| Ovarian cancer is one of the most lethal malignant tumors in women in China,and the first leading cause of death from gynaecological cancers in the world. Earlydiagnosis is the most important determinant of survival period length. Ovarian cancerranks fifth in the female cancer related death in the United States, and which has beento maintain high fatality rate for the past seventy-five years. Ovarian cancer isinsidious onset, primary more concealment. once found, most patients have beenadvanced, easily disseminated metastasis, and recurrence after operation, easy toproduce drug resistance etc..With the development of medical level, the progress ofcytoreductive surgery and combined with chemotherapy in ovarian cancer,5yearssurvival rate has been improved significantly, but the high rates for recurrence mean apoor prognosis for the patients with ovarian cancer. Therefore, exploring the effectiveprediction of early ovarian cancer occurrence, development and related factors ofpostoperative recurrence and metastasis is very important.Metastasis-associated in colon cancer-1(MACC1) is a newly identified gene bya genome-wide search for differentially expressed genes in human colon cancertissues, metastases, and normal tissues, The study found that MACC1can promotecolon cancer cell proliferation, in vitro invasion and HGF induced cancer cellproliferation, and which can promote the growth of transplanted tumor of coloncancer cells in animal experiments. A growing body of research shows that a lot oftumor invasion and metastasis is closely related to the over-expression of MACC1,such as colon cancer, gastric cancer, liver cancer, lung cancer, etc. The mechanism is closely related with the HGF/C-Met signaling pathway. MACC1is a key regulator ofHGF/C-Met signaling pathway. The present study has confirmed that HGF/C-metsignaling pathways can promote tumor cell growth, adhesion, invasion and metastasis,it play an important role in many malignant tumors such as ovarian cancer.In addition, the results of past studies of MACC1expression and HGF/C-Metsignal transduction pathways have conflicted, and the correlation between MACC1overexpression and prognosis of epithelial ovarian cancer remains uncertain. Thevalue of MACC1as a potential biomarker for epithelial ovarian cancer remainsunknown. In this study, we evaluated the expression levels and cellular locations ofMACC1and HGF/C-Met in epithelial ovarian cancer and compared them with that ofbenign epithelial ovarian tumor and normal ovarian tissue, than we examined theexpressions of MACC1, HGF or C-Met mRNA using reverse transcription-polym-erase chain reaction. Finally, the serum levels of MACC1expression in patients withepithelial ovarian cancer was detected with Enzyme-linked immunosorbent assay(ELISA). Analysis of the prognostic value of MACC1in epithelial ovarian carcinoma,and evaluated the relations between over-expressions of MACC1, HGF/C-Met andthe clinical pathological features of epithelial ovarian cancer. Discuss the threeinteractions in the development and prognosis of epithelial ovarian carcinoma.ObjectiveTo investigate the role of MACC1in epithelial ovarian tumor, We studied andanalyzed the expression of MACC1protein and determine whether MACC1expression is of prognostic significance in epithelial ovarian tissue. Furthermore, wedetection MACC1mRNA expression in Epithelial ovarian tissue specimens and theserum levels of MACC1expression in patients. Then we evaluated the effects ofMACC1over-expressed on ovarian cancer migration and invasion, and prognosis.Moreover, to show the potential correlation of MACC1and HGF/C-Met, HGF/C-Metwas also investigated. Materials and methods1．Study objects Ninety-two cases of epithelial ovarian cancer in which freshfrozen tissue from ovarian carcinoma cytoreductive surgery specimens were availablefor RNA extraction, were selected from a larger series of tumors observed at thepathology department of the Third Hospital Affiliated of Zhengzhou Universitybetween2011and2013. Ninety-two cases of epithelial ovarian tissue samples wecollected as research object, consisting of47cases of ovarian malignant epithelialtumors(30cases of serous and mucinous10cases,7cases of endometrial sample,(asmalignant group), and25cases of ovarian benign epithelial tumors (as benign group).In addition to select20patients with normal ovaries resection for other reasons for thecontrol group (as normal group). Age differences between groups have no statisticalsignificance (P>0.05).2．Methods Ninety-two cases of epithelial ovarian tissue samples we collectedas research object, consisting of47cases of ovarian malignant epithelial tumors,25cases of ovarian benign epithelial tumors, and20cases of normal ovarian tissue. Theywere used to assess expressions of MACC1mRNA and MACC1protein using reversetranscriotion-polymerase chain reaction (RT-PCR) and immunohistochemical method.HGF and C-Met was also investigated. The serum levels of MACC1expression inpatients with epithelial ovarian cancer was detected with Enzyme-linkedimmunosorbent assay(ELISA).3．Statistics approach All statistical analyses were carried out using the SPSS17.0statistical software package (SPSS Inc, Chicago, IL). All data are represented asmean standard deviation. The chi-square test or Fisher′s exact test was used tocomparison of frequencies. Spearman′s correlation test was applied to analyse thecorrelation. Multiple group comparisons were achieved by one-way analysis ofvariance.All P values were2-sided. AP value of less than0.05was consideredstatistically significant. Results1．Immunostaining showed that MACC1protein was localized in both cellmembrane and cytoplasm of epithelial ovarian tumor. The positive rate of MACC1(70.21%) in epithelial ovarian cancer tissues were significantly higher than those inepithelial benign tumor tissues(28%)and normal ovarian epithelial tissues(5%),respectively(P<0.05).2． The abnormal expression rates of HGF (63.8%)/c-met (76.59%) in epithelialovarian carcinoma tissues were significantly higher than those in epithelial benigntumor tissues (25%and36%) and normal ovarian epithelial tissues (5%and10%),difference was statistically significant (P <0.05).3．The expression of MACC1and HGF/C-Met protein in epithelial ovariancarcinomas were significantly higher than that in benign epithelial tumors(P<0.05).There was significant association of MACC1levels with clinical stage, histologicalgrade, lymph node metastasis in epithelial ovarian carcinomas(P<0.05), but not withhistological type(P<0.05). They were higher in tumor tissues with lymph nodemetastasis(P<0.05) than those without lymph node metastasis(P<0.05).4．RT-PCR showed that MACC1mRNA expression intensity is significantlyhigher in epithelial ovarian carcinoma than in benign epithelial ovarian tumor andnormal ovarian tissue in the relative expression quantity (F=295.032, P=0.00). HGFand C-Met mRNA were expressed significantly higher in epithelial ovarian carcinomatissues than in benign epithelial ovarian tumors and normal ovarian tissues(F=177.252, P=0.00; F=264.183, P=0.00).5．There was indeed a significant positive correlation between the expressionlevels of MACC1and C-Met (r=0.849, P<0.01, Pearson′s correlation test), MACC1expression was positively correlated to HGF (r=0.810, P<0.01), and the expressionlevels of HGF and C-Met was also positively correlated (r=0.831, P<0.01).6．By Enzyme-linked immunosorbent assay, the preoperative serum MACC1levels in malignant groups were significant difference compared with normal controls(z=-6.440, P<0.001, Wilcoxon rank and inspection) or patients with benigntumor(z=-6.949, P<0.001). Interestingly, we found that there was significantrelationship between the preoperative serum MACC1levels and the depth of invasion, TNM stage, lymph node metastasis.7．Further experimental data statistics and analysis, with the MACC1expressionin ovarian malignant epithelial neoplasm tissues increased, serum concentrations ofMACC1increased, linear regression analysis showed that the two are closelyrelated(r=0.870, P<0.05).Conclusions1．MACC1. HGF and C-Met may be participate in the occurrence anddevelopment of ovarian cancer, they may be associated with the biological behaviorof ovarian cancer cells. And abnormal expression promote the invasion and metastasisof epithelial ovarian carcinoma.2．We conclude that levels of MACC1and HGF/c-Met mRNA were higher inthe epithelial ovarian cancer tissue than in the normal ovarian tissue and benignepithelial ovarian tumor tissue, and previous studies have shown that MACC1andHGF/c-Met levels were correlated, there is a positive feedback loop between MACC1and HGF/c-Met, which is involved in multiple cellular responses.3．Our research prove that MACC1can increase C-Met protein transcriptionand translation, and then activate the HGF/Met signaling pathways, enhance thecapacity of cancer cell proliferation, migration.4．The serum levels of MACC1ovarian malignant epithelial neoplasm groupwas obviously higher than that of benign epithelial tumor group and normal controlgroup. And the preoperative serum MACC1levels is closely related with the depth ofinvasion, clinical stage, histological grade,lymph node metastasis.So we can speculateabout ovarian cancer patients serum level of MACC1is closely related to the courseof the disease.5．MACC1can be a new tumor markers application to the diagnosis andfollow-up of ovarian malignant epithelial tumors. It has helped to elucidate themolecular biological mechanism of ovarian cancer invasion, metastasis andrecurrence. MACC1expression in normal, benign and malignant tissues may providethe foundation for development of innovative metastasis intervention strategies based on MACC1as a therapeutic target. |
PDF Full Text Request