma, the expression of WWOX, MDM2andp73was examined in cutaneous malignant melanoma, junctional nevus and normalskin tissues. The correlation between the expression of WWOX, MDM2and p73andclinical pathology was investigated.Materials and methodsRetrospective method was used in the study. The expression level of WWOX,MDM2and p73was determined using immunohistochemistry staining in66cases ofcutaneous malignant melanoma,30cases of junctional nevus and20cases of normalskin tissues. The results were analyzed using chi-squared test and Spearman rankcorrelation test. P<0.05is considered statistically significant. P=0.0167used forchi-squared test. All statistical analyses were performed using SPSS17.0.Results1. The WWOX protein mainly expressed in the cytoplasm of cells, there was alow expression in CMM, The expression level WWOX increased progressively fromCMM, junction nevus and normal skin．The positive rate in CMM,junction nevus andnormal skin was15.15%(10/66),44.67%(14/30),80.00%(16/20).respectively and thedifference was significant among the three groups(P<0.05)．The positive rate ofWWOX protein in CMM is significantly lower than that in junction nevus,and thepositive rate in junction nevus is significantly lower than that in normal skin(P<0.0167); with the depth of tumor infiltration increasing,the expression of WWOXin CMM has decreased (P<0.05),the expression of WWOX in the tissue with lymphnode metastasis is significantly lower than that without lymph nodemetastasis(P<0.05).2. The MDM2protein mainly expressed in the nucleus of cells, presentingbrown fine granular, and Positive cells are in diffuse focal distribution, Theexpression level of MDM2decreased progressively from CMM, junction nevus and normal skin．The positive rate in CMM,junction nevus and normal skin was75.76%(50/66),36.67%(11/30),15.00%(3/20). respectively, and the difference was significantamong the three groups(P<0.05)．the positive rate was less lower in normal skin thanthat in junction nevus (P<0.0167),and the positive rate was less lower in junctionnevus than CMM(P<0.0167); with the depth of tumor infiltration increasing,theexpression of MDM2in CMM has increased (P<0.05),the expression level of MDM2in the tissue with lymph node metastasis is significantly lower than that withoutlymph node metastasis(P<0.05).3. P73protein mainly expresses in the nucleus of cells, presenting brown finegranular and Positive cells are in diffuse focal distribution; the expression level ofP73decreased progressively from CMM,junction nevus and normal skin．Thepositive rate in CMM,junction nevus and normal skin was78.79%(52/66),46.67%(14/30),10%(2/20)．respectively,and the difference was significant among thethree groups(P<0.001)．the positive rate in normal skin was less lower than that injunction nevus,and the positive rate in junction nevus was less lower than that inCMM(P<0.0167), with the depth of tumor infiltration increasing,the expression ofP73in CMM has increased (P<0.05),the expression level of P73in the tissue withlymph node metastasis is significantly higher than that without lymph nodemetastasis(P<0.05).4. The correlation analysis shows that there is a significant negative correlationbetween P73、MDM2and WWOX (P<0.05)，there is a significant correlationbetween P73and MDM2(P<0.05).Conclusions1. P73performs features of cancer gene in the CMM and promotes cancerous;and P73as well as WWOX affects the biological behavior of CMM, such asoccurrence development.metastasis, and may be considered as index for monitoringthe canceration and metastasis.2. oncogene MDM2mainly plays a role in the evolution of the CMM and can be considered as an index of early diagnosis.3. There is a significant negative correlation between P73,MDM2andWWOX. there is a significant positive correlation between P73and MDM2.Speculated that there is some kind of relationship of synergy or antagonism amongWWOX,MDM2and P73evolved in mechanisms of CMM.4. The MDM2,P73and WWOX protein play important roles in the occurrenceof the CMM progress,the joint detection of the expression of them in CMMcontributes to early diagnosis as well as treatment, and provides a new idea of genetherapy.