Expression And Significance Of KiSS-1 And MMP-9 In Transitional Cell Carcinoma Of The Bladder

Objective: Invasion and metastasis is one of the primary biologic characters ofmalignant tumors. The inactivation of anti-oncogene and the activation of oncogeneare the basis lead to the lost control of proliferation, malignant growth,invasion andmetastasis of tumors. The theory of tumor invasion demonstrated that during theinvasion process, tumor cells must traverse the basement membrane constituent oftype IV collagen laminin(LN) and fibronectin(FN) and so on many times. MMPs isthe most important group in the proteinases involved in the destroy of basementmemberane, and in MMPs family, MMP-9 has the closest relation with tumors'invasion and metastasis.Kiss-1 gene, a new metastasis suppressor gene, was found out by lee and hiscoworkers from melanoma. Studies had proved that the expression level of Kiss-1had negative correlation with the metastasis ability of human melanoma, mammarycancer and so on.In this Study, we assessed the expression of Kiss-1 and MMP-9 in bladdercarcinoma and their relationship in tumor invasion and metastasis.Methods: 40 transitional cell carcinoma patients' post-operation paraffin specimenssince 2004 to 2006 were recruited, 30 males, 10 females. According to clinicalstags, superficial tumor 16 cases, infiltrate tumor 24 cases (T₂ 9 cases, T₃ 10 cases,T₄ 5 cases) ; pathologic grades, G₁ 13 cases, G₂ 14 cases, G₃ 13 cases. Normalbladder tissue from 10 cases were used as control. The expression of Kiss-1 andMMP-9 in all patients was analyzed using immunohistochemically method (SP) andwas compared with clinicopathologic and prognostic parameters. All data wereprocessed by SPSS 13.0, comparisions were done using chi-square test. Results: 1. The expression of both of Kiss-1 and MMP-9 was negative in normalcontrols. Among 40 cases with bladder cancer, 17 cases were Kiss-1 positive, thepositive rate was 42.5%. Positive expression of Kiss-1 decrease in ingiltrated group(T₂, T₃, T₄, 5 cases ) compared with superficial group (5 vs 12, P＜0.05). Thedifference were significant between high differentiation group and middle, lowdifferentiation group (G₁ 10,G₂ 4,G₃ 3, P＜0.05), but not significant between middleand low differentiation group (P＞0.05).2. For MMP-9, among 40 cases with bladder cancer, 23 cases were positive, thepositive rate was 57.5%. Positive expression of MMP-9 increased in ingiltrated group(18 cases) compared with superficial group (18 vs 5, P＜0.05). The difference weresignificant between high, middle differentiation group and low differentiation group(G₁ 5,G₂ 6,G₃ 12, P＜0.05), but not significant between high and middle differentiation group (P＞0.05). MMP-9 is mostly located in the cytoplasm of tumor cells, andat positive cells, it is much more expressed near the boundary of epithelium andmesenchymal.3. Analysis showed that expression of Kiss-1 and MMP-9 in bladder cancer patientshas no correlation (P＞0.05).Discussion: In 1997, lee and his coworkers found out a new metastasis suppressorgene from melanoma, named Kiss-1 gene. They transfected MDA-MB-435 cell lineof mammary cancer with Kiss-1 gene, observed the neoplasma growth and spontaneous metastasis of nude mouse compared with controls, and found that Kiss-1 genehad no effect on the formation of neoplasma, but could suppress 95% of tumors'metastasis.In our study, positive expression of Kiss-1 decrease in infiltrated group comparedwith superficial group. There were significant difference between high differentiationgroup and middle, low differentiation group but not significant between middle andlow differentiation group.MMPs is a kind of zinc ion-depended endopeptidase, it can degrade all components of extracellular matrix. Among MMPs, MMP-9 is one of the most important enzymes which degrading the basement membrane. In human tissue, MMP-9 isexcreted by cells as zymogen, activated by all kinds of activation factors, then actsits enzymolysis. Studies had proved that MMP-9 played a key role in invasion andmetastasis. Damaging of MMPs' mechanism caused by some neoplastic factors mademassive outcoming of protease such as MMP-9 at tumor tissues and degrade theextracellular mesenchymal, so help tumors' invasion. These years, it was found thathigh level MMP-9 is expressed in many tumor tissues including bladder carcinoma,and the expression degree was correlated with tumors' invasion ability.Our experiment proved that there was high level expression of MMP-9 in bladdercarcinoma tissues, and much more MMP-9 at the tumor cells near the mesenchymal,to explain the main place where MMP-9 play its enzymolysis effect. Furthermore,Positive expression of MMP-9 was correlated with pathological stage and grade ofbladder carcinoma. MMP-9 increased in infiltrated group compared with superficialgroup. The difference were significant between high, middle.differentiation groupand low differentiation group.Yan and coworkers choiced six cell lines which positive for MMP-9 mRNA butdeficient in Kiss-1 mRNA. One of these cell lines, HT-1080, stably transfected witha Kiss-1 expression construct, demonstrated substantially lower MMP-9 enzymeactivity reflected reduced steady-state mRNA levels which, in turn, was due toattenuated transcription. Further studies proved that NF-KappaB binding to theMMP-9 promoter required for expression of this collagenase was reduced by Kiss-1expression. This study proved that MMP-9 showed high level expression accompanywith the increasing of TCCB grade well Kiss-1 was descending.We can confer thatKiss-1 can some-extent suppress the expression of MMP-9 in bladder cancer.Conclusions: 1. Clinically, detecting the expression level of Kiss-1 in tumor tissuecan help assess the prognosis of bladder carcinoma.2. MMP-9 plays an important role in the invasion and the malignant differentiationof bladder carcinoma. Clinically, detecting the expression level of MMP-9 in tumortissue is very important for assessing the prognosis of bladder carcinoma. 3. MMP-9 showed high level expression accompany with the increasing of TCCBgrade well Kiss-1 was descending. There are no correlation between them. Ourresults provided evidences for Yans' theory that the cancer-suppression mechanism ofKiss-1 to MMPs family happened at gene level but not protein level.