Expression Of STAT3,p-STAT3and GRIM-19in Human Renal Cell Carcinoma And Their Significance

Objective:Renal cell carcinoma (RCC) is one of the most commonmalignant tumor in urinary system. Its incidence and mortality havecontinuously increased during the last50years, and this threats humanhealth and life seriously. Molecular-targeted therapy, which has newlyemerged for the treatment of tumors, are effective for advanced stage ormetastatic RCC. The key point of molecular-targeted therapy is the targetof study. Therefore, the tumor signal transduction pathway is thetheoretical basis of molecular-targeted therapy especially the target ofchoice.Previous studies have shown that there might be a variety of mostcomplicated signal transduction systems involved in the process ofmalignant transformation. These tumor signal transduction pathwaysultimately concentrate in a limited number of transcription factors, whichbecome the final switch leading to cell malignant transformation. Thesignal transducers and activators of transcription (STAT) protein familyare important nuclear transcription factors and have been reported to playvital roles in several oncogenic processes including proliferation, survival,differentiation and angiogenesis. STAT3is an important member of theSTAT family, and constitutive activation of STAT3can promote cellproliferation and carcinogenesis. Previous studies have found that STAT3is constitutively activated in many different tumor cell lines and primarytumors, including breast, ovarian, head and neck cancer, prostate cancer,melanoma, leukemia and so on. STAT3has been recognized as anoncogene, and researchers have paid close attention to the effects ofSTAT3on malignant tumor. Therefore, STAT3may be a potentialmolecular target for cancer reatment. Gene associated with retinoid-IFN-induced mortality-19(GRIM-19)is one member of the GRIMs apoptosis-related gene family. It is a IFN-βnew cells death control factor united with RA induced expression anddiscovered by Angell et al. with the method of antisense geneexclution.GRIM-19involves in cell apoptosis by a variety of mechanisms.GRIM-19is one of the basic components of mitochondrialNADH-dehydrogenase I complex and plays an important role on themitochondrial respiratory process I. Normal expression of GRIM-19canmaintain a normal cell cycle so that cells enter apoptosis. On the contrary,low expression of certain cells should not enter apoptosis, and thus triggerthe occurrence of tumor. Interestingly, GRIM-19has been shown to becapable of binding to the STAT3gene and inhibiting its transcription;furthermore, the transactivation domain (TAD) of STAT3appears to be adirect target of GRIM-19. STAT3-GRIM19binding promotes tumorapoptosis and down-regulates downstream gene expression, includingthat of CyclinB1, CyclinD1, Bcl-2, VEGF and MMP-2.The aim of the research was to investigate the expression of STAT3,phospho-STAT3(p-STAT3) and GRIM-19in human RCC tissues andexplore the role of STAT3, p-STAT3and GRIM-19in the occurrence anddevelopment of RCC. Thus may offer a reference for the clinicaldiagnosis of RCC, and provide a novel target in targeted therapy.Methods:Immunohistochemistry method was adopted to detect theexpression of STAT3, p-STAT3and GRIM-19in20cases ofnoncancerous tissue and50cases of RCC tissue. The relationshipsbetween the expression and clinicopathological parameters of RCC wereanalyzed, and correlation among STAT3, p-STAT3and GRIM-19wasstudied.Results:(1) The positive rates of STAT3, p-STAT3weresignificantly higher in RCC tissues group than in noncancerous tissuesgroup (72.0%vs40.0%, P<0.05; and62.0%vs20.0%, P<0.01), and thepositive rate of GRIM-19was significantly higher in noncancerous tissues group than in RCC tissues group (85.0%vs36.0%, P<0.01).(2) The expression of STAT3, p-STAT3was related to clinica1stageand differentiation (P<0.05), the late clinic stage was accompanied byhigh positive rates of STAT3and p-STAT3, the poor differentiation wasassociated with high positive rates of STAT3and p-STAT3, but was notstatistically correlated with age, gender and metastasis in RCC tissues(P>0.05). The expression of GRIM-19was not statistically correlatedwith age, gender, clinical stage and metastasis in RCC tissues (P>0.05),but was related to differentiation (P<0.05), the poor differentiation wasassociated with low positive rate of GRIM-19.(3) The expression of STAT3, p-STAT3was negatively related to theexpression of GRIM-19in RCC tissues (r=-0.511, P<0.01; r=-0.529,P<0.01).Conclusion:(1) Constitutively activated STAT3signal existed inRCC tissues. The expression of STAT3and p-STAT3was related toclinical stage and differentiation in RCC. it may be involved in the clinicprogression of RCC and was closely related to the degree of malignancy.(2) The expression of GRIM-19obviously decreased in RCC tissues,its level of expression decreased with increasing degree of malignancy inRCC, but it was not related to the gender, age, clinical stage andmetastasis.(3) The overexpression of STAT3, p-STAT3and the deletedexpression of GRIM-19in human RCC tissues were closely correlatedwith the tumor carcinogenesis. Detecting these indexes can provide amore objective reference for clinical diagnosis of RCC.