The Expression And Significance Of FHIT And WWOX Proteins In Endometrial Adencarinoma Tissue

Backgroud and ObjectiveEndometrial carcinoma is one of the three malignant tumors in the female reproductive system, and the endometrial adenocarcinoma which originated from the endometrial gland is the most common application. Endometrial adenocarcinoma incidence showed ascendant trend in the worldwide in recent years, but the pathogenesis of it is still not clear. Fragile sites are involuntary sites of chromosome genome which are easy to fracture,gap and rearrangement under special conditions. Fragile histidine triad (FHIT) and WW domain containing oxidoreductase (WWOX) are new tumor-suppressor genes discovered on these sites in recent years, and the changes of FHIT and WWOX that loss of heterozygosity, homozygous deletion, abnormal formation of transcript, abnormal gene modification and the lack or decrease of protein expression ect. frequently appeared in a wide variety of tumor tissues and cell lines, which affecting the normal adjustment function of them on cell and then inducing tumorigenesis. The research on the expression of FHIT and WWOX proteins in endometrial adenocarcinoma is rare at present. In this research, the expression of FHIT and WWOX proteins in endometrial adenocarcinoma tissues are decected by immunohistochemistry method to investigate the relationship of them and to further understanding the mechanism of the molecular biology for endometrial adenocarcinoma, providing a theory basis for the diagnosis, treatment and prognosis of it.Materials and Methods1 105 cases of endometrium tissues keeping in the archives in the Department of Pathology, the First Affiliated Hospital of Zhengzhou University from January 2005 to April 2008 were included in this study, which consisted of 60 cases of endometrial adenocarcinoma,30 cases of atypical hyperplasia endometrium and 15 cases of proliferative endometrium tissues. All tissues were pathologically confirmed and none of the patients had received any radiotherapy, chemotherapy and hormone therapy before the endometrium tissues was taken. The patients age range from 36～74, the mean age is 55.6±4.1. The postsurgical pathologic staging of endometrial adenocarcimoma was determind according to the International Federation of Obestertrics and Gynecology 2000 (FIGO,2000) classification:stageⅠ:37 cases, stageⅡ:14 case, stageⅢ:9cases; The high differentiated grade (G1):35 cases, middle differentiated grade (G2):15 cases, low differentiated grade (G3):10 cases; Depth of myometrial invasion≤1/2:40 cases,>1/2:20 cases; 8 cases with lymph nodes metastases and 52 cases without lymph nodes metastases.2 Detcecting the expression of FHIT and WWOX protein by SP immuno-histochemistry method in the 3 kinds of endometrium tissues to analysis their relationship with estrogen receptor (ER), progesterone receptor (PR) and clinico-pathologic parameters and their correlationship in endometrial adenocarcimoma tissues.3 All the data was analyzed by statistic software SPSS 13.0, the expression of FHIT and WWOX protein and their correlationship with clinicopathologic parameters were analyzed by Chi-Square Tests, Correction of Chi-square Test and Fisher Exact Proba-bility Test. The relationship between FHIT and WWOX proteins in the endometrial adenocarcinoma was tested by Pearson Correlation Analysis. The criterion of test was "alpha equals 0.05".Results1 The positive expression location of FHIT protein in endometrium tissue was cell plasma. The positive rates of FHIT expression from proliferative endometrium, atypical hyperplasia endometrium to endometrial adenocarcinoma tissues were 100% (15/15),63.3%(19/30) and 60%(36/60), respectively, there were statistical significance among the 3 kinds of endometrium tissues (χ2=8.850, P=0.012). The expression of FHIT protein in atypical hyperplasia endometrium and endometrial adenocarcinoma tissues were both lower then that of proliferative endometrium significantly (P=0.008, P=0.002), while there was no significant difference of the FHIT protein expression between atypical hyperplasia endometrium and endometrial adenocarcinoma (χ2=0.094, P=0.760).The positive expression rate of FHIT protein in G1 group of endometrial adenocarcinoma tissues (25/35,71.4%) was higher than that of G2～G3 group (11/25, 44.0%), significantly (χ2=4.571, P=0.033); The positive expression rate of FHIT protein in positive and negative lymph node metastasis groups of endometrial adenocarcinoma tissue were 12.5%(1/8) and 67.3%(35/52), there was significant difference between them (χ2=6.544, P=0.011); The positive expression rate of FHIT protein in stageⅠof endometrial adenocarcinoma (26/37,70.3%) was higher than that of stageⅡ～Ⅲ(10/23,43.5%), significantly (χ2=4.242, P=0.039); The positive expression rate of FHIT protein had no significantly difference with the depth of myometrial invasion (χ2=0.000, P>0.999) and the ER (χ2=1.358, P=0.244), PR (χ2=0.110, P=0.740) status of endometrial adenocarcinoma.2 The positive expression location of WWOX protein in endometrium tissue was cell plasma. The positive rates of WWOX expression from proliferative endometrium, atypical hyperplasia endometrium to endometrial adenocarcinoma tissue were 93.3% (14/15),53.3%(16/30) and 51.7%(31/60), respectively, there were statistical significance among the 3 kinds of endometrial tissues (χ2=8.949, P=0.011). The expression of WWOX protein in typical hyperplasia endometrium and endometrial adenocarcinoma tissues were lower then that of proliferative endometrium significantly (χ2=7.200, P=0.007;χ2=8.681, P=0.003), while there was no significant difference of the WWOX protein expression between atypical hyperplasia endometrium and endometrial adenocarcinoma (χ2=0.022, P=0.881).The positive expression rate of WWOX protein in G1 group of endometrial adenocarcinoma tissues (22/35,62.9%) was higher than that of G2～G3 group (9/25, 36.0%), significantly (χ2=4.212, P=0.040); The positive expression rate of WWOX protein in positive and negative lymph node metastasis groups of endometrial adenocarcinoma were 12.5%(1/8) and 57.7%(30/52), there was significant difference between them (χ2=4.005, P=0.045); The positive expression rate of WWOX protein in stageⅠof endometrial adenocarcinoma (23/37,62.2%) was higher than that of stageⅡ～Ⅲ(8/23,34.8%), significantly (χ2=4.258, P=0.039); The positive expression rate of WWOX protein in ER positive group and ER negative groups were 66.7%(22/33)and 33.3%(9/27), there was statistical significance between them (χ2=6.607, P=0.010); The positive expression rate of WWOX protein had no significant difference with the depth of myometrial invasion (χ2=0.033, P= 0.855) and the PR status (χ2=0.212, P=0.645) of endometrial adenocarcinoma.3 In the 60 cases of endometrial adenocarcinoma, the expression of FHIT and WWOX proteins which all positive were 24 cases, all negative were 17 cases, there was significantly positive correlation between the expression of FHIT and WWOX protein in endometrial adenocarcinoma (rp=0.345,χ2=8.109, P=0.004).Conclusions1 The positive expression of FHIT and WWOX proteins reduced gradually from proliferative endometrium, atypical hyperplasia endometrium to endometrial adenocarcinoma. The low expression of FHIT protein was related to poorly differentiated histological grade, positive lymph node metastasis and late clinical stages; while the low expression of WWOX protein was related to poorly differentiated histological grade, positive lymph node metastasis, late clinical stages and negative status of ER. These indicate that the lack or decreased expression of FHIT and WWOX proteins may participate in the origin, development, invasiveness and metastasis of endometrial adenocarcinoma.2 The expression of FHIT protein is positively correlated with that of WWOX protein in endometrial adenocarcinoma tissue, which indicate that they may have synergy effcet in the origin and development of endometrial adenocarcinoma.