| Objective: Gastric carcinoma is one common malignant tumors,and itsmortality rate is the higest in malignant digestive tumors. Owing to lacking ofspecific clinical symptoms and signs during the early stage of gastriccarcinoma, most cases diagnosed in clinic are advanced gastric carcinomawith poor prognosis, and the5-year overall survival of advanced gastriccancer is lower than30%. Lots of factors can affect the prognosis of gastriccarcinoma,invasion and metastasis is the strongest prognostic factor,and themajor cause of death of patients with gastric carcinoma.The invasion andmetastasis of gastric carcinoma is controlled by a complex process includingcell migrate and adhesion,degradation of extracellular matrix,angiogenesisand so on.Multiple studies have confirmed that MMP7, a member of MatrixMetalloproteinase, can promote invasion and metastasis of gastric carcinomathrough the degradation of extracellular matrix and the components of basalmembrane.Besides, multidrug resistance of gastric carcinoma in clinic largelylimits the clinical effect of chemotherapy, and then impacts the prognosis ingastric carcinoma patients severely. MDR means when tumor cells areresistant to a chemotherapeutic drug, they are often resistant to other drugs ofdifferent structure and mechanism. MDR contains intrinsic MDR andacquired MDR. Intrinsic MDR means inherent insensitivity tochemotherapeutic drugs exist in tumor cells in early stage of chemotherapy.Acquired MDR means tumor cells are sensitive to chemotherapeutic drugs inthe beginning, but after several courses of treatment, tumor cells displaytolerability to the chemotherapy drugs.To date, a large namber of proteinswhich mediate MDR in gastric carcinoma have been identified,such asp-glycoprotein, multidrug resistance protein-1, breast cancer resistance proteinetc,and study on the mechanisms of MDR and the reversal strategy have scored remarkable gains. However, the tumorigenesis and multidrugresistance in gastric carcinoma are all multitargets, multigene and multistepinvolved complex course, which remains largely unknown. Recently the roleof zinc finger proteins in tumor has arisen wide concern. TheKrüppel-type ZNF gene family is one of the largest gene families of zincfinger transcriptional factors in the human genome. Studies have indicated thatthe members of the KRAB-ZNF family can regulate the transcription andtranslation of relative genes and then are involved in tumorigenesis andmultidrug resistance of tumors.ZNF139gene belongs to the Krüppel-typeZNF gene family, in the present there is less study on the role of ZNF139genein tumorigenesis and multidrug resistance of gastric carcinoma. So, RT-PCRand Immunohistochemistry were performed to evaluate the mRNA and proteinexpression of ZNF139, MMP-7and MRP1in gastric carcinoma, gastricmucosa adjacent to carcinoma, normal gastric mucosa and lymph node(contains20cases of metastatic lymph nodes and24cases of normal lymphnodes), investigate the relationships between their expressions and theclinicopathological parameters, and the correlation among their expressionswas also analysed. This study may reveal the role of ZNF139in tumorigenesisand durg resistance of gastric carcinoma,and help finding potential targets forgene therapy.Methods: The specimens of46cases with gastric carcinoma werecollected, including46cases of gastric carcinoma,46specimens of gastricmucosa adjacent to carcinoma,46specimens of gastric normal mucosa and44specimens of lymph nodes. RT-PCR and Immunohistochemical stainingwere performed in these tissues for the expressions of ZNF139,MMP-7andMRP1. The results were analyzed with patients' clinicopathologicalparameters, and the correlation among their expression was also analysed.SPSS13.0software was adopted to carry out the data processing and analyses,and significance was assessed in all experiments as a probability value ofP<0.05. Results:1.The expression levels of ZNF139, MMP-7, MRP1in gastric carcinomaand the relationships between their expression and patients'clinicopathological parameters:The mRNA and protein expression of ZNF139and MRP1in gastriccarcinoma were higher than that in gastric mucosa adjacent to carcinoma andgastric normal mucosa(P<0.05), but no significant difference was foundbetween gastric mucosa adjacent to carcinoma and gastric normalmucosa(P>0.05). The mRNA and protein expression of MMP-7markedlyincreased in gastric normal mucosa,gastric mucosa adjacent to carcinoma andgastric carcinoma by turns, the difference among these groups wassignificant(P<0.05).The expression of ZNF139, MMP-7and MRP1in gastriccarcinoma on mRNA and protein levels were significantly correlated withtumor differentiation, depth of invasion, TNM stages and lymphaticmetatasis(P<0.05), but not related with patient age and sex and tumor size.2.The expression levels of ZNF139, MMP-7and MRP1in lymph nodes:The mRNA expression of ZNF139, MMP-7and MRP1in metastaticlymph nodes were higher than that in normal lymph nodes (0.9771±0.3459vs0.4171±0.1607,1.0820±0.4070vs0.3569±0.1740,1.1225±0.3127vs0.5160±0.2630, all P<0.05); The positive rate of protein expression ofZNF139, MMP-7and MRP1in metastatic lymph nodes were higher than thatin normal lymph nodes (80%vs26.32,85%vs9.09%,90%vs29.17%, allP<0.05).3.Comparison between the expression levels of ZNF139, MMP-7andMRP1in gastric carcinoma and metastatic lymph nodes:The mRNA expression of ZNF139, MMP-7and MRP1in metastaticlymph nodes were higher than that in gastric carcinoma (0.9771±0.3459vs0.6584±0.3676,1.0820±0.4070vs0.7333±0.4969,1.1225±0.3127vs0.8173±0.4884, all P<0.05). The positive rate of protein expression ofZNF139, MMP-7and MRP1in metastatic lymph nodes were higher than thatin gastric carcinoma (80%vs54.35%,85%vs58.70%,90%vs65.22%, allP<0.05). 4.The correlation between the expression of ZNF139, MMP-7and MRP1in gastric carcinoma:There was a positive correlation between ZNF139and MMP-7in gastriccarcinoma both in mRNA and protein levels (r=0.559, P=0.013; r=0.374,P=0.010, respectively). There was also a positive correlation between ZNF139and MRP1in gastric carcinoma both in mRNA and protein levels (r=0.511,P=0.021; r=0.468, P=0.001, respectively). Besides, There was a positivecorrelation between MMP-7and MRP1in gastric carcinoma both in mRNAand protein levels (r=0.522, P=0.038; r=0.360, P=0.014, respectively).5.The correlation between the expression of ZNF139, MMP-7and MRP1in metastatic lymph nodes:There was a positive correlation between ZNF139and MMP-7inmetastatic lymph nodes both in mRNA and protein levels (r=0.498, P=0.026;r=0.490, P=0.028, respectively). There was also a positive correlation betweenZNF139and MRP1in metastatic lymph nodes both in mRNA and proteinlevels (r=0.633, P=0.003; r=0.667, P=0.001, respectively). Besides, There wasa positive correlation between MMP-7and MRP1in metastatic lymph nodesboth in mRNA and protein levels (r=0.499, P=0.025; r=0.793, P=0.000,respectively).Conclusions:1.The expression level of ZNF139in gastric carcinoma were higher thanthat in gastric mucosa adjacent to carcinoma and gastric normal mucosa, andits expression level were negative correlated with the tumor differentiation andpositive correlated with depth of invasion, TNM stages and lymphaticmetatasis. Besides, the expression level of ZNF139in metastatic lymph nodeswere higher than that in normal lymph nodes. All the results revealed that theincreased mRNA and protein expression of ZNF139probably palyed a role inintrinsic drug resistance in gastric carcinoma, and were probably correlatedwith the tumorigenesis and development of gastric carcinoma.2.The expression level of MMP-7markedly increased in gastric normalmucosa, gastric mucosa adjacent to carcinoma and gastric carcinoma by turns, and its expression level in gastric carcinoma were negative correlated withtumor differentiation and positive correlated with depth of invasion, TNMstages and lymphatic metatasis, which indicated MMP-7played a critical rolein the tumorigenesis and development of gastric carcinoma. The expressionlevel of MMP-7in metastatic lymph nodes were higher than that in normallymph nodes, which revealed overexpression of MMP-7accelerate themetastasis of regional lymph node in gastric carcinoma and the gastriccarcinoma cells in which MMP-7genes highly expressed may have the higherinvasion and metastasis ability.3.The expression level of MRP1in gastric carcinoma were higher thanthat in gastric mucosa adjacent to carcinoma and gastric normal mucosa, andwere negative correlated with the tumor differentiation and positive correlatedwith depth of invasion, TNM stages and lymphatic metatasis. Moreover, theexpression level of MRP1in metastatic lymph nodes were higher than that innormal lymph nodes. All the above showed that the increased expression ofMRP1in gastric carcinoma not only closely correlated with theintrinsicmultidrug resistance of gastric carcinoma, but also to a certain degreecorrelated with the tumorigenesis and development of gastric carcinoma.Theexpression level of MRP1in metastatic lymph nodes were higher than that ingastric carcinoma, which reflected there may exist different resistance tochemotherapy drugs between metastatic lymph nodes and gastric carcinoma.The gastric carcinoma cells in metastatic lymph nodes may have morestronger drug resistance, and escape the kill of chemotherapy drugs. Clinicallythis may a potentially dangerous element contributed to the treatment failureof chemotherapy and the recurrence of gastric carcinoma.4.There were positive correlations between ZNF139and MMP-7ingastric carcinoma and metastatic lymph nodes, the result revealed that as atranscription factor, ZNF139may increase the expression of MMP-7gene andthen play a synergistic role in the tumorigenesis, development, invasion andmetastasis of gastric carcinoma. 5.There were positive correlations between ZNF139and MRP1in gastriccarcinoma and metastatic lymph nodes, which indicated that ZNF139mediated drug resistance in gastric carcinoma perhaps through upregulatingthe expression of MRP1.6.There were positive correlations between MMP-7and MRP1in gastriccarcinoma and metastatic lymph nodes, which indicated that it may havecrossroads or common regulation mechanism between the pathogenesis andmultidrug resistance of gastric carcinoma. Besides, it also indicated that thehigher the multidrug resistance of gastric carcinoma cells, the higher theability of invasion and metastasis. In other words, the higher the ability ofinvasion and metastasis of gastric carcinoma cells, the higher the multidrugresistance. |
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