| Objective: To explore the mechanism in HGF/c-Met signaling pathway amongcolorectal cancer (CRC) liver metastasis and its clinical character.Methods: We analysed the expression of c-Met protein byimmunohistochemical S-P method. The frequency was assessed by chi-square test,and non-normal distribution was calculated using the Wilcoxon test. Univariateanalysis and multiple factors were evaluated by Cox model. The expression ofmRNA of c-Met was analysis of normal colorectal mucosa, adenoma tissue, primarytumor, and lymph node metastases. It was to evaluate the expression level of c-Metand VEGF among primary CRC patients using the Elisa test method. Continuousvariables were rated by independent sample t test. Correlation analysis was evaluatedusing simple linear correlation analysis.Results:(1) In normal colorectal mucosa tissues, c-Met protein was weaklyexpressed, with a positive rate of5.22%. In CRC primary tumor tissue, c-Met proteinis moderately positive expression, with a positive rate of35.07%, the difference was significant (P <0.001). The expression rate of c-Met protein in positive lymph nodeswas42.33%, the proportion is significantly higher than normal colorectal mucosatissues, was a statistically noted difference (P <0.001); Besides, the expression rateof c-Met protein in CRC liver metastases group was52.14%, this proportion issignificantly higher than normal colorectal mucosa tissues group, the difference wasstatistically significant (P <0.001). Furthermore, the expression rate of c-Met proteinin CRC lymph node was statistically significantly higher than that of CRC primarytumor (42.33%vs35.07%, P=0.000). The expression rate of c-Met protein in CRCliver metastases was significantly higher than that of CRC primary tumor (52.14%vs35.07%, P=0.000); What is more, the expression rate of c-Met protein in CRC livermetastases was significantly higher than that of CRC positive lymph node group(52.14%vs42.33%, P=0.041).The proportion of positive of high, medium and low differentiation degree oftumor CRC primary was22.36%,23.62%,54.02%, and c-Met negative group was69.34%,25.37%and5.29%, respectively (P＜0.05). The proportion of positive ofc-Met among stage T1-4were7.79%,11.06%,50.57%, and31.06%, respectively, andthe negative group were32.29%,33.65%,30.66%, and33.65%, respectively (P＜0.05). As for N0and N1-2, the positive of c-Met was24.87%, and75.13%,respectively. The proportion of c-Met negative group was34.06%, and65.94%respectively. The proportion of c-Met positive group N1-2was significantly higherthan that of negative groups, with statistically significant difference (P＜0.05). As for M0, M1, the proportion of c-Met positive was86.93%,13.07%, respectively, andc-Met negative group was97.96%,2.04%respectively. The positive group had asignificantly higher proportion of M1express negative group (13.07%vs2.04%, P＜0.05). c-Met in positive tumor diameter (≤2、2-5、≥5cm) were31.16%,32.91%,35.93%, respectively. The proportion of the negative group was30.39%,34.06%and35.55%respectively (P>0.05).(2) We set the normal colorectal tissues as the control group, and it’s relativecontent was (0.572±0.051)（pg/ml）, when measured mRNA value/decide-actin>0.61. Colorectal adenomas group (0.781±0.064), there was no statistically differencewith the control group (P>0.05). The c-Met mRNA concentration of CRC, positivelymph nodes, and liver metastases was (1.138±0.174（)pg/ml）,(1.486±0.184（)pg/ml）,and (1.372±0.168), respectively (all P＜0.05). The expression rate of c-Met proteinin CRC positive lymph nodes, CRC liver metastases groups were significantly higherthan that of CRC group (all P<0.05). Furthermore, no significantly difference wasfound between CRC positive lymph nodes group and CRC liver metastases group(P=0.681).(3) The univariate factor analysis included16factors: gender（HR:1.222;95%CI:1.021-1.468， P=0.0482）， age （HR:1.645;95%CI:1.315-2.062， P＜0.0001），family history（HR:2.313;95%CI:1.811-7.651，P=0.0004），differentiation（P＜0.0001），weight loss（HR:1.697;95%CI:1.320-2.092，P＜0.0001），T stage（P＜0.0001），N stage （P＜0.0001），CRC primary tumor c-Met expression （HR:5.558;95%CI:7.829-13.24，P＜0.0001），positive lymph node c-Metexpression（HR:4.982;95%CI:5.267-8.554，P＜0.0001），liver metastases c-Metexpression（HR:4.324;95%CI:3.753-5.957，P＜0.0001），diabete（sHR:1.503;95%CI:1.222-2.072， P=0.0007）。 Protective factors were: preoperative radiotherapy（HR:0.5749;95%CI:0.4882-0.8029，P=0.0003），preoperative chemoradiotherapy（HR:0.2122;95%CI:0.3068-0.4833，P＜0.0001）。No statistical difference is:smoking （HR:1.036;95%CI:0.8275-1.301， P=0.7525）， drinking（HR:0.970;95%CI:0.7740-1.214，P=0.7892），and preoperative low protein（HR:1.169;95%CI:0.9256-1.504，P=0.1888）.Multiple factors analysis: T staging is CRC with weak liver metastases for riskfactors（HR:1.161;95%CI:1.017-1.325，P=0.027）; Strong risk factors including:tumor differentiation degree（HR:3.601;95%CI:2.521-5.694，P=3.601）, N staging（HR:4.210;95%CI:3.45-5.137，P=4.210）, CRC primary c-Met protein positiveexpression（HR:1.678;95%CI:1.160-2.429，P=1.678）, CRC metastasis lymph nodec-Met protein positive expression（HR:1.728;95%CI:1.437-3.212，P=1.728）, livermetastases c-Met protein positive expression（HR:2.964;95%CI:1.796-4.890，P=2.964）. Where N staging (HR,4.210) effect CRC liver metastases is the strongestrisk factor; preoperative chemoradiotherapy is one of the protective factors for livermetastases.(4) The concentration of c-Met and VEGF among CRC patients were2.77times and2.77times than that of healthy (P＜0.05). c-Met with VEGF serum from CRC patients were positively correlated (r=0.9655, P＜0.0001). However, it wasnot shown any correlation among CRC patients with stage I between c-Met andVEGF (r=0.09675, P=0.09675), CRC patients with stage II, III, IV c-Met withVEGF were showed a positive correlation (P＜0.05). CRC patients with high,medium and low differentiation were showing positive correlation (P＜0.05).Conclusion: The serum of c-Met and VEGF in CRC patients were significantlyhigher than that of controls, with an obvious correlation. These results suggested that(1) c-Met plays an important role in the process of evolution of the diseased, and theexpression of c-Met protein may be closely associated with CRC disease progression.When c-Met was highly expressive, it could suggest the progression of CRC andmalignant degree.(2) high expression of protein c-Met, may be a risk factor for CRCliver metastasis.(3) the expression of c-Met protein mRNA had synchronicity withsignificantly transfer of positive lymph nodes and liver metastases.(4) theconcentration of c-Met and VEGF were2.77times and2.77times than that ofControls. It is just an efficient testing method for CRC patients diagnosis andpostoperative monitoring means. |
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